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Disease Description

GeneDiseaseDisease Description
AAASTriple-A syndrome (achalasia-addisonianism-alacrimia)The three specific features of triple-A syndrome are achalasia, Addison disease, and alacrima. Achalasia is a disorder that affects the ability to move food through the esophagus. It can lead to severe feeding difficulties and low blood sugar (hypoglycemia). Addisonism, also known as primary adrenal insufficiency, is caused by abnormal function of the small hormone-producing glands on top of each kidney (adrenal glands). The main features of addisonism include fatigue, loss of appetite, weight loss, low blood pressure, and darkening of the skin. The third major feature of this syndrome is a reduced or absent ability to secrete tears (alacrima). Most people with triple A syndrome have all three of these features, although some have only two. Many of the features of triple A syndrome are caused by dysfunction of the autonomic nervous system. People with the syndrome often experience abnormal sweating, difficulty regulating blood pressure, unequal pupil size (anisocoria), and other signs and symptoms of autonomic nervous system dysfunction (dysautonomia).
AARSEpileptic encephalopathy, early infantile, type 29Epileptic encephalopathy, early infantile, type 29 (EIEE29) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE29 patients manifest severe infantile epileptic encephalopathy, clubfoot, absent deep tendon reflexes, extrapyramidal symptoms, and persistently deficient myelination.
AARS2Combined oxidative phosphorylation deficiency 8; Leukoencephalopathy, progressive, with ovarian failureCombined oxidative phosphorylation deficiency 8 (COXPD8) is an autosomal recessive disorder due to dysfunction of the mitochondrial respiratory chain. The main clinical manifestation is a lethal infantile hypertrophic cardiomyopathy, but there may also be subtle skeletal muscle and brain involvement. Biochemical studies show combined respiratory chain complex deficiencies in complexes I, III, and IV in cardiac muscle, skeletal muscle, and brain. The liver is not affected (Gotz et al., 2011). Mutation in the AARS2 gene can also cause progressive leukoencephalopathy with ovarian failure, an autosomal recessive neurodegenerative disorder characterized by loss of motor and cognitive skills, usually with onset in young adulthood. Some patients may have a history of delayed motor development or learning difficulties in early childhood. Neurologic decline is severe, usually resulting in gait difficulties, ataxia, spasticity, and cognitive decline and dementia. Most patients lose speech and become wheelchair-bound or bedridden. Brain MRI shows progressive white matter signal abnormalities in the deep white matter. Affected females develop premature ovarian failure (summary by Dallabona et al., 2014).
AASSHyperlysinemia, type 1 and type 2Hyperlysinemia, type 1 is an autosomal recessive metabolic condition with variable clinical features. Some patients who present in infancy with nonspecific seizures, hypotonia, or mildly delayed psychomotor development have been found to have increased serum lysine and pipecolic acid on laboratory analysis. However, about 50% of probands are reported to be asymptomatic, and hyperlysinemia is generally considered to be a benign metabolic variant (Tondo et al., 2013; Houten et al., 2013).The AASS gene encodes a bifunctional enzyme: lysine alpha-ketoglutarate reductase and saccharopine dehydrogenase. In hyperlysinemia type 1, both enzymatic functions of AASS are defective; in hyperlysinemia type 2, also known as Saccharopinuria, some of the first enzymatic function is retained (Cox, 1985; Cox et al., 1985).
ABATGABA-transaminase deficiencyGABA-transaminase deficiency is characterized by neonatal or early infantile-onset encephalopathy, hypotonia, hypersomnolence, epilepsy, choreoathetosis, and accelerated linear growth. Electroencephalograms show burst-suppression, modified hypsarrhythmia, multifocal spikes, and generalized spike-wave. Severity varies, but most patients have profound developmental impairment and some patients die in infancy (Koenig et al., 2017).
ABCA1Tangier diseaseTangier disease is an autosomal recessive disorder characterized by markedly reduced levels of plasma high density lipoproteins (HDL) resulting in tissue accumulation of cholesterol esters. Clinical features include very large, yellow-orange tonsils, enlarged liver, spleen and lymph nodes, hypocholesterolemia, and abnormal chylomicron remnants (Brooks-Wilson et al., 1999).
ABCA12Ichthyosis, congenital, autosomal recessive, type 4A; ICAR, type 4B (harlequin)Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI 4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
ABCA3Surfactant metabolism dysfunction, pulmonary, type 3Surfactant dysfunction is a lung disorder that causes breathing problems. This condition results from abnormalities in the composition or function of surfactant, a mixture of certain fats (called phospholipids) and proteins that lines the lung tissue and makes breathing easy. Without normal surfactant, the tissue surrounding the alveoli sticks together (because of a force called surface tension) after exhalation, causing the alveoli to collapse. As a result, filling the lungs with air on each breath becomes very difficult, and the delivery of oxygen to the body is impaired.The signs and symptoms of surfactant dysfunction can vary in severity. The most severe form of this condition causes respiratory distress syndrome in newborns. Affected babies have extreme difficulty breathing and are unable to get enough oxygen.
ABCA4Stargardt disease type 1; Cone-rod dystrophy type 3Stargardt disease type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ABCA4 gene located on chromosomal region 1p22. The age of onset is infantile. This disease is characterized by progressive central vision loss, mild loss of color vision, delayed dark adaptation and macular atrophy with or without paramacular flecks and degeneration of the underlying retinal pigment ephitelium. The estimated prevalence is 1:8,000-10,000. Mutations in the ABCA4 gene account also for 30 to 60 percent of cases of cone-rod dystrophy that are inherited in an autosomal recessive pattern. The problems associated with this condition include a loss of visual sharpness (acuity), an increased sensitivity to light (photophobia), and impaired color vision. These vision problems worsen over time.
ABCB11Cholestasis, benign recurrent intrahepatic, type 2; Cholestasis, progressive familial intrahepatic, type 2Benign recurrent intrahepatic cholestasis is characterized by intermittent episodes of cholestasis without progression to liver failure. The cholestatic attacks vary in severity and duration and patients are asymptomatic between episodes, both clinically and biochemically (van Mil et al., 2004). Mutation in the ABCB11 gene can also cause cholestasis, progressive familial intrahepatic, type 2, a severe form of liver disease, which typically leads to liver failure. In people with PFIC, liver cells are less able to secrete a digestive fluid called bile. The buildup of bile in liver cells causes liver disease in affected individuals.
ABCB4Cholestasis, progressive familial intrahepatic, type 3Cholestasis, progressive familial intrahepatic, type 3 (PFIC3) is a reversible form of cholestasis that occurs most often in the third trimester of pregnancy and recurs in 45 to 70% of subsequent pregnancies. Symptoms include pruritus, jaundice, increased serum bile salts, and abnormal liver enzymes, all of which resolve rapidly after delivery. However, the condition is associated with fetal complications, including placental insufficiency, premature labor, fetal distress, and intrauterine death. Women with ICP are also susceptible to oral contraceptive-induced cholestasis (OCIC). Ursodeoxycholic acid (UDCA) is an effective treatment for conditions caused by ABCB4 mutations (Pasmant et al., 2012).Mutation in the ABCB4 gene accounts for about 15% of ICP cases (Ziol et al., 2008).
ABCB7X-linked sideroblastic anemia and ataxia (XLSA/A)XLSA/A is caused by pathogenic variants in the ABCB7 gene located on chromosomal region Xq13.3. The age of onset is neonatal/infantile. XLSA/A is a rare condition characterized by a blood disorder called sideroblastic anemia and movement problems known as ataxia. This condition occurs only in males. People with X-linked sideroblastic anemia and ataxia have mature red blood cells that are smaller than normal (microcytic) and appear pale (hypochromic) because of the shortage of hemoglobin. This disorder also leads to an abnormal accumulation of iron in red blood cells but does not cause a potentially dangerous buildup of iron in the body. The anemia is typically mild and usually does not cause any symptoms. The prevalence is very rare, estimated at <1:1,000,000.
ABCC6Arterial calcification, generalized, of infancy, type 2Generalized arterial calcification of infancy (GACI) is a severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. GACI is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure (Rutsch et al., 2003; Cheng et al., 2005).
ABCC8Hyperinsulinemic hypoglycemia, type 1 (congenital hyperinsulinism); Permanent neonatal diabetes mellitus (PNDM)Hyperinsulinemic hypoglycemia, also referred to as congenital hyperinsulinism or familial hyperinsulinism, is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). Furthermore, some mutations in the ABCC8 gene have been found to cause permanent neonatal diabetes mellitus (PNDM). PNDM is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins. Most clinical cases for the previous two phenotypes have autosomal recessive inheritance but dominant cases have been detected too. Remarkably, certain mutations in this gene can cause the dominant phenotypes noninsulin-dependent diabetes mellitus and hypoglycemia of infancy, leucine-sensitive.
ABCD1AdrenoleukodystrophyAdrenoleukodystrophy is an X-linked disorder which is secondary to a mutation in the ABCD1 gene and results in the apparent defect in peroxisomal beta oxidation and the accumulation of the saturated very long chain fatty acids (VLCFA) in all tissues of the body. The manifestations of the disorder occur primarily in the adrenal cortex, the myelin of the central nervous system, and the Leydig cells of the testes.ABCD1 is an ATPase binding cassette protein in the same category of transporter proteins such as the CFTR and MDR proteins.Identification of X-ALD as a lipid-storage disease, as a defect in the capacity to degrade VLCFAs, and its characterization as a peroxisomal disorder was reviewed by Moser (1997). Moser et al. (2005) provided a clinical review of ALD.
ABCD4Methylmalonic aciduria and homocystinuria, cblJ typeCombined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous metabolic disorder of cobalamin (cbl; vitamin B12) metabolism, which is essential for hematologic and neurologic function. Biochemically, the defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). The cblJ type is phenotypically and biochemically similar to the cblF type (MAHCF; 277380) (Coelho et al., 2012).
ABCG5SitosterolemiaSitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).
ABCG8SitosterolemiaSitosterolemia, also known as phytosterolemia, is an autosomal recessive metabolic condition characterized by unrestricted intestinal absorption of both cholesterol and plant-derived cholesterol-like molecules, such as sitosterol. Patients with this disorder have very high levels of plant sterols in the plasma and develop tendon and tuberous xanthomas, accelerated atherosclerosis, and premature coronary artery disease (Berge et al., 2000).
ABHD12PHARC syndrome (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa and cataract)Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract, also known as PHARC, is a slowly progressive neurologic disorder with a variable phenotype; clinical features include sensorineural hearing loss, visual problems related to cataracts, retinitis pigmentosa, pes cavus, ataxic and/or spastic gait disturbances with a progressive sensorimotor peripheral neuropathy. Other features include hyporeflexia, hyperreflexia, extensor plantar responses.
ABHD5Chanarin-Dorfman syndromeChanarin-Dorfman syndrome is a condition in which fats (lipids) are stored abnormally in the body. Affected individuals cannot break down certain fats called triglycerides, and these fats accumulate in organs and tissues, including skin, liver, muscles, intestine, eyes, and ears. People with this condition also have dry, scaly skin (ichthyosis), which is usually present at birth. Additional features of this condition include an enlarged liver (hepatomegaly), clouding of the lens of the eyes (cataracts), difficulty with coordinating movements (ataxia), hearing loss, short stature, muscle weakness (myopathy), involuntary movement of the eyes (nystagmus), and mild intellectual disability. The signs and symptoms vary greatly among individuals with Chanarin-Dorfman syndrome. Some people may have ichthyosis only, while others may have problems affecting many areas of the body.
ACAD8Isobutyryl-CoA dehydrogenase deficiencyIsobutyryl-CoA dehydrogenase (IBD) deficiency is a condition that disrupts the breakdown of certain proteins. People with IBD deficiency have inadequate levels of an enzyme that helps break down a particular amino acid called valine. Most people with IBD deficiency are asymptomatic. A few children with IBD deficiency have developed features such as a weakened and enlarged heart (dilated cardiomyopathy), weak muscle tone (hypotonia), and developmental delay. This condition may also cause low numbers of red blood cells (anemia) and very low blood levels of carnitine, which is a natural substance that helps convert certain foods into energy.
ACAD9Acyl-CoA dehydrogenase 9 deficiency (mitochondrial complex I deficiency, nuclear, type 20)Acyl-CoA dehydrogenase 9 deficiency, also known as mitochondrial complex I deficiency, nuclear, type 20, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAD9 gene located on chromosomal region 3q21.3. The age of onset is neonatal/infantile. This disease is a multisystem disorder characterized by infantile onset of acute metabolic acidosis, hypertrophic cardiomyopathy, and muscle weakness associated with a deficiency of mitochondrial complex I activity in muscle, liver, and fibroblasts (summary by Haack et al., 2010).
ACADMMedium-chain acyl-CoA dehydrogenase deficiencyMedium-chain acyl-CoA dehydrogenase (MCAD) deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADM gene located on chromosomal region 1p31. Inherited deficiency of MCAD is a condition that prevents the body from converting certain fats to energy, particularly during periods without food (fasting). Signs and symptoms of MCAD deficiency typically appear during infancy or early childhood and can include vomiting, lack of energy (lethargy), and low blood sugar (hypoglycemia). Individuals with MCAD deficiency are at risk of serious complications such as seizures, breathing difficulties, liver problems, brain damage, coma, and sudden death. The estimated prevalence is 1:4,900-1:27,000 in Caucasian populations and 1:14,600 in worldwide populations.
ACADSShort-chain acyl-CoA dehydrogenase deficiencyShort-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADS gene located on chromosomal region 12q24.31. The age of onset is infantile. This disease is characterized by seizures, developmental delay, failure to grow with poor feeding, and usually muscle weakness and hypotonia. The prevalence is <1:50,000.
ACADSBShort/branched-chain acyl-CoA dehydrogenase deficiencyShort/branched-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADSB gene located on chromosomal region 10q26.3. The age of onset is neonatal/infantile. This disease is characterized by muscle hypotonia, cerebral palsy, developmental delay, lethargy, hypoglycemia, and metabolic acidosis. The prevalence is <1:1,000,000.
ACADVLVery long-chain acyl-CoA dehydrogenase deficiencyVery long-chain acyl-CoA dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACADVL gene located on chromosomal region 17p13.1. The age of onset is neonatal/infantile. This disease is characterized by cardiomyopathy, hypoketotic hypoglycemia, liver disease, exercise intolerance and rhabdomyolysis. The prevalence is 1:100,000-9:100,000.
ACAT1Alpha-methylacetoacetic aciduria (3-ketothiolase deficiency)Alpha-methylacetoacetic aciduria, also known as 3-ketothiolase deficiency, is an inborn error of isoleucine catabolism characterized by urinary excretion of 2-methyl-3-hydroxybutyric acid, 2-methylacetoacetic acid, tiglylglycine, and 2-butanone. This deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACAT1 gene located on chromosomal region 11q22.3. The age of onset is neonatal/infantile. This disease is characterized by normal early development followed by a progressive loss of mental and motor skills. The prevalence is < 1:1,000,000.
ACERenal tubular dysgenesisRenal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and the most common cause are pathogenic variants in the ACE (chromosomal region 17q23.3). The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.
ACO2Infantile cerebellar-retinal degenerationInfantile cerebellar-retinal degeneration is a severe autosomal recessive neurodegenerative disorder characterized by onset between ages 2 and 6 months of truncal hypotonia, athetosis, seizures, and ophthalmologic abnormalities, particularly optic atrophy and retinal degeneration. Affected individuals show profound psychomotor retardation, with only some achieving rolling, sitting, or recognition of family. Brain MRI shows progressive cerebral and cerebellar degeneration (Spiegel et al., 2012).
ACOX1Peroxisomal acyl-CoA oxidase deficiencyPeroxisomal acyl-CoA oxidase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACOX1 gene located on chromosomal region 17q25.1. The age of onset is neonatal/infantile. This disease is characterized by hypotonia and seizures in the neonatal period and neurological regression in early infancy. The prevalence is < 1:1,000,000.
ACP5Spondyloenchondrodysplasia with immune dysregulationSpondyloenchondrodysplasia with immune dysregulation (SPENCDI) is an immunoosseous dysplasia combining the typical metaphyseal and vertebral bone lesions of spondyloenchondrodysplasia (SPENCD) with immune dysfunction and neurologic involvement. The skeletal dysplasia is characterized by radiolucent and irregular spondylar and metaphyseal lesions that represent islands of chondroid tissue within bone. The vertebral bodies show dorsally accentuated platyspondyly with disturbance of ossification. Clinical abnormalities such as short stature, rhizomelic micromelia, increased lumbar lordosis, barrel chest, facial anomalies, and clumsy movements may be present (Menger et al., 1989). Central nervous system involvement includes spasticity, mental retardation, and cerebral calcifications, and immune dysregulation ranges from autoimmunity to immunodeficiency. Neurologic and autoimmune manifestations have been observed in different combinations within a single family, suggesting that this disorder may be defined by specific radiographic features but has remarkably pleiotropic manifestations (Renella et al., 2006). Briggs et al. (2016) also noted variability in skeletal, neurologic, and immune phenotypes, which was sometimes marked between members of the same family.
ACSF3Combined malonic and methylmalonic aciduriaCombined malonic and methylmalonic aciduria?(CMAMMA) is a condition characterized by high levels of malonic acid and methylmalonic acid in the body. The signs and symptoms of CMAMMA can begin in childhood. In some children, it causes the blood to become too acidic (ketoacidosis), which can damage the body's tissues and organs. Other signs and symptoms may include involuntary muscle tensing (dystonia), weak muscle tone (hypotonia), developmental delay, an inability to grow and gain weight at the expected rate (failure to thrive), low blood sugar (hypoglycemia), and coma. Other people with CMAMMA do not develop signs and symptoms until adulthood. These individuals usually have neurological problems, such as seizures, loss of memory, a decline in thinking ability, or psychiatric diseases.
ACSL4Mental retardation, X-linked, type 63Mental retardation, X-linked, type 63 (MRX63) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
ACTA1Nemaline myopathy 3; Congenital fiber-type disproportion myopathy 1Nemaline myopathy is a form of congenital myopathy characterized by abnormal thread- or rod-like structures in muscle fibers on histologic examination ('nema' is Greek for 'thread'). The clinical phenotype is highly variable, with differing age at onset and severity. Muscle weakness typically involves proximal muscles, with involvement of the facial, bulbar, and respiratory muscles (Ilkovski et al., 2001). Attempts at classification of nemaline myopathies into clinical subtypes have been complicated by the overlap of clinical features and a continuous phenotypic spectrum of disease (North et al., 1997; Wallgren-Pettersson et al., 1999; Ryan et al., 2001; Sanoudou and Beggs, 2001). In general, 2 clinical groups can be readily distinguished: 'typical' and 'severe.' Typical nemaline myopathy is the most common form, presenting as infantile hypotonia and muscle weakness. It is slowly progressive or nonprogressive, and most adults achieve ambulation. The severe form of the disorder is characterized by absence of spontaneous movement or respiration at birth, arthrogryposis, and death in the first months of life. Much less commonly, late-childhood or even adult-onset can occur. However, adult-onset nemaline myopathy is usually not familial and may represent a different disease (Wallgren-Pettersson et al., 1999; Sanoudou and Beggs, 2001). Myopathy caused by mutations in the ACTA1 gene can show a range of clinical and pathologic phenotypes. Some patients have classic rods, whereas others may also show intranuclear rods, clumped filaments, cores, or fiber-type disproportion (255310), all of which are nonspecific pathologic findings and not pathognomonic of a specific congenital myopathy. The spectrum of clinical phenotypes caused by mutations in ACTA1 may result from different mutations, modifying factors affecting the severity of the disorder, variability in clinical care, or a combination of these factors (Nowak et al., 1999; Kaindl et al., 2004).
ACY1Aminoacylase 1 deficiencyAminoacylase 1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (Ferri et al., 2014).
ADASevere combined immunodeficiency due to adenosine deaminase deficiency (ADA)Severe combined immunodeficiency due to adenosine deaminase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADA gene located on chromosomal region 20q13.12. The age of onset is neonatal/infantile. This disease is characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections. The annual incidence is 1:200,000-1:1,000,000. The prevalence is 1:100,000-9:100,000.
ADAM9Cone-rod dystrophy 9Cone-rod dystrophy 9 (CORD9) is an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors.
ADAMTS10Weill-Marchesani syndrome, type 1, recessiveWeill-Marchesani syndrome is a rare connective tissue disorder characterized by short stature, brachydactyly, joint stiffness, eye anomalies, including microspherophakia, ectopia of the lenses, severe myopia, and glaucoma, and, occasionally, heart defects (Dagoneau et al., 2004).
ADAMTS13Thrombotic thrombocytopenic purpura, familial (Schulman-Upshaw syndrome)The classic pentad of TTP includes hemolytic anemia with fragmentation of erythrocytes, thrombocytopenia, diffuse and nonfocal neurologic findings, decreased renal function, and fever. Congenital TTP, also known as Schulman-Upshaw syndrome, is characterized by neonatal onset, response to fresh plasma infusion, and frequent relapses (Savasan et al., 2003; Kokame et al., 2002).Acquired TTP, which is usually sporadic, usually occurs in adults and is caused by an IgG inhibitor against the von Willebrand factor-cleaving protease.
ADAMTS17Weill-Marchesani syndrome, type 4, recessiveWeill-Marchesani syndrome is a rare connective tissue disorder characterized by microspherophakia, severe myopia, acute and/or chronic glaucoma, and cataract. Other features include brachydactyly and short stature. Patients may also have stiff joints and thickened skin, especially on the hands. Occasionally, cardiac defects or an abnormal heart rhythm is present (Shah et al., 2014).
ADAMTS18Microcornea, myopic chorioretinal atrophy, and telecanthusMicrocornea, myopic chorioretinal atrophy, and telecanthus (MMCAT) is a ocular syndrome characterized by microcornea and myopic chorioretinal atrophy. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye. In addition to ocular findings, some patients have telecanthus and posteriorly rotated ears.
ADAMTS2Ehlers-Danlos syndrome, dermatosparaxis typeEhlers-Danlos syndrome, dermatosparaxis type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTS2 gene located on chromosomal region 5q35.3. The age of onset is neonatal/infantile. This disease is characterized by extremely fragile tissues, hyperextensible skin and easy bruising. The prevalence is <1:1,000,000.
ADAMTSL2Geleophysic dysplasia type 1Geleophysic dysplasia type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADAMTSL2 gene located on chromosomal region 9q34.2. The age of onset is infantile. This disease is characterized by extremely by short stature, prominent abnormalities in hands and feet, and a characteristic facial appearance. The prevalence is <1:1,000,000.
ADAMTSL4Ectopia lentis et pupillae; Ectopia lentis, isolatedEctopia lentis et pupillae is a congenital hereditary disorder in which there is displacement of the lenses and the pupils, associated with other ocular anomalies, but without systemic manifestations. The condition is usually bilateral, with the lenses and pupils displaced in opposite directions (Cruysberg and Pinckers, 1995). Additional signs include enlarged corneal diameter, increased corneal astigmatism, increased anterior chamber depth, thinning and flattening of the iris with loss of crypts, angle malformation caused by enlarged iris processes, persistent pupillary membrane, loss of zonular fibers, tilted disc, and increased axial length. Secondary manifestations include refractive errors, glaucoma, early cataract development, and retinal detachment. Membrane formation on the posterior aspect of the iris has been observed both in histologic sections and on ultrasound biomicroscopy (Christensen et al., 2010). Autosomal recessive isolated ectopia lentis, type 2 (ECTO2) is also caused by mutation in the ADAMTSL4 gene. ECTOL2 is defined as an abnormal stretching of the zonular fibers that leads to lens dislocation, resulting in acute or chronic visual impairment (Greene et al., 2010).
ADARAicardi-Goutieres syndrome 6Aicardi-Goutieres syndrome 6 is a form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
ADGRG1Polymicrogyria, bilateral frontoparietalPolymicrogyria?is a condition characterized by abnormal development of the?brain?before birth. The surface of the brain normally has many ridges or folds, called gyri. In people with?polymicrogyria, the brain develops too many folds, and the folds are unusually small. The name of this condition literally means too many (poly-) small (micro-) folds (-gyria) in the surface of the brain. Bilateral forms of polymicrogyria tend to cause more severe neurological problems. Signs and symptoms of these conditions can include recurrent seizures (epilepsy), delayed development, crossed eyes, problems with speech and swallowing, and muscle weakness or paralysis. This condition causes severe intellectual disability, problems with movement, and seizures that are difficult or impossible to control with medication.
ADGRV1Usher syndrome, type 2CUsher syndrome type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ADGRV1 and PDZD7 genes located on chromosomal regions 5q14.3 and 10q24.32 respectively. The age of onset is infantile. This disease is characterized by the association of sensorineural prelingual deafness (usually congenital) with retinitis pigmentosa and progressive vision loss. The prevalence is 1/30,000.
ADKHypermethioninemia due to adenosine kinase deficiencyHypermethioninemia due to adenosine kinase deficiency is an autosomal recessive inborn error of metabolism characterized by global developmental delay, early-onset seizures, mild dysmorphic features, and characteristic biochemical anomalies, including persistent hypermethioninemia with increased levels of S-adenosylmethionine (AdoMet) and S-adenosylhomocysteine (AdoHcy); homocysteine is typically normal (Bjursell et al., 2011).
ADSLAdenylosuccinase deficiencyAdenylosuccinase deficiency is an autosomal recessive inborn error of metabolism caused by an enzymatic defect in de novo purine synthesis (DNPS) pathway. ADSL deficiency leads to the accumulation of toxic intermediates, including succinyladenosine (S-Ado) and succinylaminoimidazole carboxamide riboside (SAICAr) in body fluids. There are 3 major phenotypic forms of the disorder that correlate with different values of the S-Ado and SAICAr concentration ratios (S-Ado/SAICAr) in the cerebrospinal fluid. These include the most severe fatal neonatal encephalopathy (S-Ado/SAICAr ratio less than 1); childhood form (type I) with severe psychomotor retardation (S-Ado/SAICAr ratio close to 1), and a milder form (type II) with psychomotor retardation or hypotonia (S-Ado/SAICAr ratio greater than 2) (Baresova et al., 2012).
AFF2Mental retardation, X-linked, FRAXE typeMental retardation, X-linked, FRAXE type is a form of mild to moderate mental retardation associated with learning difficulties, communication deficits, attention problems, hyperactivity, and autistic behavior (Bensaid et al., 2009). FRAXE is associated with a fragile site on chromosome Xq28 and is the cause of nonsyndromic X-linked mental retardation in 1 of 50,000 newborn males. The disorder can be caused either by silencing of the AFF2 gene as a consequence of a CCG expansion located upstream of this gene or by deletion within the gene (Stettner et al., 2011).
AFG3L2Spastic ataxia, type 5, autosomal recessiveSpastic ataxia, type 5, autosomal recessive (SPAX5) is an autosomal recessive neurodegenerative disorder characterized by early-onset spasticity resulting in significantly impaired ambulation, cerebellar ataxia, oculomotor apraxia, dystonia, and myoclonic epilepsy (Pierson et al., 2011).
AGAAspartylglucosaminuria (glycosylasparaginase deficiency)Aspartylglucosaminuria, also known as glycosylasparaginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGA gene located on chromosomal region 4q34.3. The age of onset is infantile. This disease is characterized by slowly developping mental retardation, beginning with clumsiness, late speech, and hyperkinesia, mild facial dysmorphism, and slight kyphoscoliosis.
AGKCataract 38, autosomal recessive; Sengers syndromeCataract 38 is a disease charcaterized by an opacification of the crystalline lens of the eye becoming evident at birth. It frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. In general, the more posteriorly located and dense an opacity, the greater the impact on visual function. Mutation in the AGK gene can also cause Sengers syndrome, an autosomal recessive mitochondrial disorder characterized by congenital cataracts, hypertrophic cardiomyopathy, skeletal myopathy, exercise intolerance, and lactic acidosis. Mental development is normal, but affected individuals may die early from cardiomyopathy (summary by Mayr et al., 2012). Skeletal muscle biopsies of 2 affected individuals showed severe mtDNA depletion (Calvo et al., 2012).
AGLGlycogen storage disease, type 3Glycogen storage disease (GSD), type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGL gene located on chromosomal region 1p21.2. The age of onset is infantile. This metabolic disorder is caused by deficiency of the glycogen debrancher enzyme and is associated with an accumulation of abnormal glycogen with short outer chains. Most patients are enzyme-deficient in both liver and muscle (IIIa), but about 15% are enzyme-deficient in liver only (IIIb) (Shen et al., 1996). These subtypes have been explained by differences in tissue expression of the deficient enzyme (Endo et al., 2006). In rare cases, selective loss of only 1 of the 2 debranching activities, glucosidase or transferase, results in type IIIc or IIId, respectively (Van Hoof and Hers, 1967; Ding et al., 1990). Clinically, patients with GSD type 3 present in infancy or early childhood with hepatomegaly, hypoglycemia, and growth retardation. Muscle weakness in those with IIIa is minimal in childhood but can become more severe in adults; some patients develop cardiomyopathy (Shen et al., 1996).
AGPAT2Congenital generalized lipodystrophy (Berardinelli-Seip syndrome)Congenital generalized lipodystrophy type 1 (CGL1), or Berardinelli-Seip syndrome, is a rare autosomal recessive disease characterized by a near absence of adipose tissue from birth or early infancy and severe insulin resistance. Other clinical and biologic features include acanthosis nigricans, muscular hypertrophy, hepatomegaly, altered glucose tolerance or diabetes mellitus, and hypertriglyceridemia (Garg, 2004).
AGPSRhizomelic chondrodysplasia punctata, type 3Rhizomelic chondrodysplasia punctata, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGPS gene located on chromosomal region 2q31.2. The age of onset is neonatal/infantile. This disease is characterized by shortness of the femur and humerus, vertebral disorders, cataract, cutaneous lesions and severe intellectual deficit. The prevalence is 1:100,000-9:100,000.
AGRNMyasthenic syndrome, congenital, type 8Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 8, with pre- and postsynaptic defects (CMS8) is an autosomal recessive disorder characterized by prominent defects of both the pre- and postsynaptic regions. Affected individuals have onset of muscle weakness in early childhood; the severity of the weakness and muscles affected is variable (Maselli et al., 2012).
AGTRenal tubular dysgenesisRenal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.
AGTR1Renal tubular dysgenesisRenal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ACE (chromosomal region 17q23.3), AGT (1q42.2) AGTR1 (3q24) and REN (1q32.1) genes. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.
AGXTHyperoxaluria, primary, type 1Primary hyperoxaluria, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AGXT gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by variable clinical presentation, ranging from occasional symptomatic nephrolithiasis to nephrocalcinosis and end-stage renal disease with systemic involvement. The prevalence is 1:1,000,000-9:1,000,000.
AHCYHypermethioninemia with deficiency of S-adenosylhomocysteine hydrolaseHypermethioninemia with deficiency of S-adenosylhomocysteine hydrolase is a metabolic disorder characterized by hypermethioninemia associated with failure to thrive, mental and motor retardation, facial dysmorphism with abnormal hair and teeth, and myocardiopathy.
AHI1Joubert syndrome, type 3Joubert syndrome, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AHI1 gene located on chromosomal region 6q23.3. The age of onset is variable. This disease is characterized by the neurological features of Joubert syndrome (neonatal hypotonia, developmental delay, mild to severe intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia and primary position nystagmus) associated with retinal dystrophy.
AICDAImmunodeficiency with hyper-IgM, type 2Hyper-IgM syndrome type 2 (HIGM2) is a rare immunodeficiency characterized by normal or elevated serum IgM levels with absence of IgG, IgA, and IgE, resulting in a profound susceptibility to bacterial infections.
AIFM1Cowchock syndrome; Deafness, X-linked, type 5Cowchock syndrome (COWCK) is an X-linked recessive neuromuscular disorder characterized by early childhood onset of a slowly progressive axonal sensorimotor neuropathy associated in some patients with sensorineural deafness and cognitive impairment (Rinaldi et al., 2012). Hemizygous mutations in AIFM1 gene are also associated with deafness, X-linked, type 5, a neurologic disorder characterized by childhood onset of auditory neuropathy and later onset of distal sensory impairment affecting the peripheral nervous system (Zong et al., 2015).
AIMP1Leukodystrophy, hypomyelinating, type 3Leukodystrophy, hypomyelinating, type 3 (HLD3) is a severe neurologic disorder characterized by early infantile onset of global developmental delay, lack of development, lack of speech acquisition, and peripheral spasticity associated with decreased myelination in the central nervous system (Feinstein et al., 2010).The disorder is phenotypically similar to X-linked Pelizaeus-Merzbacher disease (PMD; 312080), which is caused by mutation in the PLP1 gene (300401).
AIPL1Leber congenital amaurosis type 4Leber congenital amaurosis type 4 (LCA4) is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus. Mutations in the AIPL1 gene may cause approximately 20% of recessive LCA. Other conditions caused by pathogenic variants in the AIPL1 gene are cone rod dystrophy and the less agressive form, juvenile retinitis pigmentosa. Cone-rod dystropy is characterized by decreased visual acuity, color vision defects, photoaversion and decreased sensitivity in the central visual field, later followed by progressive loss in peripheral vision and night blindness.
AIREAutoimmune polyendocrinopathy syndrome type 1Autoimmune polyendocrinopathy syndrome (APS) type 1, also known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), is characterized by the presence of 2 of 3 major clinical symptoms: Addison disease, and/or hypoparathyroidism, and/or chronic mucocutaneous candidiasis (Neufeld et al., 1981).
AK1Hemolytic anemia due to adenylate kinase deficiencyHemolytic anemia due to adenylate kinase deficiency is a rare hemolytic anemia due to an erythrocyte nucleotide metabolism disorder characterized by moderate to severe chronic nonspherocytic hemolytic anemia that may require regular blood transfusions and/or splenectomy and may be associated with psychomotor impairment.
AK2Reticular dysgenesisReticular dysgenesis (RDYS) is a fatal form of severe combined immunodeficiency, characterized by absence of granulocytes, almost complete deficiency of lymphocytes in peripheral blood, hypoplasia of the thymus and secondary lymphoid organs, and lack of innate and adaptive humoral and cellular immunity, leading to fatal septicemia within days after birth. In bone marrow of individuals with reticular dysgenesis, myeloid differentiation is blocked at the promyelocytic stage, whereas erythro- and megakaryocytic maturation is generally normal.
AKR1C246,XY disorder of sex development due to testicular 17,20-desmolase deficiency46,XY sex reversal 8 (SRXY8) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females.
AKR1D1Bile acid synthesis defect, congenital, type 2Congenital bile acid synthesis defect, type 2 (BAS defect type 2) is an anomaly of bile acid synthesis characterized by severe and rapidly progressive cholestatic liver disease, and malabsorption of fat and fat-soluble vitamins.
ALADPorphyria, acute hepaticALAD porphyria is a rare autosomal recessive disorder that has been reported and confirmed by genetic analysis in only 5 patients (Jaffe and Stith, 2007).
ALAS2X-linked sideroblastic anemia, type 1 (XLSA or SIDBA1)X-linked sideroblastic anemia type 1 is caused by pathogenic variants in the ALAS2 gene, located on chromosomal region Xp11.21. This disease is characterized by clinical features of anemia and/or iron overload such as pallor, fatigue, weakness, and more rarely breathlessness, mild splenomegaly, cardiac problems, abnormal liver function, hyperglycemia, glucose intolerance and skin hyperpigmentation. The age of clinical onset of the disorder can vary from in utero to the ninth decade. Whereas males are preferentially affected, females may present with clinically severe anemia. More commonly, female carriers of the disease have an increased red blood cell distribution width and sometimes erythrocyte dimorphism.
ALDH18A1Spastic paraplegia, type 9B, autosomal recessive; De Barsy syndromeSpastic paraplegia, type 9B, autosomal recessive (SPG9B) is a neurologic disorder characterized by early-onset complex spastic paraplegia. Affected individuals had delayed psychomotor development, intellectual disability, and severe motor impairment. More variable features include dysmorphic facial features, tremor, and urinary incontinence (Coutelier et al., 2015). Mutation in the ALDH18A1 gene can cause cutis laxa, autosomal recessive, type IIIA (De Barsy syndrome), characterized by cutis laxa, a progeria-like appearance, and ophthalmologic abnormalities (Kivuva et al., 2008).
ALDH3A2Sjogren-Larsson syndromeSjogren-Larsson syndrome is an autosomal recessive, early childhood-onset disorder characterized by ichthyosis, mental retardation, spastic paraparesis, macular dystrophy, and leukoencephalopathy. It is caused by deficiency of fatty aldehyde dehydrogenase (FALDH) (Lossos et al., 2006).
ALDH4A1Hyperprolinemia, type 2Hyperprolinemia type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH4A1 gene located on chromosomal region 1p36. The age of onset is variable. This disease is characterized by seizures, intellectual deficit and mild developmental delay.
ALDH5A1Succinic semialdehyde dehydrogenase deficiencySuccinic semialdehyde dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDH451 gene located on chromosomal region 6p22. The age of onset is infantile. This disease is characterized by psychomotor retardation, delayed speech development, hypotonia and ataxia. It is a rare disease with around 350 cases reported.
ALDH6A1Methylmalonate semialdehyde dehydrogenase deficiencyMethylmalonate semialdehyde dehydrogenase deficiency is a rare autosomal recessive inborn error of metabolism with a highly variable phenotype. Some patients may be asymptomatic, whereas others show global developmental delay, nonspecific dysmorphic features, and delayed myelination on brain imaging. Laboratory studies typically show increased urinary 3-hydroxyisobutyric acid, although additional metabolic abnormalities may also be observed (Marcadier et al., 2013).
ALDH7A1Epilepsy, pyridoxine-dependentPyridoxine-dependent epilepsy, characterized by a combination of various seizure types, usually occurs in the first hours of life and is unresponsive to standard anticonvulsants, responding only to immediate administration of pyridoxine hydrochloride. The dependence is permanent, and the interruption of daily pyridoxine supplementation leads to the recurrence of seizures. Some patients show developmental delay. The prevalence is estimated at 1 in 400,000 to 700,000 (Bennett et al., 2005).
ALDOAGlycogen storage disease type 12Glycogen storage disease type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOA gene located on chromosomal region 16p11.2. The age of onset is neonatal/infantile. This disease is characterized by myopathy with exercise intolerance and rhabdomyolysis associated with hemolytic anaemia.?
ALDOBFructose intolerance, hereditaryHereditary fructose intolerance follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALDOB gene located on chromosomal region 9q21.3-q22.2. The age of onset is neonatal/infantile. This disease is characterized by severe abdominal pain, vomiting, and hypoglycemia following ingestion of fructose or other sugars metabolised through fructose-1-phosphate. The prevalence is 1:100,000-9:100,000.
ALG1Congenital disorder of glycosylation, type 1KCongenital disorder of glycosylation type 1K follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG1 gene located on chromosomal region 16p13.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay, seizures, microcephaly and coagulation anomalies. The prevalence is <1:1,000,000.
ALG11Congenital disorder of glycosylation, type 1PCongenital disorder of glycosylation, type 1P (CDG1P) is a form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.
ALG12Congenital disorder of glycosylation, type 1GCongenital disorders of glycosylation (CDG), previously called carbohydrate-deficient glycoprotein syndromes (CDGSs), are a group of hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing (IEF) of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.
ALG13Epileptic encephalopathy, early infantile, type 36Epileptic encephalopathy, early infantile, type 36 (EIEE36) is an X-linked dominant neurodevelopmental disorder characterized by onset of seizures in infancy followed by delayed psychomotor development. Some patients may have dysmorphic features. Only females with this specific phenotype have been reported (Dimassi et al., 2016).
ALG2Myasthenic syndrome, congenital, type 14, with tubular aggregatesCongenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 14 (CMS14) is a form of congenital myasthenic syndrome. Clinical features are easy fatigability and muscle weakness. CMS14 is an autosomal recessive form characterized by onset of limb-girdle muscle weakness in early childhood. The disorder is slowly progressive, and some patients may become wheelchair-bound.?
ALG6Congenital disorder of glycosylation, type 1CCongenital disorder of glycosylation type 1C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALG6 gene located on chromosomal region 1p31.3. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay and muscular hypotonia, and possible coagulation anomalies, hormonal abnormalities and seizures. The prevalence is <1:1,000,000.
ALG8Congenital disorder of glycosylation, type 1HCDGs, previously called carbohydrate-deficient glycoprotein syndromes, grew from hereditary multisystem disorders first recognized by Jaeken et al. (1980). The characteristic biochemical abnormality of CDGs is the hypoglycosylation of glycoproteins, which is routinely determined by isoelectric focusing of serum transferrin. Type 1 CDG comprises those disorders in which there is a defect in the assembly of lipid-linked oligosaccharides or their transfer onto nascent glycoproteins, whereas type 2 CDG comprises defects of trimming, elongation, and processing of protein-bound glycans.
ALG9Congenital disorder of glycosylation, type 1L; Gillessen-Kaesbach-Nishimura syndromeCongenital disorders of glycosylation (CDGs) that represent defects of dolichol-linked oligosaccharide assembly are classified as CDG type 1. Homozygous mutation in the ALG9 gene can also cause Gillessen-Kaesbach-Nishimura syndrome (GIKANIS). GIKANIS is an autosomal recessive multiple congenital anomaly disorder characterized by skeletal dysplasia, dysmorphic facial features, and variable visceral abnormalities, including polycystic kidneys, diaphragmatic hernia, lung hypoplasia, and congenital heart defects. It may be lethal in utero or early in life. The disorder is at the severe end of the phenotypic spectrum of congenital disorders of glycosylation (summary by Tham et al., 2016).
ALMS1Alstr?m syndromeAlstr?m syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALMS1 gene located on chromosomal region 2p13.1. The age of onset is neonatal/infantile. This disease is characterized by cone-rod dystrophy, hearing loss, obesity, insulin resistance and hyperinsulinemia, type 2 diabetes mellitus, dilated cardiomyopathy and progressive hepatic and renal dysfunction. The prevalence is 1:10,000-1:1,000,000.
ALOX12BIchthyosis, congenital, autosomal recessive, type 2Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
ALOXE3Ichthyosis, congenital, autosomal recessive, type 3Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
ALPLHypophosphatasia, childhood/infantileChildhood-onset hypophosphatasia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ALPL gene located on chromosomal region 1p36.12. The age of onset is infantile. This inborn error of metabolism is characterized clinically by defective bone mineralization ranging from stillbirth without mineralized bone to pathologic fractures of the lower extremities in later adulthood; biochemically is characterized by deficient activity of the tissue-nonspecific isoenzyme of alkaline phosphatase.
ALS2Amyotrophic lateral sclerosis, type 2, juvenile; Primary lateral sclerosis, juvenile; Spastic paralysis, infantile onset ascendingAmyotrophic lateral sclerosis (ALS), type 2, juvenile is a very rare severe motor neuron disease characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. Mutations in the same gene cause juvenile primary lateral sclerosis (PLSJ) and infantile-onset ascending spastic paralysis (IAHSP). Although primary lateral sclerosis is similar to amyotrophic lateral sclerosis, they are considered to be clinically distinct progressive paralytic neurodegenerative disorders. Following a period of diagnostic confusion, the clinical distinction between ALS and PLSJ became clear and diagnostic criteria established (Pringle et al., 1992). PLS is characterized by degeneration of the upper motor neurons and the corticospinal and corticobulbar tracts, whereas ALS is a more severe disorder characterized by degeneration of both the upper and lower motor neurons. A diagnosis of PLS is essentially one of exclusion (Sotaniemi and Myllyla, 1985; Younger et al., 1988; Yang et al., 2001).
Infantile-onset ascending spastic paralysis is an autosomal recessive neurodegenerative disorder characterized by onset in the first years of life of progressive upper and lower motor neuron degeneration resulting in loss of ability to walk in childhood. It initially affects the lower limbs and then ascends to the upper limbs and bulbar muscles, causing dysarthria and dysphagia. Cognition is unaffected (summary by Wakil et al., 2014).
ALX1Frontonasal dysplasia, type 3Frontonasal dysplasia, type 3 is the most severe form of frontonasal dysplasia, an array of abnormalities affecting the eyes, forehead and nose and linked to midfacial dysraphia. The clinical picture is highly variable. Major findings include true ocular hypertelorism; broadening of the nasal root; median facial cleft affecting the nose and/or upper lip and palate; unilateral or bilateral clefting of the alae nasi; lack of formation of the nasal tip; anterior cranium bifidum occultum; a V-shaped or widow's peak frontal hairline. At least three mutations in the ALX1 gene have been found to cause frontonasal dysplasia.
ALX3Frontonasal dysplasia, type 1The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.
ALX4Frontonasal dysplasia, type 2The term frontonasal dysplasia was coined by Sedano et al. (1970) to describe a constellation of findings limited to the face and head. The disorder is defined as 2 or more of the following: (1) true ocular hypertelorism; (2) broadening of the nasal root; (3) median facial cleft affecting the nose and/or upper lip and palate; (4) unilateral or bilateral clefting of the alae nasi; (5) lack of formation of the nasal tip; (6) anterior cranium bifidum occultum (see 168500); and (7) a V-shaped or widow's peak frontal hairline (Sedano and Gorlin, 1988). Most reported cases are sporadic, but a few familial cases have been reported, characterizing frontonasal malformation (FNM) as a 'very heterogeneous group of disorders' and summarized clinical features.
AMACRBile acid synthesis defect, congenital, type 4; Alpha-methylacyl-CoA racemase deficiencyAlpha-methylacyl-CoA racemase (AMACR) deficiency is a rare autosomal recessive peroxisomal disorder characterized by adult onset of variable neurodegenerative symptoms affecting the central and peripheral nervous systems. Features may include seizures, visual failure, sensorimotor neuropathy, spasticity, migraine, and white matter hyperintensities on brain imaging. Serum pristanic acid and C27 bile acid intermediates are increased (Smith et al., 2010). AMACR deficiency is caused by mutations in the AMACR gene. AMACR gene mutations that result in a lack of functional AMACR enzyme have also been identified in infants with a life-threatening disorder called congenital bile acid synthesis defect type 4. Babies with this disorder have cholestasis, which is a reduced ability to produce and release a digestive fluid called bile. Cholestasis leads to an enlarged liver (hepatomegaly) and irreversible liver disease (cirrhosis) in the first few months of life. Some researchers consider congenital bile acid synthesis defect type 4 and AMACR deficiency (see above) to be variations of the same disorder. Because most individuals with congenital bile acid synthesis defect type 4 do not survive infancy, it is unclear whether they would have later developed the neurological symptoms seen in adults with AMACR deficiency.
AMELXAmelogenesis imperfecta, type 1EAmelogenesis imperfecta, type 1E is an inherited defect of dental enamel formation that shows both clinical and genetic heterogeneity. In the hypoplastic type of AI, the enamel is of normal hardness but does not develop to normal thickness. The thinness of the enamel makes the teeth appear small. Radiographically, enamel contrasts normally from dentin. The surface of the enamel can vary, showing smooth, rough, pitted, or local forms (Witkop, 1988).
AMER1Osteopathia striata with cranial sclerosisOsteopathia striata with cranial sclerosis is an X-linked dominant sclerosing bone dysplasia that presents in females with macrocephaly, cleft palate, mild learning disabilities, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis, and scapulae (Jenkins et al., 2009). In males, the disorder is usually associated with fetal or neonatal lethality. Occasional surviving males have, in addition to hyperostosis, cardiac, intestinal, and genitourinary malformations. Osteosclerosis in the cranial and facial bones leads to disfigurement and to disability due to pressure on cranial nerves, e.g., deafness. Osteopathia striata is a frequent feature of focal dermal hypoplasia (FDH; 305600).Although early reports of familial cases of this disorder appeared to suggest autosomal dominant inheritance (see, e.g., Horan and Beighton, 1978; Konig et al., 1996), reappraisal of the literature (Behninger and Rott, 2000; Rott et al., 2003) and the finding of a molecular basis for the disorder by Jenkins et al. (2009) confirms that the inheritance pattern is X-linked dominant. Affected males who survive have a more severe phenotype than affected females, and sporadic male cases may result from somatic mosaicism (Behninger and Rott, 2000).
AMHPersistent Mullerian duct syndrome, type 1The persistent mullerian duct syndrome is characterized by the persistence of mullerian derivatives, uterus and tubes, in otherwise normally virilized males (Knebelmann et al., 1991).
AMNMegaloblastic anemia 1 (Imerslund-Grasbeck syndrome)Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.
AMPD1Myopathy due to myoadenylate deaminase deficiencyMyoadenylate deaminase deficiency (MMDD) is an autosomal recessive condition that can manifest as exercise-induced muscle pain, occasionally associated with rhabdomyolysis and/or increased serum creatine kinase, or even infantile hypotonia. However, the finding of homozygous mutations among asymptomatic individuals have suggested to some (e.g., Verzijl et al., 1998) that AMPD1 deficiency may be a harmless entity (Castro-Gago et al., 2011). Genetta et al. (2001) stated that AMPD1 deficiency is the most prevalent genetic disease in humans, the number of people heterozygous approaching 10% of Caucasians and individuals of African descent (Sabina et al., 1989). A small percentage of homozygous-deficient individuals, approximately 1.8% of the population, display symptoms of chronic fatigue and lost productivity as well as a predisposition to stress-related ailments, including heart disease and stroke, according to Genetta et al. (2001).
AMTGlycine encephalopathyGlycine encephalopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AMT and GLDC genes located on chromosomal regions 3p21.31 and 9p24.1 respectively. The age of onset is neonatal/infantile. This disease is characterized by lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. The prevalence is 1:1,000,000-9:1,000,000.
ANGPTL3Hypobetalipoproteinemia, familial, type 2Hypobetalipoproteinemia, familial, type 2 is defined as permanently low levels, below the 5th percentile of sex- and age-matched individuals in the population, of apolipoprotein B (apoB), total cholesterol, and low-density lipoprotein (LDL) cholesterol; the lipid profile in FHBL2 includes low HDL cholesterol as well. HBL can result from environmental factors such as a strict vegetarian diet, or can be secondary to certain diseases such as intestinal fat malabsorption, chronic pancreatitis, severe liver disease, malnutrition, or hyperthyroidism. Heritable primary causes of HBL include chylomicron retention disease (CMRD; 246700), abetalipoproteinemia (200100), and familial hypobetalipoproteinemia (FHBL) (Martin-Campos et al., 2012).
ANO10Spinocerebellar ataxia, autosomal recessive, type 10Spinocerebellar ataxia, autosomal recessive, type 10 is an autosomal recessive neurodegenerative disorder with onset in the teenage or young adult years of gait and limb ataxia, dysarthria, and nystagmus associated with marked cerebellar atrophy on brain imaging (Vermeer et al., 2010). Some patients have low levels of coenzyme Q10 (CoQ10) in muscle and may show some clinical improvement with CoQ10 treatment (Balreira et al., 2014).
ANO5Limb-girdle muscular dystrophy, type 12 (LGMD R12)Limb-girdle muscular dystrophy type 12 (LGMDR12, formerly LGMD2L) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ANO5 gene located on chromosomal region 11p14.3. This disease is characterized by weakness and wasting restricted to the limb musculature. Most often is characterized by an adult onset (but ranging from 11 to 51 years) of mainly proximal lower limb weakness, with difficulties standing on tiptoes being one of the initial signs. Proximal upper limb and distal lower limb weakness is also common, as well as atrophy of the quadriceps (most commonly), biceps brachii, and lower leg muscles. Calf hypertrophy has also been reported in some cases. LGMDR12 progresses slowly, with most patients remaining ambulatory until late adulthood. The estimated prevalence is <1:1,000,000.
ANOS1Hypogonadotropic hypogonadism, type 1, with or without anosmia (Kallmann syndrome 1)Congenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia.
ANTXR1GAPO syndromeThe GAPO syndrome is the acronymic designation for a complex of growth retardation, alopecia, pseudoanodontia (failure of tooth eruption), and progressive optic atrophy (Tipton and Gorlin, 1984). Ilker et al. (1999) noted that optic atrophy is not a consistent feature of this disorder.
ANTXR2Hyaline fibromatosis syndromeHyaline fibromatosis syndrome is an autosomal recessive condition characterized by abnormal growth of hyalinized fibrous tissue usually affecting subcutaneous regions on the scalp, ears, neck, face, hands, and feet. The lesions appear as pearly papules or fleshy nodules. The severity is variable. Some individuals present in infancy and have additional visceral or systemic involvement, which can lead to early death. These patients may show intractable diarrhea and increased susceptibility to infection. Other patients have later onset of a milder disorder affecting only the face and digits. Additional features include gingival hypertrophy, progressive joint contractures resulting in severe limitation of mobility, osteopenia, and osteoporosis. Histologic analysis of skin lesions shows proliferation of spindle-shaped cells forming strands in a homogeneous and hyaline eosinophilic extracellular material in the dermis (Denadai et al., 2012).
AP1S1MEDNIK syndromeMEDNIK is a severe multisystem disorder characterized by mental retardation, enteropathy, deafness, peripheral neuropathy, ichthyosis, and keratoderma. It shows phenotypic similarities to CEDNIK (609528) (Montpetit et al., 2008).
AP1S2Mental retardation, X-linked, syndromic, type 5 (Pettigrew syndrome)Mental retardation, X-linked, syndromic, type 5, also known as Pettigrew syndrome, is characterized by mental retardation and highly variable additional features, including choreoathetosis, hydrocephalus, Dandy-Walker malformation, seizures, and iron or calcium deposition in the brain, both between and within families (Cacciagli et al., 2014).
AP3B1Hermansky-Pudlak syndrome, type 2Hermansky-Pudlak syndrome, type 2 (HPS2) is a rare autosomal recessive disease characterized by platelet defects and oculocutaneous albinism. HPS2 differs from the other forms of HPS in that it includes immunodeficiency, and patients with HPS2 have an increased susceptibility to infections due to congenital neutropenia (Jung et al., 2006).
AP3B2Epileptic encephalopathy, early infantile, type 48Epileptic encephalopathy, early infantile, type 48 (EIEE48) is a severe autosomal recessive neurologic disorder characterized by global developmental delay with intellectual disability and absent speech, poor, if any, motor development, and onset of seizures in the first year of life. Affected individuals have poor eye contact and may develop microcephaly and abnormal movements (Assoum et al., 2016).
AP4B1Spastic paraplegia, type 47, autosomal recessiveSpastic paraplegia, type 47, autosomal recessive is an autosomal recessive neurodegenerative disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011).
AP4M1Spastic paraplegia, type 50, autosomal recessiveSpastic paraplegia, type 50, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Verkerk et al., 2009).
AP4S1Spastic paraplegia, type 52, autosomal recessiveSpastic paraplegia, type 52, autosomal recessive is an autosomal recessive neurodevelopmental disorder characterized by neonatal hypotonia that progresses to hypertonia and spasticity and severe mental retardation with poor or absent speech development (Abou Jamra et al., 2011). Some patients may have seizures (Hardies et al., 2015).
AP5Z1Spastic paraplegia, type 48, autosomal recessiveSpastic paraplegia, type 48, autosomal recessive is an autosomal recessive neurologic disorder characterized by spasticity of the lower limbs resulting in gait difficulties. Most patients have onset in mid- or late-adulthood, although childhood onset has been reported in 1 patient. Additional features may include parkinsonism, urinary incontinence, neuropathy, and mild cognitive impairment (Hirst et al., 2015).
APOC2Hyperlipoproteinemia, type 1BHyperlipoproteinemia 1B (HLPP1B) is an autosomal recessive trait characterized by hypertriglyceridemia, xanthomas, and increased risk of pancreatitis and early atherosclerosis.
APOESea-blue histiocyte diseaseSea-blue histiocyte disease is characterized by splenomegaly, mild thrombocytopenia and, in the bone marrow, numerous histiocytes containing cytoplasmic granules which stain bright blue with the usual hematologic stains. The syndrome is the consequence of an inherited metabolic defect analogous to Gaucher disease and other sphingolipidoses.
APRTAdenine phosphoribosyltransferase deficiencyAdenine phosphoribosyltransferase deficiency is an autosomal recessive metabolic disorder that can lead to accumulation of the insoluble purine 2,8-dihydroxyadenine (DHA) in the kidney, which results in crystalluria and the formation of urinary stones. Clinical features include renal colic, hematuria, urinary tract infection, dysuria, and, in some cases, renal failure. The age at onset can range from 5 months to late adulthood; however, as many as 50% of APRT-deficient individuals may be asymptomatic (Sahota et al., 2001).Two types of APRT deficiency have been described based on the level of residual enzyme activity in in vitro studies of erythrocytes. Type I deficiency is characterized by complete enzyme deficiency in intact cells and in cell lysates, whereas type II deficiency is characterized by complete enzyme deficiency in intact cells, but only a partial deficiency in cell lysates. Type II alleles show reduced affinity for phosphoribosyl pyrophosphate (PRPP) compared to wildtype. In both types, APRT activity is not functional in vivo. Type II deficiency is most common among Japanese. Heterozygotes of either type do not appear to have any clinical or biochemical abnormalities (Sahota et al., 2001).
APTXAtaxia, early-onset, with oculomotor apraxia and hypoalbuminemiaAtaxia, early-onset, with oculomotor apraxia and hipoalbuminemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the APTX gene located on chromosomal region 9p13.1. Ataxia-oculomotor apraxia syndrome is an early-onset autosomal recessive, progressive, cerebellar ataxia with peripheral axonal neuropathy, oculomotor apraxia (defined as the limitation of ocular movements on command), and hypoalbuminemia. The prevalence is unknown.
AQP2Diabetes insipidus, nephrogenic, type 2Nephrogenic diabetes insipidus is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopressin (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form, type I (304800), which is caused by mutation in the gene encoding the vasopressin V2 receptor (AVPR2; 300538). The remaining 10% of patients have the autosomal form, type II, caused by mutation in the AQP2 gene (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (CDI; 125700) is caused by mutation in the gene encoding arginine vasopressin, located on 20p13.
ARAndrogen insensitivity syndrome, completeThe complete androgen insensitivity syndrome (CAIS) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the AR gene located on chromosomal region Xq12. Affected males have female external genitalia, female breast development, blind vagina, absent uterus and female adnexa, and abdominal or inguinal testes, despite a normal male 46,XY karyotype. There is unresponsiveness to age-appropriate levels of androgens. There is also a partial androgen insensitivity syndrome (PAIS; OMIM 312300) caused by mutations in the AR gene, called Reifenstein syndrome, which results in hypospadias and micropenis with gynecomastia. Note: A specific type of mutation in the AR gene (a CAG repeat expansion) also cause a rare condition known as Spinal and bulbar muscular atrophy or Kennedy disease; this mutation is not tested by this carrier test.
ARFGEF2Periventricular heterotopia with microcephalyPeriventricular heterotopia with microcephaly is a developmental disorder characterized by the presence of periventricular nodules of cerebral gray matter, resulting from a failure of neurons to migrate normally from the lateral ventricular proliferative zone, where they are formed, to the cerebral cortex. Periventricular heterotopia with microcephaly is an autosomal recessive form characterized by microcephaly (small brain), severe developmental delay and recurrent infections. No anomalies extrinsic to the central nervous system, such as dysmorphic features or grossly abnormal endocrine or other conditions, are associated with Periventricular heterotopia with microcephaly.
ARG1Argininemia (arginase deficiency)Argininemia, also known as arginase deficiency, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARG1 gene located on chromosomal region 6q23. The age of onset is neonatal/infantile. This disease is characterized by variable degrees of hyperammonemia, developing from about 3 years of age, and leading to progressive loss of developmental milestones and spasticity in the absence of treatment. The prevalence is 1:350,000-1:1,000,000.
ARHGEF9Epileptic encephalopathy, early infantile, type 8Epileptic encephalopathy, early infantile, type 8 (EIEE8) is a disorder characterized by hyperekplexia and early infantile epileptic encephalopathy. Neurologic features include exaggerated startle response, seizures, impaired psychomotor development, and mental retardation. Seizures can be provoked by tactile stimulation or extreme emotion.
ARL13BJoubert syndrome type 8Joubert syndrome type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL13B gene located on chromosomal region 3q11.1. The age of onset is neonatal/infantile. This disease is characterized by congenital malformation of the brainstem and agenesis or hypoplasia of the cerebellar vermis leading to an abnormal respiratory pattern, nystagmus, hypotonia, ataxia and delay in achieving motor milestones. The prevalence is 1/80,000 to 1/100,000.
ARL6Bardet-Biedl syndrome, type 3Bardet-Biedl syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARL6 gene located on chromosomal region 3q11.2. The age of onset is early. A syndrome characterized by usually severe pigmentary retinopathy, early-onset obesity, polydactyly, hypogenitalism, renal malformation and mental retardation. Secondary features include diabetes mellitus, hypertension and congenital heart disease.
ARSAMetachromatic leukodystrophyMetachromatic leukodystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSA gene located on chromosomal region 22q13.33. The age of onset is variable. This disease is characterized by hypotonia, walking difficulties, optic atrophy and motor regression preceding mental impairment in the late infantile form, arrested intellectual development, followed by motor regression, epileptic seizures and ataxia in the juvenile form, and motor or psychiatric disorders, but with slow progression in the adult form. The incidence is 0.5:5,000-1:50,000?and the prevalence is 1:10,000 -5/10,000.
ARSBMucopolysaccharidosis, type 6 (Maroteaux-Lamy syndrome)Mucopolysaccharidosis type 6, also known as Maroteaux-Lamy syndrome, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ARSB gene located on chromosomal region 5q14.1. The age of onset is infantile. This lysosomal storage disorder resulting from a deficiency of arylsulfatase B is characterized by educed pulmonary function, hepatosplenomegaly, hearing loss, sleep apnea, corneal clouding, carpal tunnel disease and occasionally central nervous system findings may include cervical cord compression caused by cervical spinal instability, meningeal thickening and/or bony stenosis, communicating hydrocephalus, optic nerve atrophy and blindness. The prevalence is 1:250,000-1:600,000 newborns.
ARSEChondrodysplasia punctata, brachytelephalangicX-linked chondrodysplasia punctata, brachytelephalangic follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ARSE gene located on chromosomal region Xp22.33. The age of onset is neonatal. This?is a disorder of cartilage and bone development that occurs almost exclusively in males. Include short stature and unusually short fingertips and ends of the toes. This condition is also associated with distinctive facial features, particularly a flattened-appearing nose with crescent-shaped nostrils and a flat nasal bridge. People with X-linked chondrodysplasia punctata 1 typically have normal intelligence and a normal life expectancy. However, some affected individuals have had serious or life-threatening complications including abnormal thickening (stenosis) of the cartilage that makes up the airways, which restricts breathing. Also, abnormalities of spinal bones in the neck can lead to pinching (compression) of the spinal cord, which can cause pain, numbness, and weakness. Other, less common features of X-linked chondrodysplasia punctata 1 include delayed development, hearing loss, vision abnormalities, and heart defects. The prevalence is 1:500,000.
ARXEpileptic encephalopathy, early infantile, type 1; ARX-related developmental disordersEarly infantile epileptic encephalopathy type 1 (EIEE1) follows an X-linked recessive pattern of inheritance and is caused by pathogenic variants in the ARX gene located on chromosomal region Xp21.3. The age of onset is early. This severe disease is characterized by the onset of tonic spasms within the first 3 months of life leading to psychomotor impairment and death. Particularly,it is characterized by frequent tonic seizures or spasms beginning in infancy with a specific EEG finding of suppression-burst patterns, with high-voltage bursts alternating with almost flat suppression phases. Approximately 75% of EIEE patients progress to 'West syndrome,' which is characterized by tonic spasms with clustering, arrest of psychomotor development, and hypsarrhythmia on EEG (Kato et al., 2007). EIEE1 is part of a phenotypic spectrum of disorders caused by mutation in the ARX gene comprising a nearly continuous series of developmental disorders ranging from lissencephaly (LISX2; 300215) to Proud syndrome (300004) to infantile spasms without brain malformations (EIEE1) to syndromic (Partington syndrome; 309510) and nonsyndromic (Mental retardation, X-linked type 29; 300419) mental retardation. Although males with ARX mutations are often more severely affected, female mutation carriers may also be affected (Kato et al., 2004; Wallerstein et al., 2008). The prevalence is <1:1,000,000.
ASAH1Farber lipogranulomatosis; Spinal muscular atrophy with progressive myoclonic epilepsyFarber lipogranulomatosis is an autosomal recessive lysosomal storage disorder characterized by early-onset subcutaneous nodules, painful and progressively deformed joints, and hoarseness by laryngeal involvement. Based on the age of onset, the severity of symptoms, and the difference in organs affected, 6 clinical subtypes due to deficiency of acid ceramidase have been distinguished. The most severe form is subtype 4, a rare neonatal form of the disease with death occurring before 1 year of age (Alves et al., 2013). Biallelic mutation in the ASAH1 gene can also cause spinal muscular atrophy with progressive myoclonic epilepsy (SMAPME). Spinal muscular atrophy with progressive myoclonic epilepsy is an autosomal recessive neuromuscular disorder characterized by childhood onset of proximal muscle weakness and generalized muscular atrophy due to degeneration of spinal motor neurons, followed by the onset of myoclonic seizures. The disorder is progressive, and usually results in loss of ambulation and early death from respiratory insufficiency (Zhou et al., 2012).
ASLArgininosuccinic aciduriaArgininosuccinic aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASL gene located on chromosomal region 7q11.21. The age of onset is infantile. This disease is characterized by severe hyperammonemic coma, hypotonia, growth failure, anorexia and chronic vomiting or behavioral disorders during childhood, and hyperammonemic coma or behavioral disorders that simulate psychiatric disorders later in life. The prevalence is 1:70,000 newborns.
ASNSAsparagine synthetase deficiencyAsparagine synthetase deficiency is an autosomal recessive severe neurologic disorder characterized by microcephaly, severely delayed psychomotor development, progressive encephalopathy, cortical atrophy, and seizure or hyperekplexic activity. The disorder shows onset in utero or at birth and may result in early death (Ruzzo et al., 2013).
ASPACanavan diseaseCanavan disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPA gene located on chromosomal region 17p13.3. The age of onset is neonatal/infantile. This disease is characterized by a variable spectrum between severe forms with leukodystrophy, macrocephaly and severe developmental delay, and a very rare mild/juvenile form characterized by mild developmental delay. The prevalence is 1:6,400- 1:13,500 in Askenazis Jewis.
ASPMPrimary microcephaly type 5, autosomal recessivePrimary autosomal recessive microcephaly type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASPM gene located on chromosomal region 1q31. The age of onset is neonatal/infantile. This disease is characterized by a reduction in head circumference at birth, mild to moderate non-progressive intellectual impairment and delay in early motor milestones, speech delay and hyperactive behavior are common.?The annual incidence is 1:1,000,000.
ASS1Citrullinemia, type 1Citrullinemia, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ASS1 gene located on chromosomal region 9q34.1. The age of onset is variable. This disease is characterized by hyperammonemia, progressive lethargy, poor feeding and vomiting in the neonatal form and by variable hyperammonemia in the later-onset form. The prevalence is 1:100,000-9:100,000.
ATF6Achromatopsia 7Achromatopsia 7 is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (Kohl et al., 2015).
ATICAICA-ribosiduria due to ATIC deficiencyAICA-ribosiduria due to ATIC deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATIC gene located on chromosomal region 2q35. The age of onset is neonatal/infantile. This disease is characterized by profound intellectual deficit, epilepsy, dysmorphic features of the knees, elbows, and shoulders and congenital blindness. The prevalence is <1:1,000,000.
ATMAtaxia-telangiectasiaAtaxia-telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectases, immune defects, and a predisposition to malignancy. Chromosomal breakage is a feature. AT cells are abnormally sensitive to killing by ionizing radiation (IR), and abnormally resistant to inhibition of DNA synthesis by ionizing radiation. The latter trait has been used to identify complementation groups for the classic form of the disease (Jaspers et al., 1988). At least 4 of these (A, C, D, and E) map to chromosome 11q23 (Sanal et al., 1990) and are associated with mutations in the ATM gene.
ATOH7Persistent hyperplastic primary vitreous, autosomal recessivePersistent hyperplastic primary vitreous (PHPV), also termed 'persistent fetal vasculature,' is a developmental malformation of the eye in which the primary vitreous fails to regress in utero, resulting in the presence of a retrolental fibrovascular membrane with persistence of the posterior portion of the tunica vasculosa lentis and hyaloid artery. This abnormality is usually unilateral and associated with microphthalmia, cataract, glaucoma, and congenital retinal nonattachment (Haddad et al., 1978; Khaliq et al., 2001; Prasov et al., 2012).PHPV shares phenotypic overlap with Norrie disease (310600).
ATP13A2Kufor-Rakeb syndrome; Spastic paraplegia, type 78, autosomal recessiveKufor-Rakeb syndrome is a rare autosomal recessive form of juvenile-onset atypical Parkinson disease (PARK9) associated with supranuclear gaze palsy, spasticity, and dementia. Some patients have neuroradiologic evidence of iron deposition in the basal ganglia, indicating that the pathogenesis of PARK9 can be considered among the syndromes of neurodegeneration with brain iron accumulation (NBIA; 234200) (Bruggemann et al., 2010). Biallelic mutation in the ATP13A2 gene also causes autosomal recessive spastic paraplegia, type 78, an adult-onset neurodegenerative disorder with overlapping features. Patients with SPG78 have later onset and prominent spasticity, but rarely parkinsonism. Loss of ATP13A2 function results in a multidimensional spectrum of neurologic features reflecting various regions of the brain and nervous system, including cortical, pyramidal, extrapyramidal, brainstem, cerebellar, and peripheral (Estrada-Cuzcano et al., 2017).
ATP2A1Brody myopathyBrody myopathy, a disorder of fast-twitch skeletal muscle function, is characterized by exercise-induced impairment of skeletal muscle relaxation, stiffening, and cramps, predominantly in the arms, legs, and eyelids (Odermatt et al., 2000).
ATP6V0A2Cutis laxa, autosomal recessive, type 2A; Wrinkly skin syndromeAutosomal recessive cutis laxa type 2 (ARCL2) represents a spectrum of clinical entities with variable severity of cutis laxa, abnormal growth, developmental delay, and associated skeletal abnormalities. Aside from cutis laxa, persistent wide fontanels, frontal bossing, slight oxycephaly, downward-slanted palpebral fissures, reversed-V eyebrows, and dental caries are characteristic. Patients with ARCL2 can be divided into 2 major groups: ARCL2A, comprising those with a combined N- and O-linked glycosylation defect (CDG type 2), and ARCL2B, those without a metabolic disorder (Morava et al., 2009). Van Maldergem et al. (2008) concluded that ARCL2A should be considered more of a multisystem disorder with cobblestone-like brain dysgenesis manifesting as developmental delay and an epileptic neurodegenerative syndrome rather than purely a dermatologic disorder. Mutation in the ATP6V0A2 gen can also cause wrinkly skin syndrome (WWS). WSS is characterized by wrinkling of the skin of the dorsum of the hands and feet, an increased number of palmar and plantar creases, wrinkled abdominal skin, multiple skeletal abnormalities (joint laxity and congenital hip dislocation), late closing of the anterior fontanel, microcephaly, pre- and postnatal growth retardation, developmental delay and facial dysmorphism (a broad nasal bridge, downslanting palpebral fissures and hypertelorism). The occurrence of mutations in the same gene in WSS indicates that ARCL2 and some cases of WSS represent variable manifestations of the same genetic defect.
ATP6V0A4Renal tubular acidosis, distal, autosomal recessiveRenal tubular acidosis, distal (dRTA), autosomal recessive is a disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.
ATP6V1B1Renal tubular acidosis with deafnessRenal tubular acidosis with deafness is an autosomal recessive disease characterized by the association of renal distal tubular acidosis with sensorineural hearing loss. Distal renal tubular acidosis is characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron, where vectorial proton transport is required for urinary acidification.
ATP7AMenkes disease; Occipital horn syndromeMenkes disease follows an X-linked pattern of inheritance and is caused by pathogenic variants in the ATP7A gene located on chromosomal region Xq21.1. The age of onset is neonatal/infantile. This disease is characterized by progressive neurodegeneration and marked connective tissue anomalies as well as typical sparse abnormal steely hair. The birth incidence is 1:300,000 in Europe, 1:360,000 in Japan and 1:50,000-1:100,000 in Australia, and the prevalence is 1:100,000 newborns. Mutations in the ATP7A can also cause occipital horn syndrome, which is considered a mild form of Menkes syndrome. Occipital horn syndrome is a rare connective tissue disorder characterized by hyperelastic and bruisable skin, hernias, bladder diverticula, hyperextensible joints, varicosities, and multiple skeletal abnormalities. The disorder is sometimes accompanied by mild neurologic impairment, and bony abnormalities of the occiput are a common feature, giving rise to the name (summary by Das et al., 1995).
ATP7BWilson diseaseWilson disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATP7B gene located on chromosomal region 13q14.3. The age of onset is infantile. This disease is characterized by the toxic accumulation of copper, mainly in the liver and central nervous system, and symptomatic patients may present with hepatic, neurologic or psychiatric forms. The birth incidence is 1:30,000-1:100,000 in France and The prevalence is 1:10,000-1:30,000.
ATP8B1Cholestasis, progressive familial intrahepatic, type 1; Cholestasis, benign recurrent intrahepatic, type 1Progressive familial intrahepatic, type 1 (PFIC1) is a heterogeneous group of autosomal recessive liver disorders characterized by early onset of cholestasis that progresses to hepatic fibrosis, cirrhosis, and end-stage liver disease before adulthood (Alonso et al., 1994; Whitington et al., 1994; Klomp et al., 2004). Mutations in the ATP8B1 gene can cause benign recurrent intrahepatic cholestasis type 1 (BRIC1). BRIC1 is characterized by intermittent episodes of cholestasis without extrahepatic bile duct obstruction. There is initial elevation of serum bile acids, followed by cholestatic jaundice which generally spontaneously resolves after periods of weeks to months (Summerskill and Walshe, 1959; Schapiro and Isselbacher, 1963; Brenard et al., 1989). Tygstrup et al. (1999) stated that referring to this disorder as 'benign' is a misnomer, because the disease has an impact on the quality of life in some patients. They preferred the term 'recurrent familial intrahepatic cholestasis.' Mutation in the ATP8B1 gene can also cause ).
ATRSeckel syndrome type 1Seckel syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ATR gene located on chromosomal region 3q23. The age of onset is neonatal/infantile. This disease is characterized by a proportionate dwarfism of prenatal onset, a severe microcephaly with a bird-headed like appearance and mental retardation.?The prevalence is <1:1,000,000.
ATRXMental retardation-hypotonic facies syndrome, X-linkedX-linked mental retardation-hypotonic facies syndrome comprises several syndromes previously reported separately. These include Carpenter-Waziri, Holmes-Gang, and Smith-Fineman-Myers syndromes as well as 1 family with X-linked mental retardation with spastic paraplegia. All these syndromes were found to be caused by mutation in the XH2 gene and are characterized primarily by severe mental retardation, dysmorphic facies, and a highly skewed X-inactivation pattern in carrier women (Abidi et al., 2005). Other more variable features include hypogonadism, deafness, renal anomalies, and mild skeletal defects.
AUH3-methylglutaconic aciduria, type 13-Methylglutaconic aciduria type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the AUH gene located on chromosomal region 9q22.31. The age of onset is neonatal/infantile. This disease is characterized by a variable clinical phenotype ranging from mildly delayed speech to psychomotor retardation, coma, failure to thrive, metabolic acidosis and dystonia.?The prevalence is <1:1,000,000.
AURKCMale infertility spermatogenic failure, type 5Spermatogenic failure, type 5 is a form of male infertility associated with large-headed, multiflagellar, polyploid spermatozoa (Dieterich et al., 2007).
AVPR2Diabetes insipidus, nephrogenic, type 1; Nephrogenic syndrome of inappropriate antidiuresis (NSIAD)Nephrogenic diabetes insipidus (NDI) is caused by the inability of the renal collecting ducts to absorb water in response to antidiuretic hormone (ADH), also known as arginine vasopression (AVP; 192340). Approximately 90% of patients are males with the X-linked recessive form (type I), which is caused by a defect in the vasopressin V2 receptor in renal collecting duct cells. The remaining 10% of patients have autosomal NDI (125800) (type II), which is caused by mutations in the gene encoding the aquaporin-2 water channel (AQP2; 107777) on chromosome 12q13 (Morello and Bichet, 2001).Neurogenic, or central, diabetes insipidus (125700) is caused by mutation in the gene encoding arginine vasopression, located on 20p13.
Gain-of-function mutations in the AVPR2 gene result in nephrogenic syndrome of inappropriate antidiuresis (NSIAD). The syndrome of inappropriate antidiuretic hormone secretion (SIADH) is a common cause of hyponatremia. The syndrome manifests as an inability to excrete a free water load, with inappropriately concentrated urine and resultant hyponatremia, hypoosmolality, and natriuresis. SIADH occurs in a setting of normal blood volume, without evidence of renal disease or deficiency of thyroxine or cortisol. Although usually transient, SIADH may be chronic; it is often associated with drug use or a lesion in the central nervous system or lung. When the cardinal features of SIADH were defined by Bartter and Schwartz (1967), levels of AVP could not be measured. Subsequently, radioimmunoassays revealed that SIADH is usually associated with measurably elevated serum levels of AVP. Nephrogenic syndrome of inappropriate antidiuresis (NSIAD) is characterized by a clinical picture similar to SIADH, but is associated with undetectable levels of AVP (Feldman et al., 2005).
B2MImmunodeficiency, type 43Immunodeficiency, type 43 is a disorder characterized by marked reduction in serum concentrations of immunoglobulins and albumin, and hypoproteinemia due to hypercatabolism. Patients may suffer from recurrent respiratory tract infections and severe skin disease.
B3GAT3Multiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defectsMultiple joint dislocations, short stature, craniofacial dysmorphism, with or without congenital heart defects (JDSCD). is an autosomal recessive disease characterized by dysmorphic facies, bilateral dislocations of the elbows, hips, and knees, clubfeet, and short stature, as well as cardiovascular defects.
B3GLCTPeters-plus syndromePeters-plus syndrome is an autosomal recessive disorder characterized by anterior eye-chamber abnormalities, disproportionate short stature, developmental delay, characteristic craniofacial features, cleft lip and/or palate.
B4GALT1Congenital disorder of glycosylation, type 2DCongenital disorder of glycosylation type 2D follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the B4GALT1 gene located on chromosomal region 9p13. The age of onset is neonatal/infantile. This disease is characterized by macrocephaly, hydrocephaly, hypotonia, myopathy and coagulation anomalies. The prevalence is <1:1,000,000.
B4GALT7Ehlers-Danlos syndrome, spondylodysplastic, type 1Ehlers-Danlos syndrome spondylodysplastic, type 1 is characterized by short stature, developmental anomalies of the forearm bones and elbow, and bowing of extremities, in addition to the classic stigmata of Ehlers-Danlos syndrome, including joint laxity, skin hyperextensibility, and poor wound healing. Significant developmental delay is not a consistent feature (Guo et al., 2013).
B9D1Joubert syndrome, type 27Joubert syndrome, type 27 is a form of Joubert syndrome, a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly.
B9D2Joubert syndrome type 34; Meckel syndrome type 10Joubert syndrome (JBTS) 34 is an autosomal recessive disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy, renal disease, liver fibrosis, and polydactyly. On the other side, Meckel syndrome (MKS) type 10 (MKS10) is a very rare autosomal-recessive disorder resulting in perinatal lethality and characterized by renal cysts, hepatic ductal plate malformation, and central nervous system defects, such as occipital encephalocele. JBST34 and MKS10 are caused by pathogenic variants in the B9D2 gene located on chromosomal region 19q13.2.
BBS1Bardet-Biedl syndrome, type 1Bardet-Biedl syndrome 1 is an autosomal recessive and genetically heterogeneous ciliopathy characterized by retinitis pigmentosa, obesity, kidney dysfunction, polydactyly, behavioral dysfunction, and hypogonadism. Eight proteins implicated in the disorder assemble to form the BBSome, a stable complex involved in signaling receptor trafficking to and from cilia (summary by Scheidecker et al., 2014).
BBS10Bardet-Biedl syndrome, type 10Bardet-Biedl syndrome 10 (BBS10) is characterized by progressive retinal dystrophy, obesity, polydactyly, cognitive impairment, and renal dysplasia (Stoetzel et al., 2006). BBS10 represents a major locus for BBS, with mutations in the BBS10 gene accounting for approximately 20% of BBS patients (Stoetzel et al., 2006; Zaghloul and Katsanis, 2009).
BBS12Bardet-Biedl syndrome, type 12Bardet-Biedl syndrome 12 (BBS12) is a clinically pleiotropic autosomal recessive ciliopathy. The patients with BBS12 studied by Stoetzel et al. (2007) and Harville et al. (2010) met the diagnostic criteria of Beales et al. (1999), which required the presence of either 4 primary features, including rod-cone dystrophy, polydactyly, obesity, learning disabilities, hypogonadism (in males), and/or renal anomalies; or 3 primary plus 2 secondary features (e.g., developmental delay, ataxia, cataracts).
BBS2Bardet-Biedl syndrome, type 2Bardet-Biedl syndrome 2 (BBS2) is an autosomal recessive ciliopathy characterized by retinal degeneration, polydactyly, renal disease, hypogonadism, obesity, dysmorphic features, and variable degrees of cognitive impairment (Innes et al., 2010). Mutation in the BBS2 gene is the third most frequent cause of BBS, accounting for approximately 8% of cases (Zaghloul and Katsanis, 2009).
BBS4Bardet-Biedl syndrome, type 4Bardet-Biedl syndrome 4 (BBS4) is a rare multisystemic disorder characterized primarily by retinal dystrophy, obesity, polydactyly, and renal dysfunction that accounts for less than 3% of BBS (Katsanis et al., 2002). Anosmia has been described in patients with BBS4 (Iannaccone et al., 2005), as well as polydactyly confined to the hands (Carmi et al., 1995).
BBS5Bardet-Biedl syndrome, type 5Bardet-Biedl syndrome 5 (BBS5) is a ciliopathy associated with severe and early-onset retinal dystrophy, postaxial polydactyly, obesity, renal dysfunction, hypogonadism, and learning difficulties (Scheidecker et al., 2015). Patients described by Young et al. (1999) and Moore et al. (2005) with mutations in the BBS5 gene did not have polydactyly. The contribution of BBS5 mutations to all cases of BBS has been estimated at 2% (Li et al., 2004) and 0.40% (Zaghloul and Katsanis, 2009).
BBS7Bardet-Biedl syndrome, type 7Bardet-Biedl syndrome 7 (BBS7) is an autosomal recessive disorder characterized by retinitis pigmentosa, postaxial polydactyly, mental retardation, obesity, renal anomalies, and hypogenitalism (Harville et al., 2010). Zaghloul and Katsanis (2009) estimated the contribution of BBS7 gene mutations to the total BBS mutational load to be 1.50%.
BBS9Bardet-Biedl syndrome, type 9Bardet-Biedl syndrome 9 (BBS9) is an autosomal recessive disorder characterized by obesity, polydactyly, renal anomalies, retinopathy, and mental retardation (Abu-Safieh et al., 2012).
BCAP31Deafness, dystonia, and cerebral hypomyelinationDeafness, dystonia, and cerebral hypomyelination is an X-linked recessive mental retardation syndrome characterized by almost no psychomotor development, dysmorphic facial features, sensorineural deafness, dystonia, pyramidal signs, and hypomyelination on brain imaging (Cacciagli et al., 2013).
BCKDHAMaple syrup urine disease, type 1AMaple syrup urine disease, type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHA gene located on chromosomal region 19q13.1-13.2. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:1,000,000-9:1,000,000.
BCKDHBMaple syrup urine disease, type 1BMaple syrup urine disease, type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BCKDHB gene located on chromosomal region 6q14.1. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting, a maple syrup odor in the cerumen and urine, encephalopathy and central respiratory failure if untreated. The prevalence is 1:10,000-5:10,000.
BCORMicrophthalmia, syndromic, type 2Microphthalmia, syndromic, type 2 (MCOPS2) is a very rare multiple congenital anomaly syndrome characterized by eye anomalies (congenital cataract, microphthalmia, or secondary glaucoma), facial abnormalities (long narrow face, high nasal bridge, pointed nose with cartilages separated at the tip, cleft palate, or submucous cleft palate), cardiac anomalies (atrial septal defect, ventricular septal defect, or floppy mitral valve) and dental abnormalities (canine radiculomegaly, delayed dentition, oligodontia, persistent primary teeth, or variable root length). Microphthalmia is a disorder of eye formation, ranging from small size of a single eye to complete bilateral absence of ocular tissues (anophthalmia). In many cases, microphthalmia/anophthalmia occurs in association with syndromes that include non-ocular abnormalities.
BCS1LBCS1L-related disorders, including Leigh syndromeLeigh syndrome caused by mutations in the BCS1L gene -located on chromosomal region 2q35- follows an autosomal recessive pattern of inheritance. Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation; It presents extensive genetic heterogeneity (more than 75 different genes) with mutations identified in both nuclear- and mitochondrial-encoded genes involved in energy metabolism, including mitochondrial respiratory chain complexes I, II, III, IV, and V. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The BCS1L protein is critical for the formation of mitochondrial complex III. This syndrome affects at least 1 in 40,000 newborns.
BEST1Bestrophinopathy, ARBestrophinopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BEST1 gene located on chromosomal region 11q13. The age of onset is variable. This disease is characterized by central visual loss in the first 2 decades of life associated with an absent electrooculogram light rise, and a reduced electroretinogram. Genetic heterogeneity: Mutations in this gene may cause dominant phenotypes like Macular dystrophy, vitelliform, 2 ( OMIM 153700) and Vitreoretinochoroidopathy (193220).
BHLHA9Syndactyly, mesoaxial synostotic, with phalangeal reductionMesoaxial synostotic syndactyly with phalangeal reduction (MSSD) represents a distinctive combination of clinical features that includes mesoaxial osseous synostosis at a metacarpal level, reduction of one or more phalanges, hypoplasia of distal phalanges of preaxial and postaxial digits, clinodactyly of fifth fingers, and preaxial fusion of toes (Malik et al., 2014).
BIN1Centronuclear myopathy, type 2Centronuclear myopathy, type 2 is a congenital muscle disorder characterized by progressive muscular weakness and wasting involving mainly limb girdle, trunk, and neck muscles. It may also affect distal muscles. Weakness may be present during childhood or adolescence or may not become evident until the third decade of life. Ptosis is a frequent clinical feature. The most prominent histopathologic features include high frequency of centrally located nuclei in muscle fibers not secondary to regeneration, radial arrangement of sarcoplasmic strands around the central nuclei, and predominance and hypotrophy of type 1 fibers.
BLMBloom syndromeBloom syndrome is an autosomal recessive disorder characterized by proportionate pre- and postnatal growth deficiency; sun-sensitive, telangiectatic, hypo- and hyperpigmented skin; predisposition to malignancy; and chromosomal instability.
BLVRAHyperbiliverdinemiaHyperbiliverdinemia can manifest as green jaundice, which is a green discoloration of the skin, urine, serum, and other bodily fluids, due to increased biliverdin resulting from inefficient conversion to bilirubin. Although rarely reported, affected individuals appear to have symptoms only in the context of obstructive cholestasis and/or liver failure. In some cases, green jaundice can resolve after resolution of obstructive cholestasis. Green jaundice has also been associated with malnutrition, medication, and congenital biliary atresia (Huffman et al., 2009).
BMP1Osteogenesis imperfecta, type 13Osteogenesis imperfecta (OI) is a connective tissue disorder characterized by bone fragility and low bone mass. Due to considerable phenotypic variability, Sillence et al. (1979) developed a classification of OI subtypes based on clinical features and disease severity. OI type 13, an autosomal recessive form of the disorder characterized by normal teeth, faint blue sclerae, severe growth deficiency, borderline osteoporosis, and an average of 10 to 15 fractures a year affecting both upper and lower limbs and with severe bone deformity (Martinez-Glez et al., 2012).
BMP15Ovarian dysgenesis 2Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis 2. Ovarian dysgenesis 2 accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003). Most cases are associated with major X chromosome abnormalities. Accordingly, genetic studies have identified several loci at Xq and Xp11.2-p.22.1 whose functions are relevant for ovarian development (Zinn et al., 1998; Simpson and Rajkovic, 1999; Marozzi et al., 2000).
BMPERDiaphanospondylodysostosisDiaphanospondylodysostosis is a rare, recessively inherited, perinatal lethal skeletal disorder. The primary skeletal characteristics include small chest, abnormal vertebral segmentation, and posterior rib gaps containing incompletely differentiated mesenchymal tissue. Consistent craniofacial features include ocular hypertelorism, epicanthal folds, depressed nasal bridge with short nose, and low-set ears. The most commonly described extraskeletal finding is nephroblastomatosis with cystic kidneys, but other visceral findings have been described in some cases (Funari et al., 2010).
BMPR1BAcromesomelic dysplasia, Demirhan typeAcromesomelic dysplasia, Demirhan type (AMDD) is a form of chondrodysplasia. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers).
BOLA3Multiple mitochondrial dysfunctions syndrome 2 with hyperglycinemiaMultiple mitochondrial dysfunctions syndrome, type 2 (MMDS2) with hyperglycinemia is a severe autosomal recessive disorder characterized by developmental regression in infancy. Affected children have an encephalopathic disease course with seizures, spasticity, loss of head control, and abnormal movement. Additional more variable features include optic atrophy, cardiomyopathy, and leukodystrophy. Laboratory studies show increased serum glycine and lactate. Most patients die in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including MMDS2, appear to result from defects of mitochondrial lipoate biosynthesis (Baker et al., 2014).
BPGMErythrocytosis due to bisphosphoglycerate mutase deficiencyErythrocytosis due to bisphosphoglycerate mutase deficiency is characterized by hemolytic anemia, splenomegaly, cholelithiasis and cholecystitis.
BRAT1Rigidity and multifocal seizure syndrome, lethal neonatal; Neurodevelopmental disorder with cerebellar atrophy and with or without seizuresLethal neonatal rigidity and multifocal seizure syndrome is a severe autosomal recessive epileptic encephalopathy characterized by onset of rigidity and intractable seizures at or soon after birth. Affected infants achieve no developmental milestones and die within the first months or years of life (Saitsu et al., 2014). Biallelic mutations in the BRAT1 gene can also cause neurodevelopmental disorder with cerebellar atrophy and with or without seizures (NEDCAS), a somewhat less severe disorder with overlapping features. NEDCAS is an autosomal recessive disorder characterized by psychomotor developmental delay manifesting in infancy, cerebellar atrophy, decreased myelination, and seizures in most patients. Additional features include intellectual disability, ataxia or dyspraxia, hypertonia, hyperreflexia, poor or absent speech, microcephaly, subtle dysmorphisms, and visual impairment in some patients.
BRIP1Fanconi anemia, complementation group JFanconi anemia, complementation group J is a disorder affecting all bone marrow elements and resulting in anemia, leukopenia and thrombopenia. It is associated with cardiac, renal and limb malformations, dermal pigmentary changes, and a predisposition to the development of malignancies. At the cellular level it is associated with hypersensitivity to DNA-damaging agents, chromosomal instability (increased chromosome breakage) and defective DNA repair.
BRWD3Mental retardation, X-linked, type 93Mental retardation, X-linked, type 93 (MRX93) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX93 is associated with macrocephaly.
BSCL2Congenital generalized lipodystrophy, type 2; Encephalopathy, progressive, with or without lipodystrophyCongenital generalized lipodystrophy (also called Berardinelli-Seip congenital lipodystrophy) type 2 is a rare condition caused by pathogenic variants in the BSCL2 gene located on chromosomal region 11q12.3. Its characterized by an almost total absence of adipose tissue and a very muscular appearance. A shortage of adipose tissue leads to multiple health problems, including high levels of fats called triglycerides circulating in the bloodstream (hypertriglyceridemia) and diabetes mellitus. In some cases, this form of the condition is also associated with intellectual disability, which is usually mild to moderate. Progressive encephalopathy follows an autosomal recessive pattern of inheritance and is also caused by pathogenic variants in the BSCL2 gene. This is a severe neurodegenerative disorder characterized by developmental regression of motor and cognitive skills in the first years of life, often leading to death in the first decade. Patients may show a mild or typical lipodystrophic appearance.
BSNDBartter syndrome, type 4ABartter syndrome, type 4A with deafness follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BSND gene located on chromosomal region 1p32.3. The age of onset is neonatal/infantile. This disease is characterized by maternal polyhydramnios, premature delivery, polyuria, sensorineural deafness and is associated with hypokalemic alkalosis, increased levels of plasma renin and aldosterone, low blood pressure, and vascular resistance to angiotensin II.
BTDBiotinidase deficiencyBiotinidase deficiency an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the BTD gene located on chromosomal region 3p25. The age of onset is neonatal/infantile. This disease is characterized by seizures, breathing difficulties, hypotonia, skin rash, alopecia, hearing loss and delayed development.
BTKAgammaglobulinemia X-linked, type 1Agammaglobulinemia X-linked (XLA), type 1 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the BTK gene located on chromosomal region Xq21.33-q22. The age of onset is neonatal. Individuals with XLA are more susceptible to infections because their body makes very few antibodies. In children with XLA, infections generally take longer to get better and then they come back again, even with antibiotic medications. The most common bacterial infections that occur in people with XLA are lung infections (pneumonia and bronchitis), ear infections (otitis), pink eye (conjunctivitis), and sinus infections (sinusitis). Infections that cause chronic diarrhea are also common. Recurrent infections can lead to organ damage. The X-linked form accounts for approximately 85 to 90% of cases of agammaglobulinemia. The prevalence is 3:1,000,000-6:1,000,000 men.
BUB1BMosaic variegated aneuploidy syndrome 1Mosaic variegated aneuploidy is an autosomal recessive disorder characterized by mosaic aneuploidies, predominantly trisomies and monosomies, involving multiple different chromosomes and tissues. The proportion of aneuploid cells varies but is usually more than 25% and is substantially greater than in normal individuals. Affected individuals typically present with severe intrauterine growth retardation and microcephaly. Eye anomalies, mild dysmorphism, variable developmental delay, and a broad spectrum of additional congenital abnormalities and medical conditions may also occur. The risk of malignancy is high, with rhabdomyosarcoma, Wilms tumor, and leukemia reported in several cases (Hanks et al., 2004).
C12orf57Temtamy syndromeTemtamy syndrome is a mental retardation/multiple congenital anomaly syndrome characterized by variable craniofacial dysmorphism, ocular coloboma, seizures, and brain abnormalities, including abnormalities of the corpus callosum and thalamus (Akizu et al., 2013).
C12orf65Combined oxidative phosphorylation deficiency 7; Spastic paraplegia, type 55, autosomal recessiveCombined oxidative phosphorylation deficiency 7 (COXPD7) is a mitochondrial disease resulting in encephalomyopathy. Clinical manifestations include psychomotor delay and regression, ataxia, optic atrophy, nystagmus and muscle atrophy and weakness. Homozygous mutation in the C12ORF65 gene can also cause a less severe disorder, autosomal recessive spastic paraplegia-55 (SPG55). SPG55 is a form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. Complicated forms are recognized by additional variable features including spastic quadriparesis, seizures, dementia, amyotrophy, extrapyramidal disturbance, cerebral or cerebellar atrophy, optic atrophy, and peripheral neuropathy, as well as by extra neurological manifestations.
C19orf12Neurodegeneration with brain iron accumulation, type 4Neurodegeneration with brain iron accumulation, type 4 (NBIA4) is an autosomal recessive neurodegenerative disorder characterized by progressive spastic paraplegia, parkinsonism unresponsive to L-DOPA treatment, and psychiatric or behavioral symptoms. Other neurologic features, including optic atrophy, eye movement abnormalities, dystonia, dysphagia, dysarthria, and motor axonal neuropathy, may occur. Brain MRI shows T2-weighted hypointensities in the globus pallidus and substantia nigra. Onset is usually in the first 2 decades, but later onset has been reported (Dogu et al., 2013). There is phenotypic variation: some patients may not have extrapyramidal signs and may have muscle weakness and atrophy as well as cognitive impairment or developmental delay (Deschauer et al., 2012)
C1QAC1q deficiencyC1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).
C1QBC1q deficiencyC1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).
C1QCC1q deficiencyC1q deficiency is a rare autosomal recessive disorder characterized by recurrent skin lesions, chronic infections, and an increased risk of autoimmune diseases, particularly systemic lupus erythematosus (SLE; 152700) or SLE-like diseases. It has also been associated with chronic glomerulonephritis and renal failure. C1q deficiency presents in 2 different forms, absent C1q protein or presence of a dysfunctional molecule (Topaloglu et al., 1996; Vassallo et al., 2007).
C1SC1s deficiencyC1s deficiency is a rare defect resulting in impaired activation of the complement classical pathway. C1 deficiency generally leads to severe immune complex disease with features of systemic lupus erythematosus and glomerulonephritis.
C3Complement component 3 deficiencyC3 deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the C3 gene located on chromosomal region 19p13.3-p13.2. The age of onset is infantile. It is a rare defect of the complement classical pathway. The main clinical manifestation of primary C3 deficiency is childhood-onset of recurrent bacterial infections, mainly caused by gram-negative bacteria, such as Neisseria meningitidis, Enterobacter aerogenes, Haemophilus influenzae, and Escherichia coli; infections with gram-positive bacteria also occur. Infections in the upper and lower respiratory tract, including pneumonia, episodes of sinusitis, tonsillitis, and otitis, are the most frequent consequence of the C3 deficiency. Approximately 26% of patients with C3 deficiency develop immune complex-mediated autoimmune diseases resembling systemic lupus erythematosus, and about 26% of patients develop mesangiocapillary or membranoproliferative glomerulonephritis, resulting in renal failure (summary by Reis et al., 2006). The prevalence is <1:1.000.000.
C5Complement component 5 deficiencyC5 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.
C7Complement component 7 deficiencyC7 deficiency is a rare defect of the complement classical pathway associated with susceptibility to severe recurrent infections, predominantly by Neisseria gonorrhoeae or Neisseria meningitidis.
C8BComplement component 8 deficiency, type 2Patients with deficiency of C8 suffer from recurrent neisserial infections, predominantly with meningococcus infection of rare serotypes. Most such patients are discovered among those having their first episode of meningitis at ages older than 10 years (Ross and Densen, 1984).Two kinds of inherited C8 deficiency have been reported in man: type 1, in which only C8 alpha and C8 gamma are deficient, and type 2 (613789), in which only C8 beta (C8B; 120960) is deficient (Marcus et al., 1982; Tedesco et al., 1983). The 2 types are clinically indistinguishable (Ross and Densen, 1984).
C8orf37Bardet-Biedl syndrome, type 21; Cone-rod dystrophy 16 and Retintis pigmentosa 64Bardet-Biedl syndrome 21 (BBS21) is an autosomal recessive ciliopathy characterized by obesity, postaxial polydactyly, retinal degeneration, and mild cognitive impairment (Heon et al., 2016; Khan et al., 2016). Mutation in the C8ORF37 gene can also cause cone-rod dystrophy (CORD16) and isolated retinitis pigmentosa (RP64). CORD16 and RP64 are clinically and genetically overlapping heterogeneous retinal dystrophies. RP is characterized initially by rod photoreceptor dysfunction, giving rise to night blindness, which is followed by progressive rod and cone photoreceptor dystrophy, resulting in midperipheral vision loss, tunnel vision, and sometimes blindness. In contrast to RP, CORD is characterized by a primary loss of cone photoreceptors and subsequent or simultaneous loss of rod photoreceptors. The disease in most cases becomes apparent during primary-school years, and symptoms include photoaversion, decrease in visual acuity with or without nystagmus, color vision defects, and decreased sensitivity of the central visual field. Because rods are also involved, night blindness and peripheral vision loss can occur. The diagnosis of CORD is mainly based on electroretinogram (ERG) recordings, in which cone responses are more severely reduced than, or equally as reduced as rod responses (Estrada-Cuzcano et al., 2012).
CA12Hyperchlorhidrosis, isolatedIsolated hyperchlorhidrosis is an autosomal recessive condition in which excessive salt wasting in sweat can result in severe infantile hyponatremic dehydration and hyperkalemia (Muhammad et al., 2011).
CA2Osteopetrosis with renal tubular acidosis (osteopetrosis, autosomal recessive, type 3)Osteopetrosis with renal tubular acidosis, also known as osteopetrosis, autosomal recessive, type 3, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CA2 gene located on chromosomal region 8q22. The age of onset is neonatal/infantile. This disease is characterized by osteopetrosis, renal tubular acidosis, and neurological disorders related to cerebral calcifications. The prevalence is <1:1.000.000.
CABP4Congenital stationary night blindness, type 2BCongenital nonprogressive cone-rod synaptic disorder is characterized by stable low vision, nystagmus, photophobia, a normal or near-normal fundus appearance, and no night blindness. Electroretinography shows an electronegative waveform response to scotopic bright flash, near-normal to subnormal rod function, and delayed and/or decreased to nonrecordable cone responses (Traboulsi, 2013; Khan, 2014).
CACNA1DSinoatrial node dysfunction and deafnessPatients with sinoatrial node dysfunction and deafness have congenital severe to profound deafness without vestibular dysfunction, associated with episodic syncope due to intermittent pronounced bradycardia (Baig et al., 2011).
CACNA1FCone-rod dystrophy, X-linked, type 3; Night blindness, congenital stationary, type 2A; Aland Island eye diseaseCone-rod dystrophy is a retinal disorder with predominantly cone involvement. Rod impairment may occur at the same time as the cone impairment or appear later. Patients with CORD usually have reduced visual acuity, photophobia, and color vision defects (Huang et al., 2013). Mutation in the CACNA1F gene can also cause Aland Island eye disease (AIED) and X-linked incomplete congenital stationary night blindness (CSNB2A). AIED is an X-linked recessive retinal disease characterized by fundus hypopigmentation, decreased visual acuity, nystagmus, astigmatism, protan color vision defect (303900), progressive myopia, and defective dark adaptation. Although AIED has been referred to as a form of albinism, there is no misrouting of the optic nerves, which excludes it from the formal diagnosis of classic albinism (King et al., 2001). CSNB2A is a nonprogressive retinal disorder characterized by decreased visual acuity and loss of night vision. All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa.

All affected members of the family mapped by Bergen et al. (1996) to Xp21.1 had myopia and a fine horizontal nystagmus. None of them experienced deterioration, during an average follow-up of 5 years, of their visual acuity or ERG recordings. The 6 obligate carriers and 1 possible carrier had normal visual acuity, no myopia, and no abnormalities on ERG. The affected males, apart from night blindness as shown by the dark adaptation curves, had no clinical or electrophysiologic signs of retinitis pigmentosa.
CANT1Desbuquois dysplasia, type 1; Epiphyseal dysplasia, multiple, type 7Desbuquois dysplasia (DBQD) is an autosomal recessive chondrodysplasia belonging to the multiple dislocation group and characterized by severe prenatal and postnatal growth retardation (stature less than -5 SD), joint laxity, short extremities, and progressive scoliosis. The main radiologic features are short long bones with metaphyseal splay, a 'Swedish key' appearance of the proximal femur (exaggerated trochanter), and advanced carpal and tarsal bone age with a delta phalanx (Huber et al., 2009).Desbuquois dysplasia is clinically and radiographically heterogeneous, and had been classified into 2 types based on the presence (type 1) or absence (type 2) of characteristic hand anomalies, including an extra ossification center distal to the second metacarpal, delta phalanx, bifid distal thumb phalanx, and dislocation of the interphalangeal joints (Faivre et al., 2004). However, patients with and without these additional hand anomalies have been reported to have mutations in the same gene (see, e.g., CANT1); thus, these features are not distinctive criteria to predict the molecular basis of DBQD (Furuichi et al., 2011). In addition, Kim et al. (2010) described another milder variant of DBQD with almost normal outwardly appearing hands, but significant radiographic changes, including short metacarpals, elongated phalanges, and remarkably advanced carpal bone age. However, there is no accessory ossification center distal to the second metacarpal, and patients do not have thumb anomalies. Similar changes occur in the feet. These patients also tend to develop precocious osteoarthritis of the hand and spine with age. This phenotype is sometimes referred to as the 'Kim variant' of DBQD (Furuichi et al., 2011). Other forms of skeletal dysplasia caused by mutation in the CANT1 gene include epiphyseal dysplasia, type 7 (EDM7). EDM7 is a form of multiple epiphyseal dysplasia, a generalized skeletal dysplasia associated with significant morbidity. Joint pain, joint deformity, waddling gait, and short stature are the main clinical signs and symptoms. Radiological examination of the skeleton shows delayed, irregular mineralization of the epiphyseal ossification centers and of the centers of the carpal and tarsal bones. Multiple epiphyseal dysplasia is broadly categorized into the more severe Fairbank and the milder Ribbing types. The Fairbank type is characterized by shortness of stature, short and stubby fingers, small epiphyses in several joints, including the knee, ankle, hand, and hip. The Ribbing type is confined predominantly to the hip joints and is characterized by hands that are normal and stature that is normal or near-normal. EDM7 inheritance is autosomal recessive.
CAPN3Limb-girdle muscular dystrophy, type 1 (LGMD R1)Limb-girdle muscular dystrophy type 1 (LGMDR1; formerly LGMD2A) follows an autosomal recessive pattern of inheritance and is caused by biallelic pathogenic variants in the CAPN3 gene located on chromosomal region 15q15.1. The age of onset is variable. This disease is characterized by a variable age of onset of progressive, typically symmetrical and selective weakness and atrophy of proximal shoulder- and pelvic-girdle muscles (gluteus maximus, thigh adductors, and muscles of the posterior compartment of the limbs are most commonly affected) without cardiac or facial involvement. Clinical manifestations include exercise intolerance, a waddling gait, scapular winging and calf pseudo-hypertrophy.The prevalence is 1:100,000- 9:100,000. Genetic heterogeneity: Heterozygous mutation in the CAPN3 gene can cause autosomal dominant limb-girdle muscular dystrophy-4 (LGMDD4; OMIM 618129), which has a later onset and milder features.
CARD9Candidiasis, familial, type 2, autosomal recessiveCandidiasis, familial, type 2, autosomal recessive is a primary immunodeficiency disorder with altered immune responses and impaired clearance of fungal infections, selective against Candida. It is characterized by persistent and/or recurrent infections of the skin, nails and mucous membranes caused by organisms of the genus Candida, mainly Candida albicans.
CASKMental retardation, X-linked, syndromic, Najm typeMental retardation, X-linked, syndromic, Najm type is an X-linked disorder affecting females and characterized by severe intellectual disability, microcephaly, and variable degrees of pontocerebellar hypoplasia. Affected individuals have very poor psychomotor development, often without independent ambulation or speech, and axial hypotonia with or without hypertonia. Some may have sensorineural hearing loss or eye anomalies. Dysmorphic features include overall poor growth, severe microcephaly (-3.5 to -10 SD), broad nasal bridge and tip, large ears, long philtrum, micrognathia, and hypertelorism (Moog et al., 2011).
CASQ2Ventricular tachycardia, catecholaminergic polymorphic, type 2Ventricular tachycardia, catecholaminergic polymorphic, type 2 is an arrhythmogenic disorder characterized by stress-induced, bidirectional ventricular tachycardia that may degenerate into cardiac arrest and cause sudden death. Patients present with recurrent syncope, seizures, or sudden death after physical activity or emotional stress.
CASRHyperparathyroidism, neonatalNeonatal severe hyperparathyroidism usually manifests in the first 6 months of life with severe hypercalcemia, bone demineralization, and failure to thrive. Early diagnosis is critical because untreated NSHPT can be a devastating neurodevelopmental disorder, which in some cases is lethal without parathyroidectomy. Some infants have milder hyperparathyroidism and a substantially milder clinical presentation and natural history (Egbuna and Brown, 2008).
CASTPeeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle padsPeeling skin with leukonychia, acral punctate keratoses, cheilitis, and knuckle pads is an autosomal recessive disease characterized by generalized, continuous shedding of the outer layers of the epidermis, leukonychia, acral punctate keratosis, cheilitis, knuckle pads with multiple hyperkeratotic micropapules involving the interphalangeal joints, and palmoplantar keratoderma.
CATSPER1Male infertility spermatogenic failure, type 7Spermatogenic failure, type 7 is an infertility disorder characterized by non-motile sperm or sperm motility below the normal threshold, low sperm count, increased abnormally structured spermatozoa, and reduced semen volume.
CAVIN1Lipodystrophy, congenital generalized, type 4Congenital generalized lipodystrophy type 4 combines the phenotype of classic Berardinelli-Seip lipodystrophy (608594) with muscular dystrophy and cardiac conduction anomalies (Hayashi et al., 2009).
CBSHomocystinuria due to cystathionine beta-synthaseHomocystinuria due to cystathionine beta-synthase follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CBS gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by the multiple involvement of the eye, skeleton, central nervous system and vascular system. The prevalence is 1:200,000-1:335,000.
CC2D1AMental retardation, autosomal recessive, type 3Mental retardation, autosomal recessive, type 3 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs.
CC2D2AJoubert syndrome type 9Joubert syndrome type 9 defect follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CC2D2A gene located on chromosomal region 4p15.32. The age of onset is neonatal/infantile. This disease is characterized neonatal hypotonia, developmental delay, intellectrual disability, ataxia, and abnormal eye movements including oculomotor apraxia, primary position nystagmus and congenital hepatic fibrosis.
CCBE1Hennekam lymphangiectasia-lymphedema syndrome, type 1Hennekam lymphangiectasia-lymphedema syndrome is an autosomal recessive disorder characterized by generalized lymphatic dysplasia affecting various organs, including the intestinal tract, pericardium, and limbs. Additional features of the disorder include facial dysmorphism and cognitive impairment (Alders et al., 2014).
CCDC103Ciliary dyskinesia, primary, type 17Ciliary dyskinesia, primary, type 17 (CILD17) is an autosomal recessive disorder characterized by early infantile onset of respiratory distress associated with a defect in the function of ciliary outer dynein arms. Situs inversus is variable (Panizzi et al., 2012).
CCDC39Ciliary dyskinesia, primary, type 14Ciliary dyskinesia, primary, type 14 (CILD14) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Merveille et al., 2011).
CCDC40Ciliary dyskinesia, primary, type 15Ciliary dyskinesia, primary, type 15 (CILD15) is an autosomal recessive disorder characterized by recurrent respiratory infections associated with defects in ciliary inner dynein arms and axonemal disorganization (Becker-Heck et al., 2011).
CCDC88CHydrocephalus, congenital, type 1Hydrocephalus, congenital, type 1 is characterized by onset in utero of enlarged ventricles due to a disturbance of cerebrospinal fluid accumulation. Affected individuals may have neurologic impairment (Drielsma et al., 2012).Hydrocephalus can also be caused by Arnold-Chiari malformation, atresia of foramen of Magendie, stenosis of aqueduct of Sylvius (307000), toxoplasmosis, hydranencephaly, etc. Furthermore, it develops in infancy or childhood in achondroplasia (100800) and in Hurler disease (607014).
CD19Immunodeficiency, common variable, type 3Immunodeficiency, common variable, type 3 is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.
CD27Lymphoproliferative syndrome 2Lymphoproliferative syndrome ,type 2, also known as CD27 deficiency, is an autosomal recessive immunodeficiency disorder associated with persistent symptomatic EBV viremia, hypogammaglobulinemia, and impairment in specific antibody function resulting from impaired T cell-dependent B-cell responses and T-cell dysfunction (van Montfrans et al., 2012). The phenotype can vary significantly, from asymptomatic borderline-low hypogammaglobulinemia, to a full-blown symptomatic systemic inflammatory response with life-threatening EBV-related complications, including hemophagocytic lymphohistiocytosis, a lymphoproliferative disorder, and malignant lymphoma requiring stem cell transplantation (Salzer et al., 2013).
CD3DImmunodeficiency, type 19Immunodeficiency, type 19 is an autosomal recessive form of severe combined immunodeficiency (SCID) characterized by onset in early infancy of recurrent bacterial, viral, and fungal infections. Patients usually have chronic diarrhea, recurrent respiratory infections, and failure to thrive. Immunologic work-up shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype. The disorder is lethal in early childhood without bone marrow transplantation (Yu et al., 2011).
CD3EImmunodeficiency, type 18Immunodeficiency, type 18 is an autosomal recessive primary immunodeficiency characterized by onset in infancy or early childhood of recurrent infections. The severity is variable, encompassing both a mild immunodeficiency and severe combined immunodeficiency (SCID), resulting in early death without bone marrow transplantation in some patients. Immunologic work-up of the IMD18 SCID patients shows a T cell-negative, B cell-positive, natural killer (NK) cell-positive phenotype, whereas T-cell development is not impaired in the mild form of IMD18 (de Saint Basile et al., 2004).
CD3GImmunodeficiency, type 17, CD3 gamma deficientImmunodeficiency, type 17 is an autosomal recessive primary immunodeficiency characterized by highly variable clinical severity. Some patients have onset of severe recurrent infections in early infancy that may be lethal, whereas others may be only mildly affected or essentially asymptomatic into young adulthood. More severely affected patients may have evidence of autoimmune disease or enteropathy. The immunologic pattern is similar among patients, showing partial T-cell lymphopenia, particularly of cytotoxic CD8 (186910)-positive cells, decreased amounts of the CD3 complex, and impaired proliferative responses to T-cell receptor (TCR)-dependent stimuli. B cells, natural killer (NK) cells, and immunoglobulins are usually normal. Although thymic output of functional naive T cells early in life is decreased, polyclonal expansion of functional memory T cells is substantial. The phenotype in some patients is reminiscent of severe combined immunodeficiency (SCID) (Timon et al. (1993) and Recio et al. (2007)).
CD40Immunodeficiency with hyper-IgM, type 3Immunodeficiency with hyper-IgM, type 3 (HIGM3), first described in humans by Ferrari et al. (2001), is characterized by hypogammaglobulinemia with normal or elevated levels of IgM.
CD40LGHyper-IgM syndrome, type 1 (immunodeficiency, X-linked, with hyper-IgM, type 1)Hyper-IgM syndrome, type 1, also known as X-linked immunodeficiency with hyper-IgM, type 1 (HIGM1) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the CD40LG gene located on chromosomal region Xq26. The age of onset is neonatal/infantile. This disease is characterized by lower-respiratory tract bacterial infections, opportunistic infections, recurrent or protracted diarrhea associated with failure to thrive, neutropenia, thrombocytopenia and anemia. The prevalence is 2:1,000,000 male newborns.
CD55Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy (CHAPLE)Complement hyperactivation, angiopathic thrombosis, and protein-losing enteropathy is characterized by abdominal pain and diarrhea, primary intestinal lymphangiectasia, hypoproteinemic edema, and malabsorption. Some patients also exhibit bowel inflammation, recurrent infections associated with hypogammaglobulinemia, and/or angiopathic thromboembolic disease. Patient T lymphocytes show increased complement activation, causing surface deposition of complement and generating soluble C5a (Ozen et al., 2017).
CD59CD59 DeficiencyHemolytic anemia, CD59-mediated, with or without immune-mediated polyneuropathy is an autosomal recessive disorder characterized by infantile onset of a relapsing-remitting polyneuropathy, often exacerbated by infection, and manifest as hypotonia, limb muscle weakness, and hyporeflexia. Immunosuppressive treatment may result in some clinical improvement (Nevo et al., 2013).
CD79AAgammaglobulinemia 3Agammaglobulinemia 3 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.
CD79BAgammaglobulinemia 6Agammaglobulinemia 6 is a primary immunodeficiency characterized by profoundly low or absent serum antibodies and low or absent circulating B-cells due to an early block of B-cell development. Affected individuals develop severe infections in the first years of life.
CD81Immunodeficiency, common variable, type 6Immunodeficiency, common variable, type 6 (CVID6) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.
CD8ACD8 deficiency, familialCD8 deficiency, familial is a immunologic defect characterized by absence of CD8+ cells, leading to recurrent bacterial infections.
CDAN1Dyserythropoietic anemia, congenital, type 1ADyserythropoietic anemia, congenital, type 1A is a rare inherited red blood cell disorder characterized by macrocytic anemia, ineffective erythropoiesis, and secondary hemochromatosis. It is occasionally associated with bone abnormalities, especially of the hands and feet (acrodysostosis), nail hypoplasia, and scoliosis (Tamary et al., 2005). Striking morphologic abnormalities of erythroblasts, reviewed by Wickramasinghe and Wood (2005), include the 'Swiss-cheese' abnormality of erythroblasts on electron microscopy.Four types of CDA, all of which show show ineffective erythropoiesis and multinuclear erythroblasts, have been characterized by clinical and hematopoietic findings. The classification of the first 3 types is based on that described by Wendt and Heimpel (1967). Type 1 is characterized by megaloblastic changes. The more common type 2 (224100) is characterized by normocytic binuclear or multinuclear red cells, which on electron microscopy contain double cytoplasmic membranes. Type 3 (105600), which shows autosomal dominant inheritance, has prominent erythroblastic multinuclearity forming 'gigantoblasts' with up to 12 nuclei. Type 4 (613673) is the designation given to a form of CDA with characteristics different from those of types 1, 2 and 3 (Wickramasinghe et al., 1991; Arnaud et al., 2010).
CDH23Deafness, autosomal recessive, type 12; Usher syndrome, type 1DNon-syndromic autosomal recessive deafness, type 12 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH23 gene located on chromosomal region 10p22.1. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. Mutation in the CDH23 gene can also cause the more severe Usher syndrome 1D. Usher syndrome type 1 is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction.
CDH3Ectodermal dysplasia, ectrodactyly, and macular dystrophyEctodermal dysplasia, ectrodactyly, and macular dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDH3 gene located on chromosomal region 16q22.1. The age of onset is neonatal/infantile. This disease is characterized by the association of ectodermal dysplasia, ectrodactyly, and macular dystrophy. The prevalence is <1:1,000,000.
CDHR1Cone-rod dystrophy, type 15Cone-rod dystrophy, type 15 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDHR1 gene located on chromosomal region 10q23.1. This disease is characterized by decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. The overall prevalence of all types of cone-rod dystrophy is 1-9:100,000.
CDK5RAP2Primary microcephaly type 3, autosomal recessivePrimary autosomal recessive microcephaly type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CDK5RAP2 gene located on chromosomal region 9q33.2. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.
CDKL5Epileptic encephalopathy, early infantile, type 2Epileptic encephalopathy, early infantile, type 2 (EIEE2) is an X-linked dominant severe neurologic disorder characterized by onset of seizures in the first months of life and severe global developmental delay resulting in mental retardation and poor motor control. Other features include lack of speech development, subtle dysmorphic facial features, sleep disturbances, gastrointestinal problems, and stereotypic hand movements. There is some phenotypic overlap with Rett syndrome (312750), but EIEE2 is considered to be a distinct entity (Fehr et al., 2013).
CDT1Meier-Gorlin syndrome, type 4Meier-Gorlin syndrome 4 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.
CENPJPrimary microcephaly type 6, autosomal recessivePrimary autosomal recessive microcephaly type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CENPJ gene located on chromosomal region 13q12.12.?The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.
CEP135Microcephaly 8, primary, autosomal recessiveMicrocephaly 8, primary, autosomal recessive is a disease defined as a head circumference more than 3 standard deviations below the age-related mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small. Despite this marked reduction in size, the gyral pattern is relatively well preserved, with no major abnormality in cortical architecture. Affected individuals present mental retardation. Primary microcephaly is further defined by the absence of other syndromic features or significant neurological deficits due to degenerative brain disorder.
CEP152Primary microcephaly type 9, autosomal recessivePrimary autosomal recessive microcephaly type 9 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP152 gene located on chromosomal region 15q21.1. The age of onset is neonatal/infantile. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment.
CEP290Meckel syndrome, type 4; Joubert syndrome, type 5; Leber congenital amaurosis, type 10Meckel syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CEP290 gene located on chromosomal region 12q21.32. The age of onset is neonatal. This disease is characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically occipital encephalocele), hepatic ductal dysplasia and cysts, and postaxial polydactyly. The prevalence is <1/1,000,000. Other ciliopathies are associated with mutation in CEP290 gene as Joubert syndrome, type 5 and Leber congenital amaurosis, type 10. Joubert syndrome (JBTS) is an autosomal recessive disorder presenting with psychomotor delay, hypotonia, ataxia, oculomotor apraxia, and neonatal breathing abnormalities (Valente et al., 2006). Leber congenital amaurosis is a severe retinal dystrophy, causing blindness or severe visual impairment at birth or during the first months of life (den Hollander et al., 2006).
CEP41Joubert syndrome, type 15Joubert syndrome, type 15 is an autosomal recessive developmental disorder characterized by ataxia, hypotonia, delayed psychomotor development, and variable mental retardation. Other features, such as polydactyly, breathing abnormalities, and oculomotor apraxia, are variable (Lee et al., 2012).
CEP57Mosaic variegated aneuploidy syndrome 2Mosaic variegated aneuploidy syndrome is an autosomal recessive disorder characterized by poor growth and variable phenotypic manifestations, such as facial dysmorphism and congenital heart defects, associated with mosaic aneuploidies resulting from defects in cell division (Snape et al., 2011).
CERKLRetinitis pigmentosa, type 26Retinitis pigmentosa, type 26 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CERKL gene located on chromosomal region 2q31.3. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.
CFDComplement factor D deficiencyComplement factor D deficiency is an autosomal recessive immunologic disorder characterized by increased susceptibility to bacterial infections, particularly Neisseria infections, due to a defect in the alternative complement pathway (Biesma et al., 2001).
CFHComplement factor H deficiencyComplement factor H deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFH gene located on chromosomal region 1q32. This disease is characterized by increased susceptibility to recurrent, usually severe, infections (particularly by Neisseria meningitidis, Escherichia coli, and Haemophilus influenzae), renal impairment and/or autoimmune diseases.
CFIComplement factor I deficiencyHereditary deficiency of complement factor I is associated with a propensity to pyogenic infection and follows an autosomal recessive pattern of inheritance (Vyse et al., 1996).
CFL2Nemaline myopathy, type 7, autosomal recessiveNemaline myopathy, type 7 is an autosomal recessive congenital myopathy characterized by very early onset of hypotonia and delayed motor development. Affected individuals have difficulty walking and running due to proximal muscle weakness. The disorder is slowly progressive, and patients may lose independent ambulation. Muscle biopsy shows nemaline rods and may later show minicores, abnormal protein aggregates, and dystrophic changes (Ockeloen et al., 2012).
CFPProperdin deficiency, X-linkedProperdin (factor P) is a plasma protein that is active in the alternative complement pathway of the innate immune system. It is a positive regulatory factor that binds to many microbial surfaces to stabilize the C3b,Bb convertase. Deficiency of properdin is associated in particular with a heightened susceptibility to Neisseria species (Janeway et al., 2001).
CFTRCystic fibrosisCystic fibrosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CFTR gene located on chromosomal region 7q31.2. The age of onset of severe form is neonatal or infantile but there are also variants associated with moderate clinical or late onset. This disease is characterized by the production of sweat with a high salt content, mucus secretions with an abnormal viscosity, chronic bronchitis, pancreatic insufficiency, adolescent diabetes and, more rarely, stercoral obstruction and cirrhosis. Male sterility is a constant feature. Late-onset forms, which are usually only mild or monosymptomatic. The prevalence is 1:10,000-9:10,000.
CHATMyasthenic syndrome, congenital, type 6, presynapticCongenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Myasthenic syndrome, congenital, type 6, presynaptic (CMS6) is an autosomal recessive CMS resulting from a presynaptic defect; patients have onset of symptoms in infancy or early childhood and tend to have sudden apneic episodes. Treatment with acetylcholinesterase inhibitors may be beneficial (Engel et al., 2015).
CHKBMuscular dystrophy, congenital, megaconial typeMuscular dystrophy, congenital, megaconial type is a form of autosomal recessive congenital muscular dystrophy characterized by early-onset muscle wasting and mental retardation. Some patients develop fatal cardiomyopathy. Muscle biopsy shows peculiar enlarged mitochondria that are prevalent toward the periphery of the fibers but are sparse in the center (Mitsuhashi et al., 2011).
CHMChoroideremiaChoroideremia is an X-linked disease that leads to the degeneration of the choriocapillaris, the retinal pigment epithelium, and the photoreceptor of the eye (Cremers et al., 1990). The characteristic lesion of choroideremia is chorioretinal scalloped atrophy in the midperipheral fundus, with preservation of the macula (Li et al., 2014).
CHRDL1Megalocornea 1, X-linkedMegalocornea is an inherited eye disorder in which the corneal diameter is bilaterally enlarged (greater than 13 mm) without an increase in intraocular pressure. It may also be referred to as 'anterior megalophthalmos,' since the entire anterior segment is larger than normal. Features of megalocornea in addition to a deep anterior chamber include astigmatic refractive errors, atrophy of the iris stroma, miosis secondary to decreased function of the dilator muscle, iridodonesis, and tremulousness, subluxation, or dislocation of the lens. Whereas most affected individuals exhibit normal ocular function, complications include cataract development and glaucoma following lenticular dislocation or subluxation. X-linked recessive inheritance is the most common pattern, accounting for the male preponderance of the disorder (Skuta et al., 1983).Megalocornea sometimes occurs as part of the Marfan syndrome (154700).
CHRNDMyasthenic syndrome, congenital, type 3B, fast-channel; Multiple pterygium syndrome, lethal typeFast-channel congenital myasthenic syndrome (FCCMS) is a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the acetylcholine receptor channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutations in CHRND gene can also caused multiple pterygium syndrome, lethal type (LMPS). LMPS is a multiple pterygia are found infrequently in children with arthrogryposis and in fetuses with fetal akinesia syndrome. In lethal multiple pterygium syndrome there is intrauterine growth retardation, multiple pterygia, and flexion contractures causing severe arthrogryposis and fetal akinesia. Subcutaneous edema can be severe, causing fetal hydrops with cystic hygroma and lung hypoplasia. Oligohydramnios and facial anomalies are frequent.
CHRNEMyasthenic syndrome, congenital, type 4B, fast-channel; Myasthenic syndrome, congenital, type 4C, associated with acetylcholine receptor deficiencyCongenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic, as well as by pathologic mechanism and electrophysiologic studies (i.e., acetylcholine receptor (AChR) deficiency, slow-channel or fast-channel kinetic defects at the AChR) ( Engel et al., 2003; Engel et al., 2015). Mutations in the CHRNE gene cause fast-channel congenital myasthenic syndrome (FCCMS), a disorder of the postsynaptic neuromuscular junction (NMJ) characterized by early-onset progressive muscle weakness. The disorder results from kinetic abnormalities of the AChR channel, specifically from abnormally brief opening and activity of the channel, with a rapid decay in endplate current and a failure to reach the threshold for depolarization. Treatment with pyridostigmine or amifampridine may be helpful; quinine, quinidine, and fluoxetine should be avoided (Sine et al., 2003 and Engel et al., 2015). Mutation in the CHRNE gene can also cause congenital myasthenic syndrome, type 4C (CMS4C) associated with acetylcholine receptor (AChR) deficiency. CMS4C associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients with mutations in the CHRNE gene may have compensatory increased expression of the fetal subunit CHRNG (100730) and may respond to treatment with cholinergic agents, pyridostigmine, or amifampridine (Engel et al., 2015).
CHRNGMultiple pterygium syndrome (MPS), Escobar type; MPS, lethal typeMultiple pterygium syndromes (MPS) comprise a group of multiple congenital anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis) (Morgan et al., 2006). The multiple pterygium syndromes are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types.
In people with MPS, Escobar type, the webbing typically affects the skin of the neck, fingers, forearms, inner thighs, and backs of the knee. People with this type may also have arthrogryposis. A side-to-side curvature of the spine (scoliosis) is sometimes seen. Affected individuals may also have respiratory distress at birth due to underdeveloped lungs (lung hypoplasia). People with Escobar type usually have distinctive facial features including droopy eyelids (ptosis), outside corners of the eyes that point downward (downslanting palpebral fissures), skin folds covering the inner corner of the eyes (epicanthal folds), a small jaw, and low-set ears. Males with this condition can have undescended testes (cryptorchidism). This condition does not worsen after birth, and affected individuals typically do not have muscle weakness later in life.
Lethal MPS has many of the same signs and symptoms as the Escobar type. In addition, affected fetuses may develop a buildup of excess fluid in the body (hydrops fetalis) or a fluid-filled sac typically found on the back of the neck (cystic hygroma). Individuals with this type have severe arthrogryposis. Lethal type is associated with abnormalities such as underdevelopment (hypoplasia) of the heart, lung, or brain; twisting of the intestines (intestinal malrotation); kidney abnormalities; an opening in the roof of the mouth (a cleft palate); and an unusually small head size (microcephaly). Affected individuals may also develop a hole in the muscle that separates the abdomen from the chest cavity (the diaphragm), a condition called a congenital diaphragmatic hernia. Lethal multiple pterygium syndrome is typically fatal in the second or third trimester of pregnancy.
CHST14Ehlers-Danlos syndrome, musculocontractural, type 1The Ehlers-Danlos syndromes (EDS) are a group of heritable connective tissue disorders that share the common features of skin hyperextensibility, articular hypermobility, and tissue fragility (Beighton et al., 1998).The major characteristics of the musculocontractural form of EDS include distinctive craniofacial dysmorphism, congenital contractures of thumbs and fingers, clubfeet, severe kyphoscoliosis, muscular hypotonia, hyperextensible thin skin with easy bruisability and atrophic scarring, wrinkled palms, joint hypermobility, and ocular involvement (Malfait et al., 2010). Janecke et al. (2015) reviewed the clinical findings in 34 reported EDSMC patients, 31 with CHST14 mutations and 3 with DSE (605942) mutations (615539), and stated that the disorder can be recognized based on the presence of distal arthrogryposis, including adducted thumbs or clenched fists and talipes equinovarus, as well as hands with atypically shallow palmar creases and tapering fingers, and neonatal muscular hypotonia. Characteristic craniofacial features include brachycephaly, large fontanel, hypertelorism, downslanting palpebral fissures, microcorneae, strabismus, prominent nasolabial folds, short philtrum, thin upper lip, small mouth, high palate, microretrognathia, and prominent and often low-set and posteriorly rotated ears. In addition, EDSMC patients show muscular hypoplasia and weakness, which has been confirmed by ultrasound and electromyography, and intellectual development appears to be normal.
CHST3Spondyloepiphyseal dysplasia with congenital joint dislocationsAlthough patients with mutations in the CHST3 gene may initially be given varying diagnostic labels, they have similar clinical features, including dislocation of the knees and/or hips at birth, clubfoot, elbow joint dysplasia with subluxation and limited extension, short stature, and progressive kyphosis developing in late childhood. The disorder is usually evident at birth, with short stature and multiple joint dislocations or subluxations that dominate the neonatal clinical and radiographic picture, and affected individuals may receive an initial clinical diagnosis of Larsen syndrome (245600) or humerospinal dysostosis. During childhood, the dislocations improve, both spontaneously and with surgical treatment, and features of spondyloepiphyseal dysplasia become apparent, leading to arthritis of the hips and spine with intervertebral disc degeneration, rigid kyphoscoliosis, and trunk shortening by late childhood; at this stage, the clinical features are those previously described as the Omani type of SED (Unger et al., 2010).
CHST6Macular corneal dystrophyMacular corneal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CHST6 gene located on chromosomal region 16q22. The age of onset is variable. This disease is characterized by bilateral ill-defined cloudy regions within a hazy stroma, and eventually severe visual impairment. The prevalence is 1:100,000-9:100,000.
CHSY1Temtamy preaxial brachydactyly syndromeTemtamy preaxial brachydactyly syndrome (TPBS)is a syndrome characterized by multiple congenital anomalies, mental retardation, sensorineural deafness, talon cusps of upper central incisors, growth retardation, and bilateral symmetric digital anomalies mainly in the form of preaxial brachydactyly and hyperphalangism.
CHUKCocoon syndromeCocoon syndrome (COCOS) is a lethal syndrome characterized by multiple fetal malformations including defective face and seemingly absent limbs, which are bound to the trunk and encased under the skin.
CIB2Deafness, autosomal recessive, type 48; Usher syndrome, type 1JDeafness, autosomal recessive, type 48 (DFNB48) is an autosomal recessive form of deafness. Affected individuals have prelingual onset of severe to profound sensorineural hearing loss affecting all frequencies. Riazuddin et al. (2012) estimated that CIB2 mutations may account for up to 7.25% of Pakistani families with autosomal recessive deafness. Mutations in CIB2 gene are also associated with Usher syndrome, type 1J (USH1J), a form of USH. This disease is a genetically heterogeneous condition characterized by the association of retinitis pigmentosa with sensorineural deafness. Age at onset and differences in auditory and vestibular function distinguish Usher syndrome type 1 (USH1), Usher syndrome type 2 (USH2) and Usher syndrome type 3 (USH3). USH1 is characterized by profound congenital sensorineural deafness, absent vestibular function and prepubertal onset of progressive retinitis pigmentosa leading to blindness.
CIITABare lymphocyte syndrome, type 2, complementation group ABare lymphocyte syndrome type 2 (BLS II) is an inherited disorder of the immune system categorized as a form of combined immunodeficiency (CID). People with BLS II lack virtually all immune protection from bacteria, viruses, and fungi. They are prone to repeated and persistent infections that can be very serious or life-threatening. These infections are often caused by "opportunistic" organisms that ordinarily do not cause illness in people with a normal immune system. BLS 2 is typically diagnosed in the first year of life. Most affected infants have persistent infections in the respiratory, gastrointestinal, and urinary tracts. Because of the infections, affected infants have difficulty absorbing nutrients (malabsorption), and they grow more slowly than their peers. Eventually, the persistent infections lead to organ failure. Without treatment, individuals with BLS 2 usually do not survive past early childhood.
CISD2Wolfram syndrome 2Wolfram syndrome-2 is an autosomal recessive neurodegenerative disorder characterized by diabetes mellitus, high frequency sensorineural hearing loss, optic atrophy or neuropathy, and defective platelet aggregation resulting in peptic ulcer bleeding (Mozzillo et al., 2014).
CLCF1Cold-induced sweating syndrome 2Cold-induced sweating syndrome is an autosomal recessive disorder characterized in the neonatal period by orofacial weakness with impaired sucking and swallowing resulting in poor feeding necessitating medical intervention. Affected infants show a tendency to startle, with contractions of the facial muscles in response to tactile stimuli or during crying, trismus, abundant salivation, and opisthotonus. During the first year, most infants have spiking fevers. These features, referred to as 'Crisponi syndrome' in infancy, can result in early death without advanced care. After the first 2 years, the abnormal muscle contractions and fevers abate, and most patients show normal psychomotor development. From childhood onward, the most disabling symptoms stem from impaired thermoregulation and disabling abnormal sweating, which can be treated with clonidine. Patients have hyperhidrosis, mainly of the upper body, in response to cold temperatures, and sweat very little with heat. Other features include characteristic facial anomalies, such as round face, chubby cheeks, micrognathia, high-arched palate, low-set ears, and depressed nasal bridge, dental decay, camptodactyly, and progressive kyphoscoliosis (Hahn et al., 2010).
CLCN1Myotonia congenita, recessiveMyotonia congenita follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN1 gene located on chromosomal region 7q35. The age of onset is neonatal/infantile. This is a nondystrophic skeletal muscle disorder characterized by muscle stiffness and an inability of the muscle to relax after voluntary contraction. Most patients have symptom onset in the legs, which later progresses to the arms, neck, and facial muscles. Many patients show marked hypertrophy of the lower limb muscles. The prevalence is 1:100,000.
CLCN2Leukoencephalopathy with ataxiaLeukoencephalopathy with ataxia is an autosomal recessive neurologic disorder with a characteristic pattern of white matter abnormalities on brain MRI. Affected individuals have prominent signal abnormalities and decreased apparent diffusion coefficient (ADC) values in the posterior limbs of the internal capsules, middle cerebral peduncles, pyramidal tracts in the pons, and middle cerebellar peduncles. The findings suggest myelin microvacuolation restricted to certain brain regions. Clinical features include ataxia and unstable gait; more variable abnormalities may include visual field defects, headaches, and learning disabilities (Depienne et al., 2013).
CLCN5Dent disease; Hypophosphatemic ricketsDent disease?is a chronic kidney disorder that occurs almost exclusively in males. In affected individuals, kidney problems result from damage to structures called proximal tubules. Signs and symptoms of this condition appear in early childhood and worsen over time. The most frequent sign of Dent disease is the presence of an abnormally large amount of proteins in the urine (tubular proteinuria). Other common signs of the disorder include excess calcium in the urine (hypercalciuria), calcium deposits in the kidneys (nephrocalcinosis), and kidney stones (nephrolithiasis). Researchers have described two forms of Dent disease, which are distinguished by their genetic cause and pattern of signs and symptoms.
CLCN7Osteopetrosis, autosomal recessive type 4Osteopetrosis type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLCN7 gene located on chromosomal region 16p13. The age of onset is neonatal/infantile. This disease is characterized bone marrow failure, fractures and visual impairment. The incidence is 1:200,000 live births and the prevalence is 1:100,000.
CLCNKABartter syndrome, type 4B, digenicBartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).
CLCNKBBartter syndrome, type 3Bartter syndrome refers to a group of disorders that are unified by autosomal recessive transmission of impaired salt reabsorption in the thick ascending loop of Henle with pronounced salt wasting, hypokalemic metabolic alkalosis, and hypercalciuria. Clinical disease results from defective renal reabsorption of sodium chloride in the thick ascending limb (TAL) of the Henle loop, where 30% of filtered salt is normally reabsorbed (Simon et al., 1997).Patients with antenatal (or neonatal) forms of Bartter syndrome (e.g., BARTS1, 601678) typically present with premature birth associated with polyhydramnios and low birth weight and may develop life-threatening dehydration in the neonatal period. Patients with classic Bartter syndrome present later in life and may be sporadically asymptomatic or mildly symptomatic (Simon et al., 1996 and Fremont and Chan, 2012).
CLDN1Ichthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitisIchthyosis, leukocyte vacuoles, alopecia, and sclerosing cholangitis is a rare autosomal recessive complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, mild diffuse ichthyosis, sclerosing cholangitis and leukocyte vacuolization.
CLDN14Deafness type 29, autosomal recessiveDeafness type 29, autosomal recessive follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN14 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.
CLDN16Hypomagnesemia, type 3, renalFamilial hypomagnesemia with hypercalciuria and nephrocalcinosis is a progressive renal disorder characterized by excessive urinary Ca(2+) and Mg(2+) excretion. There is progressive loss of kidney function, and in about 50% of cases, the need for renal replacement therapy arises as early as the second decade of life (Muller et al., 2006).A similar disorder with renal magnesium wasting, renal failure, and nephrocalcinosis (HOMG5; 248190) is caused by mutations in another tight-junction gene, CLDN19 (610036), and is distinguished by the association of severe ocular involvement.
CLDN19Rena hypomagnesemia type 5, with ocular involvementRenal hypomagnesemia type 5, with ocular involvement follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLDN19 gene located on chromosomal region 1p34.2. The age of onset is infantile. This disease is characterized by excessive magnesium and calcium renal wasting, bilateral nephrocalcinosis, progressive renal failure and severe ocular abnormalities. The prevalence is <1:1,000,000.
CLMPCongenital short bowel syndromeInfants with congenital short bowel syndrome are born with a shortened small intestine, with a mean length of 50 cm compared to the normal length of 190 to 280 cm, and intestinal malrotation. Severe malnutrition develops as a result of the hugely reduced absorptive surface of the small intestine, and infants require parenteral nutrition for survival; however, parenteral nutrition itself causes life-threatening complications such as sepsis and liver failure which are associated with a high rate of mortality early in life (van der Werf et al., 2012).
CLN3Ceroid lipofuscinosis, neuronal, type 3Neuronal ceroid lipofuscinosis, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN3 gene located on chromosomal region 16p12.1. The age of onset is infantile. This disease is characterized by onset at early school age with vision loss due to retinopathy, seizures and the decline of mental and motor capacities. The annual birth incidence is 1:217,000-1:450,000 in Sweden and 1:143,000 in Germany, and the prevalence is 1.5:1,000,000-9:1,000,000.
CLN5Ceroid lipofuscinosis, neuronal, type 5Neuronal ceroid lipofuscinosis, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN5 gene located on chromosomal region 3q21.1-q32. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.
CLN6Ceroid lipofuscinosis, neuronal, type 6Neuronal ceroid lipofuscinosis, type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN6 gene located on chromosomal region 15q23. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy and vision loss through retinal degeneration. The prevalence is <1:1,000,000.
CLN8Ceroid lipofuscinosis, neuronal, type 8Neuronal ceroid lipofuscinosis, type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLN8 gene located on chromosomal region 8p23.3. The age of onset is infantile. This disease is characterized by onset during infancy or early childhood with decline of mental and motor capacities, epilepsy, and vision loss through retinal degeneration. The prevalence is <1:1,000,000.
CLRN1Usher syndrome, type 3AUsher syndrome type 3A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CLRN1 gene located on chromosomal region 3q25.1. The age of onset is neonatal/infantile. This disease is characterized by the association of sensorineural deafness with retinitis pigmentosa and progressive vision loss. The prevalence is 1:1.000.000- 9/1.000.000.
CNGA1Retinitis pigmentosa type 49Retinitis pigmentosa 49 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGA1 gene located on chromosomal region 4p12. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000-5:10,000.
CNGA3Achromatopsia 2Achromatopsia 2, also referred to as rod monochromacy or total colorblindness, is a rare congenital autosomal recessive disorder characterized by photophobia, reduced visual acuity, nystagmus, and the complete inability to discriminate between colors. Electroretinographic recordings show that in achromatopsia the rod photoreceptor function is normal, whereas cone photoreceptor responses are absent (Kohl et al., 1998).
CNGB1Retinitis pigmentosa type 45Retinitis pigmentosa 45 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB1 gene located on chromosomal region 16q13. The age of onset is variable. This disease is characterized by night blindness, peripheral visual field impairment and over time loss of central vision. The prevalence is 1:10,000 to 5:10,000.
CNGB3Achromatopsia, type 3Achromatopsia type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CNGB3 gene located on chromosomal region 8q21.3. The age of onset is neonatal/Infantile. This disease is characterized by reduced visual acuity, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, and reduced or complete loss of color discrimination. Most individuals have complete form, with total lack of function in all three types of cones. Rarely, individuals have incomplete form, with similar, but generally less severe symptoms. The prevalence is 1/30,000-1/50,000.
CNKSR2Mental retardation, X-linked, syndromic, Houge typeThe Houge type of X-linked syndromic mental retardation is characterized by delayed development, intellectual disability, speech and language delay, and early-onset seizures. EEG tends to show continuous spike-wave activity or centrotemporal spikes. Some patients may have remission of seizures by adolescence. Carrier females may be mildly affected (Damiano et al., 2017).
CNNM2Hypomagnesemia, seizures, and mental retardationHypomagnesemia, seizures, and mental retardation (HOMGSMR1) is a disorder characterized by onset of seizures associated with low serum magnesium in the first year of life. Affected individuals show variable degrees of delayed psychomotor development (Arjona et al., 2014).
CNNM4Jalili syndromeJalili syndrome is characterized by the association of cone-rod dystrophy and amelogenesis imperfecta. Cone-rod dystrophy is a rare retinal disorder that leads to an initial loss of central vision, color vision and photophobia before the age of 10 years with subsequent night blindness and visual field restriction. Amelogenesis imperfecta is a generic term for an inherited group of dental diseases in which the common clinical feature is an abnormality of tooth enamel. The enamel may be thin but normal, and/or hypomineralized.
CNPY3Epileptic encephalopathy, early infantile, type 60Epileptic encephalopathy, early infantile, type 60 (EIEE60) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE60 is an autosomal recessive condition characterized by onset of seizures in the first months of life.
CNTNAP2Pitt-Hopkins like syndrome 1Pitt-Hopkins like syndrome 1 (PTHSL1) is an autosomal recessive neurodevelopmental disorder characterized by delayed psychomotor development, intellectual disability, severe speech impairment or regression, and behavioral abnormalities. Most patients have onset of seizures within the first years of life. Some patients may have cortical dysplasia on brain imaging (Smogavec et al., 2016).
COG4Congenital disorder of glycosylation, type 2JCongenital disorder of glycosylation, type 2J (CDG2J) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions.
COG5Congenital disorder of glycosylation, type 2ICongenital disorder of glycosylation type 2I (CDG2I) is an inherited condition that causes neurological problems and other abnormalities. The pattern and severity of this disorder's signs and symptoms vary among affected individuals. Patients typically develop signs and symptoms of the condition during infancy. These individuals often have weak muscle tone (hypotonia) and delayed development. Other neurological features include moderate to severe intellectual disability, poor coordination, and difficulty walking.
COG6Congenital disorder of glycosylation, type 2L; Shaheen syndromeCongenital disorder of glycosylation, type 2L (CDG2L) is an autosomal recessive multisystem disorder apparent from birth or early infancy. It is characterized by poor growth, gastrointestinal and liver abnormalities, delayed psychomotor development, hypotonia, recurrent infections, hematologic abnormalities, increased bleeding tendency, and hyperhidrosis or hyperkeratosis. More variable features include nonspecific dysmorphic facial features and cardiac septal defects. The disorder often results in death in infancy or the first years of life (Rymen et al., 2015). Biallelic mutation in the COG6 gene can also cause Shaheen syndrome, an autosomal recessive form of syndromic mental retardation. Affected individuals show severe intellectual disability, hypohidrosis, dental enamel hypoplasia, and hyperkeratosis of the palms and soles. Some may develop mild microcephaly (Shaheen et al., 2013).
COG7Congenital disorder of glycosylation, type 2ECongenital disorder of glycosylation, type 2E (CDG2E) is caused by a mutation that impairs the integrity of the conserved oligomeric Golgi (COG) complex and alters Golgi trafficking, resulting in the disruption of multiple glycosylation pathways.
COG8Congenital disorder of glycosylation, type 2HCongenital disorder of glycosylation, type 2H (CDG2H) is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions
COL11A1Fibrochondrogenesis type 1Fibrochondrogenesis type 1 (FBCG1) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL11A1 gene located on chromosomal region 1p21. The age of onset is neonatal. Fibrochondrogenesis is a severe short-limbed skeletal dysplasia clinically characterized by a flat midface with a small nose and anteverted nares, significant shortening of all limb segments but relatively normal hands and feet, and a small bell-shaped thorax with a protuberant abdomen. Radiographically, the long bones are short and have broad metaphyseal ends, giving them a dumb-bell shape. The vertebral bodies are flat and, on lateral view, have a distinctive pinched appearance, with a hypoplastic posterior end and a rounded anterior end. The ribs are typically short and wide and have metaphyseal cupping at both ends (Tompson et al., 2010). Genetic heterogeneity: Fibrochondrogenesis type 2 (FBCG2; OMIM 614524) is caused by mutations in the COL11A2 gene on chromosome 6p21.3.
COL17A1Epidermolysis bullosa, junctional, non-Herlitz typeEpidermolysis bullosa, junctional, non-Herlitz type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL17A1 gene located on chromosomal region 10q24.3. The age of onset is neonatal/infantile. This disease is characterized by a generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.
COL18A1Knobloch syndrome, type 1Knobloch syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL18A1 gene located on chromosomal region 21q22.3. The age of onset is neonatal/infantile. This disease is characterized by vitreoretinal and macular degeneration, and occipital encephalocele.?The prevalence is <1:1,000,000.
COL25A1Fibrosis of extraocular muscles, congenital, type 5Fibrosis of extraocular muscles, congenital, type 5 is an ocular motility disorder characterized by congenital dysinnervation of various cranial nerves to ocular muscles. Clinical features are ophthalmoplegia, anchoring of the eyes in downward gaze, ptosis, and backward tilt of the head.
COL4A3Alport syndrome, autosomal recessive, type 2Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.
COL4A4Alport syndrome, autosomal recessive, type 2Alport syndrome, autosomal recessive, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL4A3 and COL4A4 genes located on chromosomal region 2q36.3. The age of onset is infantile. This disease is characterized by renal, cochlear, and ocular involvement. Renal disease progresses from microscopic hematuria to proteinuria, progressive renal insufficiency, and end-stage renal disease. Progressive sensorineural hearing loss is usually present by late childhood or early adolescence. Ocular findings include anterior lenticonus, maculopathy, corneal endothelial vesicles, and recurrent corneal erosion. The prevalence is 1:50,000 newborn.
COL4A5Alport syndrome, X-linkedAlport syndrome is an inherited disorder of the basement membrane, resulting in progressive renal failure due to glomerulonephropathy, variable sensorineural hearing loss, and variable ocular anomalies (rKashtan, 1999). Alport syndrome is a genetically heterogeneous disorder, with all forms resulting from mutations in genes encoding type 4 collagen, which is a major structural component of the basement membrane. Approximately 85% of cases of Alport syndrome are X-linked and about 15% are autosomal recessive (203780); autosomal dominant inheritance (104200) is rare (Kashtan, 1999).
COL6A1Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A1 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.
COL6A2Ullrich congenital muscular dystrophy, type 1; Bethlem myopathy 1Ullrich congenital muscular dystrophy, type 1 is characterized by generalized muscle weakness and striking hypermobility of distal joints in conjunction with variable contractures of more proximal joints and normal intelligence. Additional findings may include kyphoscoliosis, protruded calcanei, and follicular hyperkeratosis. Some patients manifest at birth and never achieve independent ambulation, whereas others maintain ambulation into adulthood. Progressive scoliosis and deterioration of respiratory function is a typical feature (Kirschner, 2013). Mutation in the COL6A2 gene can cause Bethlem myopathy-1 (BTHLM1), an allelic disorder that shows autosomal dominant and recessive inheritance and a milder phenotype.
COL6A3Dystonia, type 27Dystonia, type 27 is an autosomal recessive neurologic disorder characterized by onset of segmental isolated dystonia mainly affecting the craniocervical region and upper limbs in the first 2 decades of life (Zech et al., 2015).
COL7A1Dystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type and non-HS type; DEB pruriginosa; DEB pretibialDystrophic epidermolysis bullosa (DEB), Hallopeau-Siemens (HS) type, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL7A1 gene located on chromosomal region 3p21.1. The age of onset is neonatal/infantile. This disease is characterized by generalized cutaneous and mucosal blistering and scarring associated with severe deformities and major extracutaneous involvement. Some mutations may also cause a milder recessive form (non-HS type). Also, distint subclinical types of DEB include like Pruriginosa form (OMIM 604129), Pretibial form (OMIM 131850) and other are caused by mutations in this gene with variable modes of inheritace, including subclinical types caused by dominant mutations. In addition, less commonly, mutations in the COL7A1 gene may cause strictly dominant DEB. The overall prevalence of DEB is <1:1,000,000.
COL9A1Stickler syndrome, type 4Stickler syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COL9A1 gene located on chromosomal region 6q13. The age of onset is infantile. This disease is characterized by opthalmological (myopia, retinal detachment and cataracts), orofacial (micrognathia, midface hypoplasia and cleft palate) auditory (sensorineural hearing loss) and articular (epiphyseal dysplasia) symptoms. The prevalence is <1:1,000,000.
COLEC113MC syndrome, type 2The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (Rooryck et al., 2011).
COLQMyasthenic syndrome, congenital, type 5Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. Endplate acetylcholinesterase deficiency is an autosomal recessive congenital myasthenic syndrome characterized by a defect within the synapse at the neuromuscular junction (NMJ). Mutations in COLQ result in a deficiency of acetylcholinesterase (AChE), which causes prolonged synaptic currents and action potentials due to extended residence of acetylcholine in the synaptic space. Treatment with ephedrine may be beneficial; AChE inhibitors and amifampridine should be avoided (Engel et al., 2015).
COQ2Primary coenzyme Q10 deficiency, type 1Primary coenzyme Q10 deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ2 gene located on chromosomal region 4q21.23. The age of onset is neonatal/infantile. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.
COQ4Coenzyme Q10 deficiency, primary, type 7Coenzyme Q10 deficiency, primary, type 7 (COQ10D7) is an autosomal recessive disorder resulting from mitochondrial dysfunction. Most patients have onset of severe cardiac or neurologic symptoms soon after birth, usually resulting in death. Rare patients may have later onset with a more protracted course. Tissue samples from affected individuals show decreased levels of coenzyme Q10 (CoQ10) (Brea-Calvo et al., 2015).
COQ6Coenzyme Q10 deficiency, primary, type 6Coenzyme Q10 deficiency, primary, type 6 (COQ10D6) is an autosomal recessive disorder characterized by onset in infancy of severe progressive nephrotic syndrome resulting in end-stage renal failure and sensorineural deafness. Renal biopsy usually shows focal segmental glomerulosclerosis (FSGS). Some patients may show a favorable response to oral coenzyme Q supplementation (Heeringa et al., 2011).
COQ8APrimary coenzyme Q10 deficiency, type 4Primary coenzyme Q10 deficiency type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the COQ8A gene located on chromosomal region 1q42.13. The age of onset is infantile. This disease is characterized by progressive ataxia, cerebellar atrophy, and often exercise intolerance with elevated lactate levels and mild intellectual deficit.
COQ9Coenzyme Q10 deficiency, primary, type 5Coenzyme Q10 deficiency, primary, type 5 (COQ10D5) is a form of coenzyme Q10 deficiency, an autosomal recessive disorder with variable manifestations consistent with 5 major phenotypes. The phenotypes include an encephalomyopathic form with seizures and ataxia; a multisystem infantile form with encephalopathy, cardiomyopathy and renal failure; a predominantly cerebellar form with ataxia and cerebellar atrophy; Leigh syndrome with growth retardation; and an isolated myopathic form.
CORO1AImmunodeficiency, type 8Immunodeficiency, type 8 is a disease of the immune system leading to recurrent infections, and characterized by CD4+ T-cells lymphopenia. Patients can develop B-cell lymphoproliferation associated with Epstein-Barr virus infection.
COX10Mitochondrial complex IV deficiency; Leigh syndrome due to mitochondrial COX4 deficiencyThe COX10 gene encodes a cytochrome c oxidase (COX) assembly protein involved in the mitochondrial heme biosynthetic pathway. Mutations in COX10 gene cause differentes phenotypes such as mitochondrial complex IV deficiency and Leigh syndrome. Complex IV (cytochrome c oxidase) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare. Leigh syndrome is an early-onset progressive neurodegenerative disorder with a characteristic neuropathology consisting of focal, bilateral lesions in one or more areas of the central nervous system, including the brainstem, thalamus, basal ganglia, cerebellum, and spinal cord. The lesions are areas of demyelination, gliosis, necrosis, spongiosis, or capillary proliferation. Clinical symptoms depend on which areas of the central nervous system are involved. The most common underlying cause is a defect in oxidative phosphorylation (Dahl, 1998).Leigh syndrome may be a feature of a deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).
COX15Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, type 2; Leigh syndrome due to cytochrome c oxidase deficiencyCytochrome c oxidase (COX), the terminal component of the mitochondrial respiratory chain, is a multiheteromeric enzyme embedded in the mitochondrial inner membrane. Mutations in COX gene cause different phenotypes susch as cardioencephalomyopathy and Leigh syndrome. Cardioencephalomyopathy due to cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder characterized by onset of cardiomyopathy either in utero or in the first days of life. Most patients also show neurologic abnormalities, such as abnormal breathing pattern, nystagmus, and gyral abnormalities, consistent with encephalopathy. The disorder is usually fatal in early infancy (Papadopoulou et al., 1999). Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).
CPAceruloplasminemiaAceruloplasminemia is a disorder in which iron gradually accumulates in the brain and other organs. Iron accumulation in the brain results in neurological problems that generally appear in adulthood and worsen over time. People with aceruloplasminemia develop a variety of movement problems. They may experience involuntary muscle contractions (dystonia) of the head and neck, resulting in repetitive movements and contortions. Other involuntary movements may also occur, such as rhythmic shaking (tremors), jerking movements (chorea), eyelid twitching (blepharospasm), and grimacing. Affected individuals may also have difficulty with coordination (ataxia). Some develop psychiatric problems and a decline of intellectual function (dementia) in their forties or fifties.
CPA6Febrile seizures, familial, type 11Familial febrile seizures, type 11 is an autosomal recessive seizure disorder characterized by early childhood onset of simple or complex seizures associated with fever. These seizures usually remit later in childhood with no neurologic sequelae (Salzmann et al., 2012).
CPS1Carbamoylphosphate synthetase 1 deficiencyCarbamoylphosphate synthetase deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPS1 gene located on chromosomal region 2q35. The age of onset is infantile. This disease is characterized by congenital hyperammonemia and defective citrulline synthesis. The prevalence is 1:800,000 newborn in Japan.
CPT1ACarnitine palmitoyltransferase type 1A deficiency, hepaticCarnitine palmitoyl transferase 1A deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT1A gene located on chromosomal region 11q13.2. The age of onset is neonatal/infantile. This disease is characterized by recurrent attacks of fasting-induced hypoketotic hypoglycemia and risk of liver failure. The prevalence is 1.3:1,000 newborn.
CPT2Carnitine palmitoyltransferase type 2 deficiency, lethal neonatal; Carnitine palmitoyltransferase type 2 deficiency, infantileCarnitine palmitoyltransferase deficiency, type 2, lethal neonatal form follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CPT2 gene located on chromosomal region 1p32. The age of onset is neonatal/infantile. This disease is characterized by a severe fasting intolerance leading to metabolic derangements of hypoketotic hypoglycemia, resulting in coma and seizures, and hepatic encephalopathy leading to liver failure.?The prevalence is <1:1,000,000.
CR2Immunodeficiency, common variable, type 7Immunodeficiency, common variable, type 7 (CVID7) is a primary immunodeficiency characterized by antibody deficiency, hypogammaglobulinemia, recurrent bacterial infections and an inability to mount an antibody response to antigen. The defect results from a failure of B-cell differentiation and impaired secretion of immunoglobulins; the numbers of circulating B-cells is usually in the normal range, but can be low.
CRADDMental retardation, autosomal recessive, type 34, with variant lissencephalyMental retardation, autosomal recessive, type 34, with variant lissencephaly (MRT34) is an autosomal recessive neurologic disorder characterized by mild to moderate intellectual disability and megalencephaly or enlarged head circumference. Brain imaging shows a mild variant of lissencephaly with anterior-predominant pachygyria with shallow and unusually wide sulci and mildly thickened cortex. Some patients may have seizures (Di Donato et al., 2016).
CRB1Retinitis pigmentosa, type 12; Leber congenital amaurosis, type 8Retinitis pigmentosa type 12 and Leber congenital amaurosis type 8 follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the CRB1 gene located on chromosomal region 1q31-q32.1. Retinitis pigmentosa type 12 is characterized by night blindness, peripheral visual field impairment and over time loss of central visionm, and its prevalence is 1-5:10,000. Leber congenital amaurosis, with a neonatal/infantile age of onset, comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Other clinical findings of this disease may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus.
CRBNMental retardation, autosomal recessive, type 2Mental retardation, autosomal recessive, type 2A (MRT2A) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs. MRT2A patients display mild mental retardation with a standard IQ ranged from 50 to 70. IQ scores are lower in males than females. Developmental milestones are mildly delayed. There are no dysmorphic or autistic features.
CRLF1Cold-induced sweating syndrome type 1Cold-induced sweating syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRLF1 gene located on chromosomal region 19p12. The age of onset is infantile. This disease is characterized by profuse sweating (involving the chest, face, arms and trunk) induced by cold ambient temperature kyphoscoliosis, a high-arched palate, depressed nasal bridge and impaired peripheral sensitivity to pain and temperature. The prevalence is <1:1,000,000.
CRTAPOsteogenesis imperfecta, type 7Osteogenesis imperfecta, type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CRTAP gene located on chromosomal region 3p22.3. The age of onset is variable. This disease is characterized by increased bone fragility, low bone mass, and susceptibility to bone fractures with variable severity. The prevalence is 6:100,000-7:100,000.
CRYAACataract 9, multiple typesMutations in the CRYAA gene have been found to cause multiple types of cataract, which have been described as nuclear, zonular central nuclear, laminar, lamellar, anterior polar, posterior polar, cortical, embryonal, anterior subcapsular, fan-shaped, and total. Cataract associated with microcornea, sometimes called the cataract-microcornea syndrome, is also caused by mutation in the CRYAA gene. Both autosomal dominant and autosomal recessive modes of inheritance have been reported. The symbol CATC1 was formerly used for the autosomal recessive form of cataract caused by mutation in the CRYAA gene.
CRYABMyopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related; Cataract 16, multiple typesMyopathy, myofibrillar, fatal infantile hypertonic, alpha-B crystallin-related is a severe autosomal recessive muscular dystrophy with onset in the first weeks of life after a normal neonatal period. Affected infants show rapidly progressive muscular rigidity of the trunk and limbs associated with increasing respiratory difficulty resulting in death before age 3 years (Del Bigio et al., 2011). Mutations in the CRYAB gene have been found to cause multiple types of cataract, which have been described as congenital posterior polar, congenital lamellar, and juvenile. Autosomal dominant and autosomal recessive forms have been described.
CRYBB1Cataract 17, multiple typesMutations in the CRYBB1 gene have been found to cause multiple types of cataract, which have been described as congenital nuclear, congenital nuclear with anterior and posterior Y-suture and polar opacities, and pulverulent.
CRYBB3Cataract 22Mutations in the CRYBB3 gene have been identified in families with cataract, described as congenital nuclear cataract with cortical riders, nuclear, posterior polar, anterior polar, and cortical.The preferred title/symbol of this entry was formerly 'Cataract, Congenital Nuclear, Autosomal Recessive 2; CATCN2.'
CSF2RBSurfactant metabolism dysfunction, pulmonary, type 5Pulmonary surfactant metabolism dysfunction, type 5 (SMDP5) is an autosomal recessive lung disorder manifest clinically and pathologically as pulmonary alveolar proteinosis (PAP). PAP is a rare lung disease characterized by the ineffective clearance of surfactant by alveolar macrophages. This results in the accumulation of surfactant-derived lipoproteinaceous material in the alveoli and terminal bronchioles, causing respiratory failure (Greenhill and Kotton, 2009).
CSF3RNeutropenia, severe congenital, type 7, autosomal recessiveNeutropenia, severe congenital, type 7 is an autosomal recessive immunodeficiency characterized by onset of recurrent infections in infancy or early childhood. Patients have peripheral neutropenia, although bone marrow biopsy shows normal granulocyte maturation. The neutropenia is not responsive to treatment with G-CSF, but may be responsive to GM-CSF (Triot et al., 2014; Klimiankou et al., 2015).
CSTAPeeling skin syndrome, type 4Peeling skin syndrome 4 (PSS4) is a genodermatosis characterized by congenital exfoliative ichthyosis, sharing some features with ichthyosis bullosa of Siemens and annular epidermolytic ichthyosis. PSS4 presents shortly after birth as dry, scaly skin over most of the body with coarse peeling of non- erythematous skin on the palms and soles, which is exacerbated by excessive moisture and minor trauma.
CSTBEpilepsy, progressive myoclonic type 1A (Unverricht and Lundborg)Progressive myoclonic epilepsy type 1A (Unverricht and Lundborg) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CSTB gene located on chromosomal region 21q22.3. The age of onset is infantile. This disease is characterized by severe, stimulus-sensitive myoclonus and tonic-clonic seizures. The onset, occurring between 6 and 13 years of age, is characterized by convulsions. Myoclonus begins 1 to 5 years later. The twitchings occur predominantly in the proximal muscles of the extremities and are bilaterally symmetrical, although asynchronous. At first small, they become late in the clinical course so violent that the victim is thrown to the floor. Mental deterioration and eventually dementia develop. The prevalence is 1:20,000 newborn.
CTC1Cerebroretinal microangiopathy with calcifications and cystsCerebroretinal microangiopathy with calcifications and cysts (CRMCC), also known as Coats plus syndrome, is an autosomal recessive pleomorphic disorder characterized primarily by intracranial calcifications, leukodystrophy, and brain cysts, resulting in spasticity, ataxia, dystonia, seizures, and cognitive decline. Patients also have retinal telangiectasia and exudates (Coats disease) as well as extraneurologic manifestations, including osteopenia with poor bone healing and a high risk of gastrointestinal bleeding and portal hypertension caused by vasculature ectasias in the stomach, small intestine, and liver. Some individuals also have hair, skin, and nail changes, as well as anemia and thrombocytopenia (Anderson et al., 2012; Polvi et al., 2012). Leukoencephalopathy, brain calcifications, and cysts (LCC), also known as Labrune syndrome (614561), has similar central nervous system features as CRMCC in the absence of extraneurologic or systemic manifestations. Although Coats plus syndrome and Labrune syndrome were initially thought to be manifestations of the same disorder, namely CRMCC, molecular evidence has excluded mutations in the CTC1 gene in patients with Labrune syndrome, suggesting that the 2 disorders are not allelic (Anderson et al., 2012; Polvi et al., 2012).
CTHCystathioninuriaCystathioninuria, an autosomal recessive phenotype with no striking pathologic features, is characterized by abnormal accumulation of plasma cystathionine, leading to increased urinary excretion. Because of the inconsistency and wide variety of disease associations, cystathioninuria is considered to be a benign biochemical anomaly (Mudd et al., 2001).
CTNSNephropathic cystinosisNephropathic cystinosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTNS gene located on chromosomal region 17p13. The age of onset is neonatal/infantile. This disease is characterized by hypothyroidism, insulin-dependent diabetes, hepatosplenomegaly with portal hypertension, and muscle, cerebral and ocular involvement, caused by cystine deposits in various organs. The prevalence is 1:100,000-1:200,000.
CTSAGalactosialidosisGalactosialidosis is a lysosomal storage disease associated with a combined deficiency of beta-galactosidase (611458) and neuraminidase (608272), secondary to a defect in protective protein/cathepsin A (PPCA). All patients have clinical manifestations typical of a lysosomal disorder, such as coarse facies, cherry red spots, vertebral changes, foam cells in the bone marrow, and vacuolated lymphocytes. Three phenotypic subtypes are recognized. The early infantile form is associated with fetal hydrops, edema, ascites, visceromegaly, skeletal dysplasia, and early death. The late infantile type is characterized by hepatosplenomegaly, growth retardation, cardiac involvement, and rare occurrence of neurologic signs. The juvenile/adult form is characterized by myoclonus, ataxia, angiokeratoma, mental retardation, neurologic deterioration, absence of visceromegaly, and long survival. The majority of reported patients belong to the juvenile/adult group and are mainly of Japanese origin (d'Azzo et al., 2001).
CTSCHaim-Munk syndrome; Papillon-Lefevre syndromeHaim-Munk syndrome is an autosomal recessive disorder characterized by palmoplantar keratoderma, severe periodonitis, arachnodactyly, acroosteolysis, atrophic changes of the nails, and a radiographic deformity of the fingers (Hart et al., 2000). Mutations in the CTSC gene also cause Papillon-Lefevre syndrome (PLS). PLS is an autosomal recessive disorder characterized by palmoplantar keratoderma, periodontitis, and premature loss of dentition (Lefevre et al., 2001).
CTSDCeroid lipofuscinosis, neuronal, type 10Neuronal ceroid lipofuscinosis, type 10 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSD gene located on chromosomal region 11p15.5. The age of onset is adult. This disease is characterized by dementia, seizures and loss of motor capacities, and sometimes associated with visual loss caused by retinal degeneration. The prevalence is 2:100,000-4:100,000 newborn.
CTSKPycnodysostosisPycnodysostosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CTSK gene located on chromosomal region 1q21. The age of onset is variable. This disease is characterized by osteosclerosis, short stature or dwarfism, acroosteolysis of the distal phalanges, fragile bones associated with spontaneous fractures and dysplasia of the clavicles. The prevalence is 1/1,000,000 to 9/1,000,000.
CUBNMegaloblastic anemia 1 (Imerslund-Grasbeck syndrome)Imerslund-Grasbeck syndrome is a form of congenital megaloblastic anemia due to vitamin B12 deficiency caused by a defect in the vitamin B12/intrinsic factor receptor resulting in megaloblastic anemia, which is responsive to parenteral vitamin B12 therapy and appears in childhood. Other manifestations include failure to thrive and grow, infections and neurological damage. Imerslund-Grasbeck syndrome was described by Imerslund (1960) in Norway and Grasbeck et al. (1960) in Finland; the Finnish cases were found to be due to mutations in cubilin, whereas the Norwegian cases were found to be due to mutations in AMN.
CUL4BMental retardation, X-linked, syndromic, type 15 (Cabezas type)This form of syndromic X-linked mental retardation is characterized primarily by short stature, hypogonadism, and abnormal gait, with other more variable features such as speech delay, prominent lower lip, and tremor (Cabezas et al., 2000).
CUL73-M syndrome 13M syndrome 1 is an autosomal recessive disorder characterized by distinctive facial features, severe prenatal and postnatal growth retardation, and normal mental development. The main skeletal anomalies are long, slender tubular bones, reduced anteroposterior diameter of the vertebral bodies, and delayed bone age. Other skeletal manifestations include joint hypermobility, joint dislocation, winged scapulae, and pes planus (Badina et al., 2011).
CYB5A46,XY disorder of sex development due to isolated 17,20-lyase deficiencyMethemoglobinemia and ambiguous genitalia is due to isolated 17,20-lyase deficiency, defined by apparently normal 17-alpha-hydroxylase activity but severely reduced 17,20-lyase activity of the CYP17A1 enzyme (609300), which results in sex steroid deficiency but normal glucocorticoid and mineralocorticoid reserve. The clinical phenotype is characterized by male undermasculinization, with absent or disturbed pubertal development in both 46,XY and 46,XX individuals. Mild to severe methemoglobinemia has been reported in these patients (Idkowiak et al., 2012).Other autosomal recessive methemoglobinemias include types I and II (250800), caused by mutation in the CYB5R3 gene (613213). Isolated 17,20-lyase deficiency can also be caused by mutation in the CYP17A1 gene (609300), and mutation in the POR gene can manifest clinically as isolated 17,20-lyase deficiency (124015.0016).
CYB5R3Methemoglobinemia, type 1; Methemoglobinemia, type 2Methemoglobinemia due to NADH-cytochrome b5 reductase deficiency is an autosomal recessive disorder characterized clinically by decreased oxygen carrying capacity of the blood, with resultant cyanosis and hypoxia (Percy and Lappin, 2008).There are 2 types of methemoglobin reductase deficiency. In type 1, the defect affects the soluble form of the enzyme, is restricted to red blood cells, and causes well-tolerated methemoglobinemia. In type 2, the defect affects both the soluble and microsomal forms of the enzyme and is thus generalized, affecting red cells, leukocytes, and all body tissues. Type 2 methemoglobinemia is associated with mental deficiency and other neurologic symptoms. The neurologic symptoms may be related to the major role played by the cytochrome b5 system in the desaturation of fatty acids (Vives-Corrons et al., 1978; Kaplan et al., 1979).
CYBAChronic granulomatous disease, autosomal recessive, due to deficiency of CYBAChronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the NADPH oxidase enzyme complex which generates the microbicidal 'respiratory burst.'
CYBBChronic granulomatous disease, X-linkedChronic granulomatous disease is a genetically heterogeneous immunodeficiency disorder resulting from an inability of phagocytes to kill microbes that they have ingested. This impairment in killing is caused by any of several defects in the phagocyte NADPH oxidase (phox) complex, which generates the microbicidal 'respiratory burst' (Dinauer et al., 2001; Johnston, 2001).
CYP11A146,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiencyAdrenal insufficiency, congenital, with 46XY sex reversal, partial or complete is also known as P450scc deficiency and is a rare disorder that can present as acute adrenal insufficiency in infancy or childhood. ACTH and plasma renin activity are grossly elevated and adrenal steroids are inappropriately low or absent; the 46,XY patients have female external genitalia, sometimes with clitoromegaly. The phenotypic spectrum ranges from prematurity, complete underandrogenization, and severe early-onset adrenal failure to term birth with clitoromegaly and later-onset adrenal failure (Kim et al., 2008). Although hormonal and phenotypic features can resemble those of congenital lipoid adrenal hyperplasia (lipoid CAH; 201710), no patient with P450scc deficiency has been described with the massive adrenal enlargement typical of lipoid CAH (Sahakitrungruang et al., 2011).
CYP11B1Adrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiencyAdrenal hyperplasia, congenital, due to 11-beta-hydroxylase deficiency is an autosomal recessive disorder of corticosteroid biosynthesis resulting in androgen excess, virilization, and hypertension. The defect causes decreased synthesis of cortisol and corticosterone in the zona fasciculata of the adrenal gland, resulting in accumulation of the precursors 11-deoxycortisol and 11-deoxycorticosterone; the latter is a potent salt-retaining mineralocorticoid that leads to arterial hypertension (White et al., 1991).CAH due to 11-beta-hydroxylase deficiency accounts for approximately 5 to 8% of all CAH cases; approximately 90% of cases are caused by 21-hydroxylase deficiency (201910) (White et al., 1991).
CYP11B2Hypoaldosteronism, congenital, due to CMO I deficiencyCMO type I deficiency is an autosomal recessive disorder caused by a defect in the penultimate biochemical step of aldosterone biosynthesis, the 18-hydroxylation of corticosterone (B) to 18-hydroxycorticosterone (18-OHB). This enzymatic defect results in decreased aldosterone and salt-wasting. In CMO I deficiency, aldosterone is undetectable, whereas its immediate precursor, 18-OHB, is low or normal. These patients have an increased ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).The CYP11B2 gene product also catalyzes the final step in aldosterone biosynthesis: the 18-oxidation of 18-OHB to aldosterone. A defect in that enzymatic step results in CMO type II deficiency (610600), an allelic disorder with an overlapping phenotype but distinct biochemical features. In CMO II deficiency, aldosterone can be low or normal, but at the expense of increased secretion of 18-OHB. These patients have a low ratio of corticosterone to 18-OHB (Portrat-Doyen et al., 1998).
CYP17A117 alpha(α)-hydroxylase/17,20-lyase deficiency17 alpha(α)-hydroxylase/17,20-lyase deficiency is a condition that affects the function of certain hormone-producing glands called the gonads (ovaries in females and testes in males) and the adrenal glands. 17α-hydroxylase/17,20-lyase deficiency is one of a group of disorders, known as congenital adrenal hyperplasias, that impair hormone production and disrupt sexual development and maturation. Hormone imbalances lead to the characteristic signs and symptoms of 17α-hydroxylase/17,20-lyase deficiency, which include high blood pressure (hypertension), low levels of potassium in the blood (hypokalemia), and abnormal sexual development.
CYP19A1Aromatase deficiencyAromatase deficiency is a rare autosomal recessive disorder in which individuals cannot synthesize endogenous estrogens. If a fetus lacks aromatase activity, dehydroepiandrosterone sulfate produced by the fetal adrenal glands cannot be converted to estrogen by the placenta, and is converted to testosterone peripherally and results in virilization of both fetus and mother. Virilization manifests as pseudohermaphroditism in female infants, with hirsutism and acne in the mother; the maternal indicators resolve following delivery. Affected females are usually diagnosed at birth because of the pseudohermaphroditism. Cystic ovaries and delayed bone maturation can occur during childhood and adolescence in these girls, who present at puberty with primary amenorrhea, failure of breast development, virilization, and hypergonadotropic hypogonadism. Affected males do not present with obvious defects at birth. Their clinical symptoms include tall stature, delayed skeletal maturation, delayed epiphyseal closure, bone pain, eunuchoid body proportions, and excess adiposity. Estrogen replacement therapy reverses the symptoms in males and females.
CYP1B1Glaucoma, primary congenital, type 3APrimary congenital glaucoma is the most common type of childhood glaucoma, with autosomal recessive inheritance and an incidence ranging from 1 in 30,000 to 1 in 1,250. Signs of the disease include early onset (birth to 3 years of age), increased intraocular pressure, increased corneal diameter, enlarged globe, Haab striae (breaks in Descemet membrane), corneal edema, and optic nerve head cupping. Congenital glaucoma is a chronic disease and a serious cause of blindness worldwide (Azmanov et al., 2011).
CYP21A2Congenital adrenal hyperplasia due to 21-hydroxylase deficiencyClassic congenital adrenal hyperplasia due to 21-hydroxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP21A2 gene located on chromosomal region 6p21.3. The age of onset is neonatal/infantile. This disease is characterized by simple virilizing or salt wasting forms that can manifest with genital ambiguity in females, and in both sexes with adrenal insufficiency with dehydration during the neonatal period, life threatening hypoglycemia and hyperandrogenia. The prevalence is 1/100,000 to 9/100,000. There is a common milder form of congenital adrenal hyperplasia (Nonclassic) characterized by a later onset of androgen excess symptoms seen in females and precocious pseudopuberty in both sexes. Cortisol and aldosterone levels are normal but there is an increased amount of androgens. Nonclassic form onset occurs in adolescence with variable degrees of postnatal androgen excess (precocious pubarche, hirsutism, acne, alopecia, anovulation and menstrual irregularies and in the post-pubertal period it can mimic polycystic ovary syndrome. It is also sometimes asymptomatic. The prevalence ranges from 1/1,000-1/500 in the general Caucasian population, but up to 1-2% among inbred populations, such as Eastern European (Ashkenazi) Jews.
CYP24A1Hypercalcemia, infantile, type 1Infantile hypercalcemia is characterized by severe hypercalcemia, failure to thrive, vomiting, dehydration, and nephrocalcinosis. An epidemic of idiopathic infantile hypercalcemia occurred in the United Kingdom in the 1950s after the implementation of an increased prophylactic dose of vitamin D supplementation; however, the fact that most infants receiving the prophylaxis remained unaffected suggested that an intrinsic hypersensitivity to vitamin D might be implicated in the pathogenesis (Schlingmann et al., 2011).
CYP27A1Cerebrotendinous xanthomatosisCerebrotendinous xanthomatosis is a rare inherited lipid-storage disease characterized clinically by progressive neurologic dysfunction (cerebellar ataxia beginning after puberty, systemic spinal cord involvement and a pseudobulbar phase leading to death), premature atherosclerosis, and cataracts. Large deposits of cholesterol and cholestanol are found in virtually every tissue, particularly the Achilles tendons, brain, and lungs. Cholestanol, the 5-alpha-dihydro derivative of cholesterol, is enriched relative to cholesterol in all tissues. The diagnosis can be made by demonstrating cholestanol in abnormal amounts in the serum and tendon of persons suspected of being affected. Plasma cholesterol concentrations are low normal in CTX patients. Dotti et al. (2001) examined the ophthalmologic findings of 13 CTX patients. In addition to cataracts, which were found in all cases, optic disc pallor was identified in 6 of the patients. Premature retinal senescence was also observed.In a tabular presentation, Moghadasian et al. (2002) compared and contrasted CTX with 2 other lipid disorders with certain similarities and clinical course: familial hypercholesterolemia (143890) and sitosterolemia (210250).
CYP27B1Vitamin D-dependent rickets, type 1Vitamin D3 (cholecalciferol), synthesized in the epidermis in response to UV radiation, and dietary vitamin D2 (ergocalciferol, synthesized in plants) are devoid of any biologic activity. Vitamin D hormonal activity is due primarily to the hydroxylated metabolite of vitamin D3, 1-alpha,25-dihydroxyvitamin D3 (calcitriol), the actions of which are mediated by the vitamin D receptor (VDR; 601769) (Koren, 2006; Liberman and Marx, 2001).In the liver, vitamin D 25-hydroxylase (CYP2R1; 608713) catalyzes the initial hydroxylation of vitamin D at carbon 25; in the kidney, 1-alpha-hydroxylase (CYP27B1; 609506) catalyzes the hydroxylation and metabolic activation of 25-hydroxyvitamin D3 into 1,25-dihydroxyvitamin D3. The active metabolite 1,25(OH)2D3 binds and activates the nuclear vitamin D receptor, with subsequent regulation of physiologic events such as calcium homeostasis and cellular differentiation and proliferation (Takeyama et al., 1997). Disorders of vitamin D metabolism or action lead to defective bone mineralization and clinical features including intestinal malabsorption of calcium, hypocalcemia, secondary hyperparathyroidism, increased renal clearance of phosphorus, and hypophosphatemia. The combination of hypocalcemia and hypophosphatemia causes impaired mineralization of bone that results in rickets and osteomalacia (Liberman and Marx, 2001).
CYP4F22Ichthyosis, congenital, autosomal recessive, type 5Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
CYP4V2Bietti crystalline corneoretinal dystrophyBietti crystalline corneoretinal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP4V2 gene located on chromosomal region 4q35.2. The age of onset is adult. This disease is characterized by nightblindness, decreased vision, paracentral scotoma, and, in the end stages of the disease, legal blindness.
CYP7B1Spastic paraplegia type 5A, autosomal recessiveSpastic paraplegia type 5A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the CYP7B1 gene located on chromosomal region 8q21.3. The age of onset is neonatal/infantile. This disease is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. The prevalence is below 1,000,000.
D2HGDHD-2-hydroxyglutaric aciduriaD-2-Hydroxyglutaric aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the D2HGDH gene located on chromosomal region 2q37.3. The age of onset is variable. This disease is characterized by extremely variable clinical manifestations, with severe cases characterized by neonatal or early infantile-onset epileptic encephalopathy, and marked hypotonia, and cerebral visual failure, developmental delay, seizures, involuntary movements, and cardiomyopathy are also common in these cases. The prevalence is below 1,000,000.
DAG1Muscular dystrophy-dystroglycanopathy type A9; Muscular dystrophy-dystroglycanopathy type C9Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A9 is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, and congenital muscular dystrophy. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS), which is associated with death in infancy. The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1), collectively known as 'dystroglycanopathies' (Geis et al., 2013 and Riemersma et al., 2015). Mutation in the DAG1 gene can also cause the less severe disorder limb-girdle muscular dystrophy-dystroglycanopathy, type C9 (MDDGC9). MDDGC9 is an autosomal recessive muscular dystrophy showing onset in early childhood. It is part of a group of similar disorders resulting from defective glycosylation of DAG1, collectively known as 'dystroglycanopathies' (Hara et al., 2011).
DARS2Leukoencephalopathy with brain stem and spinal cord involvement and lactate elevationLeukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL) is defined on the basis of a highly characteristic constellation of abnormalities observed by magnetic resonance imaging and spectroscopy (Scheper et al., 2007). Affected individuals develop slowly progressive cerebellar ataxia, spasticity, and dorsal column dysfunction, sometimes with a mild cognitive deficit or decline.
DBHDopamine beta-hydroxylase deficiencyDopamine beta (β)-hydroxylase deficiency is a condition that affects the autonomic nervous system, which controls involuntary body processes such as the regulation of blood pressure and body temperature. Problems related to this disorder can first appear during infancy. Early signs and symptoms may include episodes of vomiting, dehydration, decreased blood pressure (hypotension), difficulty maintaining body temperature, and low blood sugar (hypoglycemia). Individuals with dopamine β-hydroxylase deficiency typically experience a sharp drop in blood pressure upon standing (orthostatic hypotension), which can cause dizziness, blurred vision, or fainting.
DBTMaple syrup urine disease, type 2Maple syrup urine disease, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DBT gene located on chromosomal region 1p21.2. The age of onset in neonatal/infantil. This disease is characterized by a maple syrup odor to the urine, deficient diet, lethargy and focal dystonia, followed by progressive encephalopathy and central respiratory failure if not treated. The prevalence is 1-5/10,000.
DCAF17Woodhouse-Sakati syndromeWoodhouse-Sakati syndrome is a multisystemic disorder characterized by hypogonadism, alopecia, diabetes mellitus, intellectual deficit and extrapyramidal signs with choreoathetoid movements and dystonia.
DCCGaze palsy, familial horizontal, with progressive scoliosis, type 2Gaze palsy, familial horizontal, with progressive scoliosis, 2 is an autosomal recessive neurologic disorder characterized by global developmental delay, delayed walking, intellectual disability, horizontal gaze palsy, and childhood-onset progressive scoliosis.
DCDC2Sclerosing cholangitis, neonatal; Nephronophthisis 19Neonatal sclerosing cholangitis is a rare autosomal recessive form of severe liver disease with onset in infancy. Affected infants have jaundice, cholestasis, acholic stools, and progressive liver dysfunction resulting in fibrosis and cirrhosis; most require liver transplantation in the first few decades of life. Cholangiography shows patent biliary ducts, but there are bile duct irregularities (Girard et al., 2016; Grammatikopoulos et al., 2016). Nephronophthisis 19 (NPHP19) is also caused by homozygous or compound heterozygous mutation in the DCDC2 gene. NPHP19 is an autosomal recessive disorder characterized by chronic tubulointerstitial nephritis resulting in end-stage renal disease. NPHP19 patients also manifest hepatosplenomegaly, hepatic fibrosis, destruction of the bile ducts, focal bile ductal proliferation, ductal plate malformation, and cholestasis.
DCLRE1COmenn syndrome; Severe combined immunodeficiency, Athabascan typeOmenn syndrome and Athabascan type severe combined immunodeficiency follow an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the DCLRE1C gene located on chromosomal region 10p13. Omenn syndrome has an early age of onset and it is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency. The age of onset of Athabascan type severe combined immunodeficiency is neonatal/infantile and it is characterized by severe and recurrent infections, diarrhea, failure to thrive, and cell sensitivity to ionizing radiation. The prevalence is 1-9/1,000,000.
DCXLissencephaly, X-linkedLissencephaly ('smooth brain') results from migrational arrest of cortical neurons short of their normal destination, and can result in profound mental retardation and seizures. In X-linked lissencephaly-1, affected males generally have more a severe phenotype compared to females. DCX mutations cause classic lissencephaly with mental retardation in hemizygous males and a milder phenotype known as subcortical band heterotopia in females, sometimes in the same family. The subcortical lamina heterotopia found in heterozygous females is also referred to as 'double cortex' (DC) syndrome (des Portes et al., 1997).There are several X-linked loci that affect neuronal migration, including the Aicardi locus (304050).
DDB2Xeroderma pigmentosum, complementation group EXeroderma pigmentosum complementation group E follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDB2 gene located on chromosomal region 11p12-p11. The age of onset is variable. This disease is characterized by mild xeroderma pigmentosum symptoms and no neurological abnormalities. The prevalence is 1/1,000,000.
DDCAromatic L-amino acid decarboxylase deficiencyAromatic L-amino acid decarboxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DDC gene located on chromosomal region 7p12.2. The age of onset is neonatal/infantile. This disease is characterized by severe developmental delay, weak muscle tone (hypotonia), muscle stiffness, difficulty moving, and involuntary writhing movements of the limbs (athetosis). The prevalence is below 1,000,000.
DDR2Spondylometaepiphyseal dysplasia, short limb-hand typeSpondyloepimetaphyseal dysplasia short limb-hand type is a disease characterized by short-limbed dwarfism, a narrow chest with pectus excavatum, brachydactyly in the hands and feet, a characteristic craniofacial appearance and premature calcifications. The radiological findings are distinctive and comprise short long bones throughout the skeleton with striking epiphyses that are stippled, flattened and fragmented and flared, irregular metaphyses. Platyspondyly in the spine with wide intervertebral spaces is observed and some vertebral bodies are pear-shaped with central humps, anterior protrusions and posterior scalloping.
DDX11Warsaw breakage syndromeWarsaw breakage syndrome is a condition that can cause multiple abnormalities. People with Warsaw breakage syndrome have intellectual disability that varies from mild to severe. They also have impaired growth from birth leading to short stature and a small head size (microcephaly). Affected individuals have distinctive facial features that may include a small forehead, a short nose, a small lower jaw, a flat area between the nose and mouth (philtrum), and prominent cheeks. Other common features include hearing loss caused by nerve damage in the inner ear (sensorineural hearing loss) and heart malformations.
DDX3XMental retardation, X-linked, type 102Mental retardation, X-linked, type 102 (MRX102) is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX102 features include mild to severe intellectual disability, hypotonia, movement disorders, behavior problems, corpus callosum hypoplasia, and epilepsy. Additionally, patients manifest variable non-neurologic features such as joint hyperlaxity, skin pigmentary abnormalities, cleft lip and/or palate, hearing and visual impairment, and precocious puberty.
DESMyopathy, myofibrillar, type 1Myofibrillar myopathy, type 1 is a noncommittal term that refers to a group of morphologically homogeneous, but genetically heterogeneous chronic neuromuscular disorders. The morphologic changes in skeletal muscle in MFM result from disintegration of the sarcomeric Z disc and the myofibrils, followed by abnormal ectopic accumulation of multiple proteins involved in the structure of the Z disc, including desmin, alpha-B-crystallin (CRYAB; 123590), dystrophin (300377), and myotilin (TTID; 604103).
DGUOKDGUOK-related mitochondrial DNA depletion syndromeMitochondrial DNA depletion syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DGUOK gene located on chromosomal region 2p13. The age of onset is neonatal/infantile. This disease is characterized by progressive liver failure, hypoglycemia and neurologic abnormalities including hypotonia, encephalopathy and peripheral neuropathy
DHCR24DesmosterolosisDesmosterolosis is a rare autosomal recessive disorder characterized by multiple congenital anomalies and elevated levels of the cholesterol precursor desmosterol in plasma, tissue, and cultured cells (Waterham et al., 2001).
DHCR7Smith-Lemli-Opitz syndromeSmith-Lemli-Opitz syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHCR7 gene located on chromosomal region 11q13.4. The age of onset is neonatal/infantile. This disease is characterized by multiple congenital anomalies, intellectual deficit, and behavioral problems.?The prevalence is 1/20,000 to 1/40,000 newborn.
DHDDSRetinitis pigmentosa, type 59Retinitis pigmentosa, type 59 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DHDDS gene located on chromosomal region 1p36.11. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1/10,000 to 5/10,000.
DHFRMegaloblastic anemia due to dihydrofolate reductase deficiencyDihydrofolate reductase deficiency is an autosomal recessive metabolic disorder characterized by the hematologic findings of megaloblastic anemia and variable neurologic symptoms, ranging from severe developmental delay and generalized seizures in infancy (Banka et al., 2011) to childhood absence epilepsy with learning difficulties to lack of symptoms (Cario et al., 2011). Treatment with folinic acid can ameliorate some of the symptoms.
DHH46,XY complete gonadal dysgenesis46,XY sex reversal 7 (SRXY7) is a disorder of sex development. Affected individuals have a 46,XY karyotype but present as phenotypically normal females. SRXY7 patients have no functional gonads.
DHODHMiller syndromeMiller syndrome, or postaxial acrofacial dysostosis, is a rare autosomal recessive disorder characterized clinically by severe micrognathia, cleft lip and/or palate, hypoplasia or aplasia of the postaxial elements of the limbs, coloboma of the eyelids, and supernumerary nipples (Ng et al., 2010).
DIAPH1Seizures, cortical blindness, microcephaly syndromeSeizures, cortical blindness, and microcephaly syndrome (SCBMS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, early-onset seizures, severely delayed psychomotor development, and cortical blindness. Affected individuals also tend to show poor overall growth with short stature (Ercan-Sencicek et al., 2015).
DIS3L2Perlman syndromePerlman syndrome is an autosomal recessive congenital overgrowth syndrome with similarities to Beckwith-Wiedemann syndrome (BWS; 130650). Affected children are large at birth, are hypotonic, and show organomegaly, characteristic facial dysmorphisms (inverted V-shaped upper lip, prominent forehead, deep-set eyes, broad and flat nasal bridge, and low-set ears), renal anomalies (nephromegaly and hydronephrosis), frequent neurodevelopmental delay, and high neonatal mortality. Perlman syndrome is associated with a high risk of Wilms tumor, with a 64% incidence in infants surviving beyond the neonatal period. The tumor is diagnosed at an earlier age in these individuals compared with sporadic cases (less than 2 years and 3-4 years of age, respectively), and there is a high frequency of bilateral tumors (55%). Histologic examination of the kidneys in children with Perlman syndrome shows frequent nephroblastomatosis, which is a precursor lesion for Wilms tumor (Astuti et al., 2012).
DKC1Dyskeratosis congenita, X-linkedX-linked dyskeratosis congenita follows an X-linked pattern of inheritance and is caused by pathogenic variants in the DKC1 gene located on chromosomal region Xq28. Tha age of onset is infantile. This disease is classically defined by the triad of abnormal skin pigmentation, nail dystrophy, and leukoplakia of the oral mucosa. Progressive bone marrow failure occurs in over 80% of cases and is the main cause of early mortality. The phenotype is highly variable, and affected individuals may have multiple additional features.
DLATPyruvate dehydrogenase E2 deficiencyPyruvate dehydrogenase (PDH) deficiency is a major cause of primary lactic acidosis and neurological dysfunction in infancy and early childhood. In Pyruvate dehydrogenase E2 deficiency form episodic dystonia is the major neurological manifestation, with other more common features of pyruvate dehydrogenase deficiency, such as hypotonia and ataxia, being less prominent.
DLDDihydrolipoamide dehydrogenase deficiencyDihydrolipoamide dehydrogenase deficiency E3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DLD gene located on chromosomal region 7q31-q32. The age of onset is neonatal/infantile. This disease is characterized by poor feeding, lethargy, vomiting and a maple syrup odor in the cerumen (and later in urine) noted soon after birth, followed by progressive encephalopathy and central respiratory failure if untreated. The prevalence is 1/1,000,000 to 9/1,000,000.
DLG3Mental retardation, X-linked, type 90Mental retardation, X-linked, type 90 (MRX90) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
DLL3Spondylocostal dysostosis type 1Spondylocostal dysostosis type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DLL3 gene located on chromosomal region 19q13. The age of onset is neonatal/infantile. This disease is associated with vertebral and rib segmentation defects and characterised by a short neck with limited mobility, winged scapulae, a short trunk, and short stature with multiple vertebral anomalies at all levels of the spine. The prevalence is below 1/1,000,000.
DMDDuchenne/Becker muscular dystrophyDuchenne muscular dystrophy follows an X-linked pattern of inheritance and is caused by pathogenic variants in the DMD gene located on chromosomal region Xp21.2. The age of onset is infantile. This disease is characterized by progressive muscle wasting and weakness due to degeneration of skeletal, smooth and cardiac muscle. The incidence is 1/3,300 male newborns and the prevalence is 1/16,000 to 1/125,000. Becker muscular dystrophy is characterized by progressive muscle wasting and weakness due to degeneration of skeletal, smooth and cardiac muscle. The incidence is 1/18,000 to 1/31,000 male newborns and the prevalence is 1/10,000 to 5/10,000.
DMP1Hypophosphatemic rickets, autosomal recessiveHypophosphatemic rickets follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DMP1 gene located on chromosomal region 4q21. The age of onset is variable. This disease is associated with vertebral and rib segmentation defects and characterised by hypophosphatemia, rickets and/or osteomalacia and slow growth. The prevalence is below 1/20,000 newborns.
DNAAF1Ciliary dyskinesia, primary, type 13Ciliary dyskinesia, primary, type 13 (CILD13) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome. At ultrastructural level, CILD13 is characterized by a marked reduction or absence of both dynein arms from the patients cilia.
DNAAF2Ciliary dyskinesia, primary, type 10Ciliary dyskinesia, primary, type 10 (CILD10) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome.
DNAAF3Ciliary dyskinesia, primary, type 2Ciliary dyskinesia, primary, type 2 (CILD2) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node.
DNAAF4Ciliary dyskinesia, primary, type 25Ciliary dyskinesia, primary, type 25 (CILD25) is an autosomal recessive disorder caused by defective ciliary movement. Affected individuals have recurrent upper and lower airway disease, bronchiectasis, and decreased fertility. About half of patients show laterality defects, including situs inversus totalis. Respiratory cilia from patients show defects in the inner and outer dynein arms (Tarkar et al., 2013).
DNAAF5Ciliary dyskinesia, primary, type 18Ciliary dyskinesia, primary, type 18 (CILD18) is an autosomal recessive disorder characterized by early infantile onset of recurrent sinopulmonary infections due to ciliary dysfunction and impaired airway clearance. Males are infertile and about half of patients have situs inversus. Electron microscopy of cilia shows a defect of the outer and inner dynein arms and impaired ciliary function (Horani et al., 2012).
DNAH11Ciliary dyskinesia, primary, type 7, with or without situs inversusCiliary dyskinesia, primary, type 7 (CILD7) is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003).
DNAH5Ciliary dyskinesia, primary, type 3, with or without situs inversusCiliary dyskinesia, primary, type 3 (CILD3) is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003).
DNAI1Ciliary dyskinesia, primary, type 1, with or without situs inversusCiliary dyskinesia, primary, type 1 (CILD1) is a genetically heterogeneous autosomal recessive disorder resulting from loss of function of different parts of the primary ciliary apparatus, most often dynein arms. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus (270100), and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003)
DNAI2Ciliary dyskinesia, primary, type 9, with or without situs inversusCiliary dyskinesia, primary, type 9 (CILD9) is an autosomal recessive disorder resulting from loss of normal ciliary function. Kartagener (pronounced KART-agayner) syndrome is characterized by the combination of primary ciliary dyskinesia and situs inversus, and occurs in approximately half of patients with ciliary dyskinesia. Since normal nodal ciliary movement in the embryo is required for normal visceral asymmetry, absence of normal ciliary movement results in a lack of definitive patterning; thus, random chance alone appears to determine whether the viscera take up the normal or reversed left-right position during embryogenesis. This explains why approximately 50% of patients, even within the same family, have situs inversus (Afzelius, 1976; El Zein et al., 2003).
DNAJB2Spinal muscular atrophy, distal, autosomal recessive, type 5Spinal muscular atrophy, distal, autosomal recessive, type 5 (DSMA5) is an autosomal recessive neurologic disorder characterized by young adult onset of slowly progressive distal muscle weakness and atrophy resulting in gait impairment and loss of reflexes due to impaired function of motor nerves. Sensation and cognition are not impaired (Blumen et al., 2012).
DNAJC193-methylglutaconic aciduria, type 53-methylglutaconic aciduria, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DNAJC19 gene located on chromosomal region 3q26.33. The age of onset is infantile. This disease is characterized by severe early onset (before the age of three years) dilated cardiomyopathy with conduction defects (long QT syndrome), non-progressive cerebellar ataxia, testicular dysgenesis, and 3-methylglutaconic aciduria.
DNAJC6Parkinson disease, type 19A, juvenile-onset; Parkinson disease, type 19B, early-onsetParkinson disease, type 19A (PARK19A) is an autosomal recessive neurodegenerative disorder characterized by onset of parkinsonism in the first or second decade. Some patients may have additional neurologic features, including mental retardation and seizures (Edvardson et al., 2012; Koroglu et al., 2013).Parkinson disease, type 19B (PARK19B) is an autosomal recessive neurodegenerative disorder with onset of parkinsonism between the third and fifth decades. It is slowly progressive, shows features similar to classic late-onset Parkinson disease (PD), and has a beneficial response to dopaminergic therapy (Olgiati et al., 2016).
DNAL1Ciliary dyskinesia, primary, type 16Ciliary dyskinesia, primary, type 16 (CILD16) is an autosomal recessive disorder characterized by early infantile onset of respiratory distress associated with absence of ciliary outer dynein arms (Mazor et al., 2011).
DNM1LEncephalopathy due to defective mitochondrial and peroxisomal fission, type 1Encephalopathy due to defective mitochondrial and peroxisomal fission, type 1 is characterized by delayed psychomotor development and hypotonia that may lead to death in childhood. Many patients develop refractory seizures, consistent with an epileptic encephalopathy, and thereafter show neurologic decline. The age at onset, features, and severity are variable, and some patients may not have clinical evidence of mitochondrial or peroxisomal dysfunction (Sheffer et al., 2016; Fahrner et al., 2016).
DNM2Lethal congenital contracture syndrome, type 5Lethal congenital contracture syndrome 5 (LCCS5) is a form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non- progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth.
DNMT3BImmunodeficiency-centromeric instability-facial anomalies syndrome, type 1Immunodeficiency, centromeric instability, and facial dysmorphism (ICF) syndrome is a rare autosomal recessive disease characterized by facial dysmorphism, immunoglobulin deficiency, and branching of chromosomes 1, 9, and 16 after phytohemagglutinin (PHA) stimulation of lymphocytes. Hypomethylation of DNA of a small fraction of the genome is an unusual feature of ICF patients that is explained by mutations in the DNMT3B gene in some, but not all, ICF patients (Hagleitner et al., 2008).
DOCK6Adams-Oliver syndrome 2Adams-Oliver syndrome 2 is an autosomal recessive multiple congenital anomaly syndrome characterized by aplasia cutis congenita (ACC) and terminal transverse limb defects, in association with variable involvement of the brain, eyes, and cardiovascular systems (Shaheen et al., 2011).
DOCK8Hyper-IgE recurrent infection syndrome, autosomal recessiveAutosomal dominant hyper-IgE recurrent infection syndrome (147060) is a primary immunodeficiency disorder characterized by recurrent Staphylococcus aureus skin abscesses, increased serum IgE, and abnormalities of the connective tissue, skeleton, and dentition (Buckley et al., 1972; Grimbacher et al., 1999).The autosomal recessive form shares hyper-IgE, eosinophilia, and recurrent Staphylococcal infections, but is distinguished from autosomal dominant HIES by the lack of connective tissue and skeletal involvement (Renner et al., 2004).
DOK7Fetal akinesia deformation sequence, type 3; Myasthenic syndrome, congenital, type 10The fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome. Mutation in the DOK7 gene can also cause a form of congenital myasthenic syndrome (CMS10). Congenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynaptic. CMS10 is an autosomal recessive CMS resulting from a postsynaptic defect affecting endplate maintenance of the NMJ. Patients present with limb-girdle weakness in the first decade. Treatment with ephedrine or salbutamol may be beneficial; cholinesterase inhibitors should be avoided (Engel et al., 2015).
DOLKCongenital disorder of glycosylation, type 1MCongenital disorder of glycosylation, type 1M (CDG1M) is a form of congenital disorder of glycosylation, a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. CDG1M is a very severe disease with death occurring in early life.
DPAGT1Congenital disorder of glycosylation, type 1J; Myasthenic syndrome, congenital, type 13Congenital disorder of glycosylation, type 1J (CDG1J) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DPAGT1 gene located on chromosomal region 11q23.3. The age of onset is neonatal/infantile. This disease is characterized by severe psychomotor delay, seizures, hypotonia and dysmorphism (microcephaly, ocular exotropia, micrognathia and clinodactyly). The prevalence is below 1,000,000. Mutation in the DPAGT1 gene can also cause congenital myasthenic syndrome, type 13 (CMS13). CMS13 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. CMS13 is characterized by muscle weakness mostly affecting proximal limb muscles, minimal involvement of facial, ocular and bulbar muscles, and tubular aggregates present on muscle biopsy. Symptoms include difficulty walking and frequent falls. Younger patients show hypotonia and poor head control. Neurophysiological features indicate a disorder of neuromuscular transmission on electromyography.
DPM1Congenital disorder of glycosylation, type 1ECongenital disorder of glycosylation, type 1E (CDG1E) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DPM1 gene located on chromosomal region 20q13.13. The age of onset is neonatal/infantile. This disease is characterized by psychomotor delay, seizures, hypotonia, facial dysmorphism and microcephaly. The prevalence is below 1,000,000.
DPY19L2Male infertility spermatogenic failure, type 9Spermatogenic failure, type 9 is associated with globozoospermia, a rare phenotype of primary male infertility characterized by the production of a majority of round-headed spermatozoa without an acrosome (Harbuz et al., 2011).
DPYDDihydropyrimidine dehydrogenase deficiencyDihydropyrimidine dehydrogenase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DPYD gene located on chromosomal region 1p22. This disease shows large phenotypic variability, ranging from no symptoms to a convulsive disorder with motor and mental retardation in homozygous patients. In people with severe dihydropyrimidine dehydrogenase deficiency, the disorder becomes apparent in infancy. These affected individuals have recurrent seizures (epilepsy), intellectual disability, a small head size (microcephaly), increased muscle tone (hypertonia), delayed development of motor skills such as walking, and autistic behaviors that affect communication and social interaction. The prevalence is unknow.
In addition, homozygous and heterozygous mutation carriers can develop severe toxicity after the administration of the antineoplastic drug 5-fluorouracil (5FU).
DPYSDihydropyrimidinuriaDihydropyrimidinuria (DPYS) deficiency is an autosomal recessive disease characterized by the presence of dihydropyrimidinuria. The clinical phenotype is highly variable, ranging from early infantile onset of severe neurologic involvement, dysmorphic features, and feeding problems to late onset of mild intellectual disability and even asymptomatic individuals. Patients with a complete or partial deficiency have an increased risk of developing severe toxicity after administration of the anticancer drug 5-fluorouracil (5-FU) (Nakajima et al., 2017).
DSG1Erythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgEErythroderma, congenital, with palmoplantar keratoderma, hypotrichosis, and hyper IgE is a syndrome characterized by severe dermatitis, multiple allergies and metabolic wasting. Clinical features include erythroderma, yellowish papules and plaques arranged at the periphery of the palms, along the fingers and over weight-bearing areas of the feet, skin erosions and scaling, and hypotrichosis. Additionally, patients manifest severe food allergies, elevated immunoglobulin E (IgE) levels and recurrent infections with marked metabolic wasting.
DSG4Hypotrichosis, type 6Hypotrichosis, type 6 is characterized by fragile hairs that break easily, leaving short, sparse scalp hairs. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas. In some patients with congenital hypotrichosis, monilethrix-like hairs showing elliptical nodes have been observed (Schaffer et al., 2006).
DSPCardiomyopathy, dilated, with woolly hair and keratoderma; Epidermolysis bullosa, lethal acantholyticDilated cardiomyopathy with woolly hair and keratoderma, known as Carvajal syndrome, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DSP gene located on chromosomal region 6p24. The age of onset is neonatal/infantile. This disease is characterized by woolly hair is present at birth and the palmoplantar keratoderma appears during the first year of life. The cardiac anomaly presents during childhood and is marked by dilation of the left ventricle accompanied by alterations in muscle contractility. The dilated cardiomyopathy may lead to life-threatening congestive heart failure and death. The prevalence is below 1,000,000. Furthermore, mutations in the DSP gene have been identified in people with an autosomal recessive disorder called lethal acantholytic epidermolysis bullosa. Features of this condition include very fragile skin that blisters and detaches easily, a complete absence of hair (alopecia), abnormal or missing fingernails, teeth that are present from birth (neonatal teeth), and abnormalities of the heart muscle (cardiomyopathy). The skin abnormalities lead to a severe loss of fluids and death in early infancy.
DSTEpidermolysis bullosa simplex, autosomal recessive, type 2Epidermolysis bullosa simplex, autosomal recessive, type 2 (EBSB2) is a mild autosomal recessive dermatologic disorder characterized by trauma-induced blistering mainly occurring on the feet and ankles. Ultrastructural analysis of skin biopsy shows abnormal hemidesmosomes with poorly formed inner plaques (Liu et al., 2012).
DTNBP1Hermansky-Pudlak syndrome 7Hermansky-Pudlak syndrome 7 (HPS7) is a form of Hermansky-Pudlak syndrome, a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in this patients.
DUOX2Thyroid dyshormonogenesis, type 6Thyroid dyshormonogenesis, type 6 (TDH6) is a disorder due to thyroid dyshormonogenesis, causing hypothyroidism, goiter, and variable mental deficits derived from unrecognized and untreated hypothyroidism.
DUOXA2Thyroid dyshormonogenesis, type 5Thyroid dyshormonogenesis, type 5 (TDH5) is a disorder due to thyroid dyshormonogenesis, causing hypothyroidism, goiter, and variable mental deficits derived from unrecognized and untreated hypothyroidism.
DYMSmith-McCort dysplasia; Dyggve-Melchior-Clausen diseaseSmith-McCort dysplasia is a rare autosomal recessive osteochondrodysplasia characterized by short limbs and trunk with barrel-shaped chest. The radiographic phenotype includes platyspondyly, generalized abnormalities of the epiphyses and metaphyses, and a distinctive lacy appearance of the iliac crest. Spinal cord compression due to atlantoaxial instability occurs in both SMC and DMC (Spranger et al., 1976; Nakamura et al., 1997). . Mutations in the DYM gene cause Dyggve-Melchior-Clausen disease (DMC), which is radiologically identical but has the additional feature of mental retardation. Dyggve-Melchior-Clausen syndrome (DMCS) is a rare autosomal recessive disorder belonging to the group of spondyloepimetaphyseal dysplasias. DMC is characterized by progressive short stature with short trunk dwarfism, microcephaly, protruding sternum, and psychomotor retardation. Radiological features include a platyspondyly with double vertebral humps, an epiphyso-metaphyseal dysplasia and lacy pelvis iliac crests.?
DYNC2H1Short-rib thoracic dysplasia, type 3, with or without polydactylyShort-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (Huber and Cormier-Daire, 2012; Schmidts et al., 2013).
DYSFMiyoshi muscular dystrophy, type 1; Limb-girdle muscular dystrophy, type 2 (LGMD R2)Miyoshi muscular dystrophy, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the DYSF gene located on chromosomal region 2p13.3. The age of onset is young adulthood. This disease is characterized by weakness and atrophy in the distal lower extremity posterior compartment (gastrocnemius and soleus muscles) and is associated with difficulties in standing on tip toes. The prevalence is 1/1,000,000 to 9/1,000,000. Mutations in the DYSF gene can also cause muscular dystrophy, limb-girdle, autosomal recessive, type 2. This disease is characterized by an onset in late adolescence or early adulthood of slowly progressive, proximal weakness and atrophy of shoulder and pelvic girdle muscles. Cardiac and respiratory muscles are not involved. Hypertrophy of the calf muscles and highly elevated serum creatine kinase levels are frequently observed.
EARS2Combined oxidative phosphorylation deficiency 12Combined oxidative phosphorylation deficiency 12 (COXPD12) is an autosomal recessive mitochondrial neurologic disorder characterized by onset in infancy of hypotonia and delayed psychomotor development, or early developmental regression, associated with T2-weighted hyperintensities in the deep cerebral white matter, brainstem, and cerebellar white matter. Serum lactate is increased due to a defect in mitochondrial respiration. There are 2 main phenotypic groups: those with a milder disease course and some recovery of skills after age 2 years, and those with a severe disease course resulting in marked disability (Steenweg et al., 2012).
EBPMEND syndrome; Chondrodysplasia punctataMend syndrome (MEND), also known as male EBP disorder with neurologic defects, is an X-linked recessive disorder representing a continuous phenotypic spectrum with variable manifestations associated with a defect in sterol biosynthesis. Features include intellectual disability, short stature, scoliosis, digital abnormalities, cataracts, and dermatologic abnormalities. Not all patients show all features, and the severity is highly variable. Molecular studies indicate that affected males are hemizygous for a nonmosaic hypomorphic EBP allele. Carrier females are generally clinically asymptomatic, but may show biochemical abnormalities (summary by Arnold et al., 2012 and Barboza-Cerda et al., 2014). MEND is caused by hemizygous mutation in the EBP gene on chromosome Xp11. Mutation in the EBP gene can also cause the X-linked disorder chondrodysplasia punctata-2 (CDPX2), which shows some overlapping features. Chondrodysplasia punctata (CDP) is a clinically and genetically heterogeneous disorder characterized by punctiform calcification of the bones. X-linked dominant CDP, also known as Conradi-Hunermann syndrome, is the most well-characterized form. CDPX2 arises almost exclusively in females and is usually lethal in males. In addition to radiographic stippling, the disorder is characterized by rhizomelic shortness, transient congenital ichthyosis following the lines of Blaschko, patchy alopecia, cataracts, and midface hypoplasia. Affected males are extremely rare and the clinical features in males almost always result from postzygotic mosaicism for an EBP mutation (Aughton et al., 2003; Arnold et al., 2012).
ECM1Urbach-Wiethe diseaseLipoid proteinosis of Urbach and Wiethe is a rare autosomal recessive disorder typified by generalized thickening of skin, mucosae, and certain viscera. Classic features include beaded eyelid papules and laryngeal infiltration leading to hoarseness. The disorder is clinically heterogeneous, with affected individuals displaying differing degrees of skin scarring and infiltration, variable signs of hoarseness and respiratory distress, and in some cases neurologic abnormalities such as temporal lobe epilepsy. Histologically, there is widespread deposition of hyaline (glycoprotein) material and disruption/reduplication of basement membrane (Hamada et al., 2002 and Hamada et al., 2003).
EDAEctodermal dysplasia, type 1, hypohidrotic, X-linkedHypohidrotic ectodermal dysplasia, type 1, hypohidrotic, X-linked follows an X-linked pattern of inheritance and is caused by pathogenic variants in the EDA gene located on chromosomal region Xq12-q13.1. The age of onset is neonatal/infantile. This disease is characterized by malformation of ectodermal structures such as skin, hair, teeth and sweat glands. The prevalence is 1/5,000 to 1/10,000 newborns.
EDAREctodermal dysplasia 10B, hypohidrotic/hair/tooth typeSome ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings.Hypohidrotic, or anhidrotic, ectodermal dysplasia is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples (Cluzeau et al., 2011).
EDARADDEctodermal dysplasia 11B, hypohidrotic/hair/tooth typeSome ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings.Hypohidrotic, or anhidrotic, ectodermal dysplasia (HED/EDA) is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples (Cluzeau et al., 2011).
EDN1Auriculocondylar syndrome, type 3Auriculocondylar syndrome (ARCND) is a rare craniofacial disorder involving first and second pharyngeal arch derivatives and includes the key features of micrognathia, temporomandibular joint and condyle anomalies, microstomia, prominent cheeks, and question mark ears (QMEs). QMEs consist of a defect between the lobe and the upper two-thirds of the pinna, ranging from a mild indentation in the helix to a complete cleft between the lobe and helix (Gordon et al., 2013).
EDN3Waardenburg syndrome, type 4BWaardenburg-Shah syndrome, type 4B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the EDN3 gene located on chromosomal region 20q13.2-q13.3. The age of onset is neonatal/infantile. This disease is characterized by the association of Waardenburg syndrome (sensorineural hearing loss and pigmentary abnormalities) and Hirschsprung disease (signs of intestinal obstruction). The prevalence is below 1/40,000.
EDNRBABCD syndromeABCD syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the EDNRB gene located on chromosomal region 13q22.3. This disease is characterized by albinism, black lock at temporal occipital region, bilateral deafness, aganglionosis of the large intestine and total absence of neurocytes and nerve fibers in the small intestine. ABCD syndrome is not a separate entity, but rather an expression of Shah-Waardenburg syndrome (WS4)
EFEMP2Cutis laxa, autosomal recessive, type 1BAutosomal recessive cutis laxa type 1B (ARCL1B) is characterized by the presence of severe systemic connective tissue abnormalities, including emphysema, cardiopulmonary insufficiency, birth fractures, arachnodactyly, and fragility of blood vessels. All symptoms refer to disturbed elastic fiber formation (Hoyer et al., 2009).
EFNB1Craniofrontonasal dysplasiaCraniofrontonasal syndrome is an X-linked developmental disorder that shows paradoxically greater severity in heterozygous females than in hemizygous males. Females have frontonasal dysplasia, craniofacial asymmetry, craniosynostosis, bifid nasal tip, grooved nails, wiry hair, and abnormalities of the thoracic skeleton, whereas males typically show only hypertelorism (Twigg et al., 2004; Wieland et al., 2004).
EGFR?Inflammatory skin and bowel disease, neonatal, 2Neonatal inflammatory skin and bowel disease is a rare, life-threatening, autoinflammatory syndrome with immune deficiency disorder characterized by early-onset, life-long inflammation, affecting the skin and bowel, associated with recurrent infections. Patients present perioral and perianal psoriasiform erythema and papular eruption with pustules, failure to thrive associated with chronic malabsorptive diarrhea, intercurrent gastrointestinal infections and feeding troubles, as well as absent, short or broken hair and trichomegaly. Recurrent cutaneous and pulmonary infections lead to recurrent blepharitis, otitis externa and bronchiolitis.
EGR2Dejerine-Sottas diseaseDejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (Baets et al., 2011).
EIF2AK3Wolcott-Rallison syndromeWolcott-Rallison syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the EIF2AK3 gene located on chromosomal region 2p12. The age of onset is neonatal/infantile. This disease is characterized by permanent neonatal diabetes mellitus with multiple epiphyseal dysplasia and other clinical manifestations, including recurrent episodes of acute liver failure. The prevalence is above 1/10,000 newborns.
EIF2B2Leukoencephalopathy with vanishing white matterVanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (Van der Knaap et al., 1998; Schiffmann et al., 1997).
EIF2B3Leukoencephalopathy with vanishing white matterVanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (Van der Knaap et al., 1998; Schiffmann et al., 1997).
EIF2B4Leukoencephalopathy with vanishing white matterVanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (Van der Knaap et al., 1998; Schiffmann et al., 1997).
EIF2B5Leukoencephalopathy with vanishing white matterVanishing white matter leukodystrophy is an autosomal recessive neurologic disorder characterized by variable neurologic features, including progressive cerebellar ataxia, spasticity, and cognitive impairment associated with white matter lesions on brain imaging. The age at onset can range from early infancy to adulthood. Rapid neurologic deterioration can occur following minor head trauma. Female mutation carriers may develop ovarian failure, manifest as primary amenorrhea or as secondary amenorrhea lasting more than 6 months, associated with elevated gonadotropin levels at age less than 40 years (Van der Knaap et al., 1998; Schiffmann et al., 1997).
ELAC2Combined oxidative phosphorylation deficiency 17Combined oxidative phosphorylation deficiency 17 (COXPD17) is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (Smits et al., 2011)
ELOVL4Ichthyosis, spastic quadriplegia, and mental retardationIchthyosis, spastic quadriplegia, and mental retardation (ISQMR) is a severe autosomal recessive disorder characterized by ichthyosis apparent from birth, profound psychomotor retardation with essentially no development, spastic quadriplegia, and seizures (Aldahmesh et al., 2011).
ELP1Dysautonomia, familialFamilial dysautonomia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ELP1 gene located on chromosomal region 9q31.3. The age of onset is infantile. This disease is characterized by sensory dysfunction and severe impairment of the autonomic nervous system activity, resulting in multisystem dysfunction. The prevalence is <1:1,000,000
ELP2Mental retardation, autosomal recessive, type 58Mental retardation, autosomal recessive, type 58 (MRT58) is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT58 transmission pattern is consistent with autosomal recessive inheritance.
EMDEmery-Dreifuss muscular dystrophy, type 1, X-linkedEmery-Dreifuss muscular dystrophy, type 1, X-linked follows an X-linked pattern of inheritance and is caused by pathogenic variants in the EMD gene located on chromosomal region Xq28. ?This is a condition that primarily affects muscles used for movement (skeletal?muscles) and the heart (cardiac muscle). Among the earliest features of this disorder are joint deformities called contractures. Contractures restrict the movement of certain joints, most often the elbows, ankles, and neck, and usually become noticeable in early childhood. Most affected individuals also experience muscle weakness and?wasting?that worsen slowly over time, beginning in muscles of the upper arms and lower legs and later also affecting muscles in the shoulders and hips. Almost all people with Emery-Dreifuss muscular dystrophy develop heart problems by adulthood. The X-linked type of this disorder affects an estimated 1 in 100,000 people.
ENAMAmelogenesis imperfecta, type 1CAmelogenesis imperfecta, type 1C is an autosomal recessive defect of dental enamel formation. Teeth show local hypoplastic and unmineralized enamel, and a yellow-brown discoloration. Enamel defects can be associated with facial and oral features including vertical dysgnathia and anterior openbite malocclusion.
ENPP1Arterial calcification, generalized, of infancy, type 1Arterial calcification, generalized, of infancy, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ENPP1 gene located on chromosomal region 6q22-q23. The age of onset is neonatal/infancy. A severe autosomal recessive disorder characterized by calcification of the internal elastic lamina of muscular arteries and stenosis due to myointimal proliferation. The disorder is often fatal within the first 6 months of life because of myocardial ischemia resulting in refractory heart failure.
ENTPD1Spastic paraplegia, type 64, autosomal recessiveSpastic paraplegia, type 64, autosomal recessive is a form of spastic paraplegia, a neurodegenerative disorder characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body.
EPB41Elliptocytosis, type 1Elliptocytosis is a hematologic disorder characterized by elliptically shaped erythrocytes and a variable degree of hemolytic anemia. Usually inherited as an autosomal dominant trait, elliptocytosis results from mutation in any one of several genes encoding proteins of the red cell membrane skeleton (McGuire et al., 1988).
EPB42Spherocytosis, type 5Spherocytosis is a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal.
EPCAMCongenital tufting enteropathyCongenital tufting enteropathy (CTE) is a rare inherited intractable diarrhea of infancy characterized by villous atrophy and absence of inflammation, with intestinal epithelial cell dysplasia manifesting as focal epithelial tufts in the duodenum and jejunum. CTE presents in the first few months of life with chronic watery diarrhea and failure to thrive, and most affected individuals require parenteral nutrition for normal growth and development (Sivagnanam et al., 2008).Semiquantitative assessment of the epithelial surface in CTE patients revealed that 80 to 90% contained tufts, compared to only 16% in patients with celiac disease and less than 10% in normal jejunum (Reifen et al., 1994).
EPM2AEpilepsy, progressive myoclonic, type 2A (Lafora)The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (Ramachandran et al., 2009).
ERBB3Lethal congenital contractural syndrome, type 2Lethal congenital contracture syndrome 2 (LCCS2) is a form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non- progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS2 patients manifest craniofacial/ocular findings, lack of hydrops, multiple pterygia, and fractures, as well as a normal duration of pregnancy and a unique feature of a markedly distended urinary bladder (neurogenic bladder defect). The phenotype suggests a spinal cord neuropathic etiology.
ERCC1Cerebrooculofacioskeletal syndrome, type 4Cerebrooculofacioskeletal syndrome, type 4 is a severe autosomal recessive disorder characterized by growth retardation, dysmorphic facial features, arthrogryposis, and neurologic abnormalities. Cellular studies show a defect in both transcription-coupled and global genome nucleotide excision repair (TC-NER and GG-NER) (Jaspers et al., 2007; Kashiyama et al., 2013).
ERCC2Trichothiodystrophy, type 1Trichothiodystrophy (TTD), type 1 is a heterogeneous group of disorders that follows an autosomal recessive pattern of inheritance. It is caused by pathogenic variants in the ERCC2 gene located on chromosomal region 19q13.32. The age of onset is neonatal or infantile. This disease, with variable clinical expression, is characterized by brittle and fragile hair, often combined with growth retardation and intellectual deficit, congenital ichthyosis and nail abnormalities, among other symptoms. About half of the patients with TTD exhibit marked photosensitivity.
ERCC3Trichothiodystrophy, type 2Trichothiodystrophy (TTD), type 2 is a heterogeneous group of disorders that follows an autosomal recessive pattern of inheritance. It is caused by pathogenic variants in the ERCC3 gene located on chromosomal region 2q14.3. The age of onset is neonatal or infantile. This disease, with variable clinical expression, is characterized by brittle and fragile hair, often combined with growth retardation and intellectual deficit, congenital ichthyosis and nail abnormalities, among other symptoms. About half of the patients with TTD exhibit marked photosensitivity.
ERCC5Cerebrooculofacioskeletal syndrome, type 3Cerebrooculofacioskeletal syndrome type 3, also known as COFS syndrome, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ERCC5 gene located on chromosomal region 13q33.1. COFS syndrome is characterized by prenatal onset of arthrogryposis, microcephaly and growth failure. Postnatal features include severe developmental delay, congenital cataracts (in some), and marked UV sensitivity of the skin. Survival beyond 6 years of age is rare. The prevalence is below 1/1,000,000.
ERCC6Cockayne syndrome, type B; Cerebrooculofacioskeletal syndrome, type 1Cockayne syndrome (CS), type B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ERCC6 gene located on chromosomal region 10q11.23. The age of onset is variable. This disease is characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit. Mutations in the ERRC6 gene have been also found in patients with COFS syndrome type 1, an extreme prenatal form of the CS clinical spectrum. This autosomal recessive progressive neurodegenerative disorder is characterized by microcephaly, congenital cataracts, severe mental retardation, facial dysmorphism, and arthrogryposis.
ERCC8Cockayne syndrome, type ACockayne syndrome, type A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ERCC8 gene located on chromosomal region 5q12.1. The age of onset is variable. This disease is characterized by short stature, a characteristic facial appearance, premature aging, photosensitivity, progressive neurological dysfunction, and intellectual deficit. The prevalence is 2.7/1,000,000 newborns in Western Europe.
ERLIN2Spastic paraplegia, type 18, autosomal recessiveSpastic paraplegia, type 18, autosomal recessive is a severe autosomal recessive neurologic disorder characterized by onset in early childhood of progressive spastic paraplegia resulting in motor disability. Most affected individuals have severe psychomotor retardation. Some may develop significant joint contractures (Alazami et al., 2011 and Yildirim et al., 2011).
ESCO2Roberts syndromeRoberts syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ESCO2 gene located on chromosomal region 8p21.1. The age of onset is neonatal/infantile. This disease is characterized by pre- and postnatal growth retardation, severe symmetric limb reduction defects, craniofacial anomalies and severe intellectual deficit.
ESPNDeafness, autosomal recessive, type 36Autosomal recessive nonsyndromic sensorineural deafness type 36 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ESPN gene located on chromosomal region 1p36.31. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.
ESR1Estrogen resistanceEstrogen resistance is a disorder characterized by partial or complete resistance to estrogens, in the presence of elevated estrogen serum levels. Clinical features include absence of the pubertal growth spurt, delayed bone maturation, unfused epiphyses, reduced bone mineral density, osteoporosis, continued growth into adulthood and very tall adult stature. Glucose intolerance, hyperinsulinemia and lipid abnormalities may also be present.
ESRRBDeafness, autosomal recessive, type 35Autosomal recessive nonsyndromic sensorineural deafness type 35 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ESRRB gene located on chromosomal region 14q24.3. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.
ETFAGlutaric acidemia, type 2AGlutaric acidemia, type 2A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ETFA gene located on chromosomal region 15q23-q25. The age of onset is variable. This disease is characterized by clinically heterogeneous symptoms ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.
ETFBGlutaric acidemia, type 2BGlutaric acidemia, type 2B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ETFB gene located on chromosomal region 19q13.3. The age of onset is variable. This disease is characterized by clinically heterogeneous symptoms ranging from a severe neonatal presentation with metabolic acidosis, cardiomyopathy and liver disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.
ETFDHGlutaric acidemia, type 2CGlutaric acidemia, type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ETFDH gene located on chromosomal region 4q32-q35. The age of onset is variable. This disease is characterized by clinically heterogeneous symptoms disease, to a mild childhood/adult disease with episodic metabolic decompensation, muscle weakness, and respiratory failure.
ETHE1Ethylmalonic encephalopathyEthylmalonic encephalopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ETHE1 gene located on chromosomal region 19q13.31. The age of onset is neonatal/infantile. This disease is characterized by elevated excretion of ethylmalonic acid with recurrent petechiae, orthostatic acrocyanosis and chronic diarrhoea associated with neurodevelopmental delay, psychomotor regression and hypotonia with brain magnetic resonance imaging abnormalities. The prevalence is below 1/1,000,000, with total of 30 cases of patients reported worldwide, mainly for Mediterranean and Arab populations.
EVCEllis-van Creveld syndromeEllis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (Ruiz-Perez et al., 2000).The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).
EVC2Ellis-van Creveld syndromeEllis-van Creveld syndrome is an autosomal recessive skeletal dysplasia characterized by short limbs, short ribs, postaxial polydactyly, and dysplastic nails and teeth. Congenital cardiac defects, most commonly a defect of primary atrial septation producing a common atrium, occur in 60% of affected individuals (Ruiz-Perez et al., 2000).The clinical features of the Ellis-van Creveld syndrome appear to be identical regardless of whether the disorder is caused by mutation in the EVC gene (604831) or in the EVC2 gene (607261) (Ruiz-Perez et al., 2003, Galdzicka et al., 2002).
EXOSC3Pontocerebellar hypoplasia, type 1BPontocerebellar hypoplasia, type 1B is a severe autosomal recessive neurologic disorder characterized by a combination of cerebellar and spinal motor neuron degeneration beginning at birth. There is diffuse muscle weakness, progressive microcephaly, global developmental delay, and brainstem involvement (Wan et al., 2012). PCH1B can be divided into mild, moderate, and severe subgroups that vary in age at onset, progression, clinical and neuroradiologic severity, and survival (Halevy et al., 2014).
EXT1ChondrosarcomaChondrosarcoma is a malignant bone tumor arising from cartilaginous tissue, most frequently occuring at the ends of the femur and tibia, the proximal end of the humerus and the pelvis; and presenting with a palpable mass and progressive pain. Chondrosarcoma is usually slow growing at low histological grades and can be well managed by intralesional curettage or en-block wide resection.
EXTL3Immunoskeletal dysplasia with neurodevelopmental abnormalitiesImmunoskeletal dysplasia with neurodevelopmental abnormalities is an autosomal recessive disorder characterized by variable skeletal abnormalities and neurodevelopmental defects. Neurologic manifestations include intellectual disability and motor delay. Some patients manifest hypotonia and seizures. Skeletal features include disproportionate short stature, cervical malformations, epiphyseal and metaphyseal dysplasia, and rarely premature craniosynostosis with progressive microcephaly. Severe combined immunodeficiency with a complete absence of T cells is observed in some patients.
EYSRetinitis pigmentosa, type 25Retinitis pigmentosa, type 25 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the EYS gene located on chromosomal region 6q12. The age of onset is variable. This disease is characterized by night blindness (nyctalopia), peripheral visual field impairment and over time loss of central vision. The prevalence is 1/10,000 to 5/10,000.
F10Factor X deficiencyFactor X deficiency is a rare autosomal recessive bleeding disorder showing variable phenotypic severity. Affected individuals can manifest prolonged nasal and mucosal hemorrhage, menorrhagia, hematuria, and occasionally hemarthrosis. The disorder can be caused either by reduced levels of the factor X protein or by synthesis of a dysfunctional factor X protein (Millar et al., 2000).
F13A1Factor XIIIA deficiencyFactor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (Kangsadalampai et al., 1999). Ichinose et al. (1996, 2000) proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2.
F13BFactor XIIIB deficiencyFactor XIII deficiency is an autosomal recessive hematologic disorder characterized by increased bleeding and poor wound healing. Most cases of congenital factor XIII deficiency result from mutation in the A subunit (Kangsadalampai et al., 1999). Ichinose et al. (1996, 2000) proposed a classification of factor XIII deficiency: XIIIA deficiency (formerly 'type II' F13 deficiency) and XIIIB deficiency (formerly 'type I' F13 deficiency), as well as a possible combined deficiency of the 2.
F2Prothrombin deficiencyProthrombin deficiency is an extremely rare autosomal recessive bleeding disorder characterized by low levels of circulating prothrombin; it affects about 1 in 2,000,000 individuals. There are 2 main types: type 1 deficiency, known as true prothrombin deficiency or 'hypoprothrombinemia,' is defined as plasma levels of prothrombin being less than 10% of normal with a concomitant decrease in activity. These patients have severe bleeding from birth, including umbilical cord hemorrhage, hematomas, ecchymoses, hematuria, mucosal bleeding, hemarthroses, intracranial bleeding, gastrointestinal bleeding, and menorrhagia. Type 2 deficiency, known as 'dysprothrombinemia,' is characterized by normal or low-normal synthesis of a dysfunctional protein. Bleeding symptoms are more variable, depending on the amount of residual functional activity. Variant prothrombin gene alleles can result in 'hypoprothrombinemia' or 'dysprothrombinemia,' and individuals who are compound heterozygous for these 2 types of alleles have variable manifestations. Heterozygous mutation carriers, who have plasma levels between 40 and 60% of normal, are usually asymptomatic, but can show bleeding after tooth extraction or surgical procedures (Lancellotti and De Cristofaro, 2009).
F7Factor VII deficiencyFactor VII deficiency is an autosomal recessive bleeding disorder showing variable severity (Millar et al., 2000). Perry (2002) provided a comprehensive review of factor VII deficiency with a description of F7 polymorphisms, gene structure, and a summary of 120 mutations.
F8Hemophilia AHemophilia A follows an X-linked pattern of inheritance and is caused by pathogenic variants in the F8 gene located on chromosomal region Xq28. The age of onset is neonatal/infantile. This disease is characterized by spontaneous or prolonged hemorrhages due to factor VIII deficiency. The prevalence is 1/4,000 to 1/ 5,000 male newborns.
F9Hemophilia BHemophilia B follows an X-linked pattern of inheritance and is caused by pathogenic variants in the F9 gene located on chromosomal region Xq27.1-q27.2. The age of onset is neonatal/infantile. This disease is characterized by spontaneous or prolonged hemorrhages due to factor IX deficiency. The prevalence is 1/100,000 to 9/100,000.
FA2HSpastic paraplegia, type 35, autosomal recessiveSpastic paraplegia, type 35, autosomal recessive is a complicated form of SPG characterized by childhood onset of gait difficulties due to progressive spastic paraparesis, dysarthria, and mild cognitive decline associated with leukodystrophy on brain imaging. Other variable neurologic features, such as dystonia, optic atrophy, and seizures may also occur (Dick et al., 2010). In addition, some patients with mutations in the FA2H gene have radiographic evidence of neurodegeneration with brain iron accumulation (NBIA), thus expanding the phenotype. Kruer et al. (2010) referred to this phenotypic spectrum of disorders as fatty acid hydrolase-associated neurodegeneration (FAHN).
FAHTyrosinemia, type 1Tyrosinemia, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FAH gene located on chromosomal region 15q25.1. The age of onset is variable. This disease is characterized by progressive liver disease, renal tubular dysfunction, porphyria-like crises and a dramatic improvement in prognosis following treatment with nitisinone. The birth incidence is 1/100,000, notably in Qu?bec, Canada, and the prevalence is 1/100,000 to 1/120,000 newborns.
FAM126AHypomyelinating leukodystrophy, type 5Hypomyelinating leukodystrophy, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FAM126A gene located on chromosomal region 7p15.3. The age of onset is neonatal/infantile. This disease is characterized by the onset of cataract either at birth or in the first two months of life, delayed psychomotor development by the end of the first year of life and moderate intellectual deficit. The prevalence is below 1/1,000,000.
FAM161ARetinitis pigmentosa, type 28Retinitis pigmentosa, type 28 (RP28) is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.
FAM20AAmelogenesis imperfecta, type 1G (Enamel-renal syndrome)Amelogenesis imperfecta, type 1G, also known as enamel-renal syndrome, is characterized by hypoplastic enamel on primary and secondary dentition, pulp stones, delayed or failed eruption of secondary dentition, gingival overgrowth, and nephrocalcinosis. Blood chemistry analyses are typically normal, and nephrocalcinosis, which is found on renal ultrasound, may not appear until later in life (Wang et al., 2013).
FAM20CRaine syndromeRaine syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FAM20C gene located on chromosomal region 7p22.3. The age of onset is neonatal/infantile. This disease is characterized by generalized osteosclerosis with periosteal bone formation, characteristic facial dysmorphism, brain abnormalities including intracerebral calcifications, and neonatal lethal course. The prevalence is below 1/1,000,000.
FANCAFanconi anemia, complementation group AFanconi anemia, complementation group A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FANCA gene located on chromosomal region 16q24.3. The age of onset is infantile. This disease is characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. The prevalence is 1/1,000,000 to 9/1,000,000.
FANCBFanconi anemia, complementation group BFanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (Deakyne and Mazin, 2011). Patients with FANCB mutations often present with multiple additional congenital anomalies, including the constellation of features designated VACTERL-H, for vertebral defects, anal atresia, tracheoesophageal fistula, esophageal atresia, radial or renal dysplasia, and hydrocephalus. Many patients with these features die in early infancy before developing anemia (McCauley et al., 2011).
FANCCFanconi anemia, complementation group CFanconi anemia, complementation group C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FANCC gene located on chromosomal region 9q22.3. The age of onset is infantile. This disease is characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. The prevalence is 1/1,000,000 to 9/1,000,000.
FANCD2Fanconi anemia, complementation group D2Fanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (Deakyne and Mazin, 2011).
FANCEFanconi anemia, complementation group EFanconi anemia (FA) is characterized by bone marrow failure, developmental abnormalities, cancer predisposition, and cellular hypersensitivity to DNA cross-linking agents such as mitomycin C (Winter et al., 2000).
FANCFFanconi anemia, complementation group FFanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (Deakyne and Mazin, 2011).
FANCGFanconi anemia, complementation group GFanconi anemia, complementation group G follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FANCG gene located on chromosomal region 9p13. The age of onset is infantile. This disease is characterized by progressive pancytopenia with bone marrow failure, variable congenital malformations and predisposition to develop hematological or solid tumors. The prevalence is 1/1,000,000 to 9/1,000,000.
FANCIFanconi anemia, complementation group IFanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (Deakyne and Mazin, 2011).
FANCLFanconi anemia, complementation group LFanconi anemia (FA) is a clinically and genetically heterogeneous disorder that causes genomic instability. Characteristic clinical features include developmental abnormalities in major organ systems, early-onset bone marrow failure, and a high predisposition to cancer. The cellular hallmark of FA is hypersensitivity to DNA crosslinking agents and high frequency of chromosomal aberrations pointing to a defect in DNA repair (Deakyne and Mazin, 2011).
FARS2Combined oxidative phosphorylation deficiency 14; Spastic paraplegia, type 77, autosomal recessiveCombined oxidative phosphorylation deficiency 14 (COXPD14) is a severe multisystemic autosomal recessive disorder characterized by neonatal onset of global developmental delay, refractory seizures, and lactic acidosis. Biochemical studies show deficiencies of multiple mitochondrial respiratory enzymes. Neuropathologic studies in 1 patient showed laminar cortical necrosis, characteristic of Alpers syndrome (203700) (Elo et al., 2012). Biallelic mutation in the FARS2 gene can also cause Spastic paraplegia, type 77, autosomal recessive (SPG77; 617046), a much less severe disorder. SPG77 is an autosomal recessive neurologic disorder characterized by early-childhood onset of spasticity affecting the lower limbs and resulting in gait difficulties. The disorder is progressive and may be associated with childhood seizures, developmental delay, and mitochondrial dysfunction (Yang et al., 2016; Vernon et al., 2015; Vantroys et al., 2017).
FBLN5Cutis laxa, autosomal recessive, type 1ACutis laxa is a collection of disorders that are typified by loose and/or wrinkled skin that imparts a prematurely aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The skin lacks elastic recoil, in marked contrast to the hyperelasticity apparent in classical Ehlers-Danlos syndrome (130000). These properties are nearly always attributable to loss, fragmentation, or severe disorganization of dermal elastic fibers (Davidson and Giro, 2002).The clinical spectrum of autosomal recessive cutis laxa is highly heterogeneous with respect to organ involvement and severity. Type 1 autosomal recessive cutis laxa (ARCL1) is a specific, life-threatening disorder with organ involvement, lung atelectasis and emphysema, diverticula of the gastrointestinal and genitourinary systems, and vascular anomalies. Associated cranial anomalies, late closure of the fontanel, joint laxity, hip dislocation, and inguinal hernia have been observed but are uncommon. Diminution of elastic fibers throughout the dermis and abnormal elastin components by electron microscopy are pathognomonic (Morava et al., 2009).Classification of autosomal recessive cutis laxa is further divided into type 2 (ARCL2), associated with bone dystrophy, joint laxity, and developmental delay; and type 3 (ARCL3), or de Barsy syndrome, which presents very severe symptoms, with ocular involvement and mental retardation (Davidson and Giro, 2002).
FBP1Fructose-1,6-bisphosphatase deficiencyFructose-1,6-bisphosphatase deficiency is an autosomal recessive disorder characterized by impaired gluconeogenesis. Patients present with hypoglycemia and metabolic acidosis on fasting and may have episodes of hyperventilation, apnea, hypoglycemia, and ketosis. Although the disorder may be lethal in the newborn period, proper treatment yields an excellent prognosis (Kikawa et al., 1997; Matsuura et al., 2002).
FBXO7Parkinson disease, type 15, autosomal recessiveParkinson disease, type 15 (PARK15) is a neurodegenerative disorder characterized by parkinsonian and pyramidal signs. Clinical manifestations include tremor, bradykinesia, rigidity, postural instability, spasticity, mainly in the lower limbs, and hyperreflexia.
FECHProtoporphyria, erythropoietic, autosomal recessiveErythropoietic protoporphyria is an inborn error of porphyrin metabolism caused by decreased activity of the enzyme ferrochelatase, the terminal enzyme of the heme biosynthetic pathway, which catalyzes the insertion of iron into protoporphyrin to form heme. EPP is characterized clinically by photosensitivity to visible light commencing in childhood, and biochemically by elevated red cell protoporphyrin levels (Todd, 1994).
FERMT1Kindler syndromeKindler syndrome is an autosomal recessive dermatosis characterized by congenital blistering, skin atrophy, photosensitivity, skin fragility, and scaling (Jobard et al., 2003).
FERMT3Leukocyte adhesion deficiency, type 3Leukocyte adhesion deficiency, type 3 (LAD3), also known as LAD1 variant (LAD1V), is an autosomal recessive disorder characterized by LAD1 (116920), type like immune deficiency and Glanzmann thrombasthenia (GT; 273800), type like bleeding problems. LAD3 results from mutations in FERMT3, or KINDLIN3, which encodes an intracellular protein that interacts with beta, type integrins in hematopoietic cells. In LAD3, the adhesive functions of integrins on both leukocytes and platelets are disrupted, most likely due to defects in activation, type dependent alterations of surface integrins that enable high, type avidity binding to ligands on target cells, a process termed 'inside, type out signaling' (Svensson et al., 2009; Zimmerman, 2009).
FGAAfibrinogenemia, congenitalCongenital afibrinogenemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FGA gene located on chromosomal region 4q28. The age of onset is variable. This disease is characterized by bleeding symptoms ranging from mild to severe resulting from reduced quantity and/or quality of circulating fibrinogen. The prevalence is 1/1,000,000 to 9/1,000,000.
FGBCongenital afibrinogenemiaCongenital afibrinogenemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FGB gene located on chromosomal region 4q28. The age of onset is variable. This disease is characterized by bleeding symptoms ranging from mild to severe resulting from reduced quantity and/or quality of circulating fibrinogen. The prevalence is 1/1,000,000 to 9/1,000,000.
FGD1Aarskog-Scott syndrome; Mental retardation, X-linked syndromic, type 16Aarskog-Scott syndrome, also known as faciogenital dysplasia, is an X-linked disorder characterized by short stature, hypertelorism, shawl scrotum, and brachydactyly, although there is wide phenotypic variability and other features, such as joint hyperextensibility, short nose, widow's peak, and inguinal hernia, may also occur. Most patients do not have mental retardation, but some may have neurobehavioral features. Carrier females may present with subtle features, such as widow's peak or short stature (Orrico et al., 2010). Aarskog-Scott syndrome with attention deficit-hyperactivity disorder and a form of syndromic X-linked mental retardation (MRXS16) are also caused by mutation in the FGD1 gene.
FGD4Charcot-Marie-Tooth disease, type 4HCharcot-Marie-Tooth disease, type 4H follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FGD4 gene located on chromosomal region 12p11.21. The age of onset is neonatal/infantile. This disease is characterized by slowly progressive muscle weakness in the distal extremities, and other common features include delayed walking, an abnormal gait, scoliosis and pes equines with toe retraction. The prevalence is 1/3,300.
FGF23Tumoral calcinosis, hyperphosphatemic, familial, type 2Hyperphosphatemic familial tumoral calcinosis (HFTC) is a condition characterized by an increase in the levels of phosphate in the blood (hyperphosphatemia) and abnormal deposits of phosphate and calcium (calcinosis) in the body's tissues. Calcinosis typically develops in early childhood to early adulthood. Calcinosis usually occurs in and just under skin tissue around the joints, most often the hips, shoulders, and elbows. Calcinosis may also develop in the soft tissue of the feet, legs, and hands. Rarely, calcinosis occurs in blood vessels or in the brain and can cause serious health problems. The deposits develop over time and vary in size. Larger deposits form masses that are noticeable under the skin and can interfere with the function of joints and impair movement. These large deposits may appear tumor-like (tumoral), but they are not tumors or cancerous. The number and frequency of deposits varies among affected individuals; some develop few deposits during their lifetime, while others may develop many in a short period of time.
FGF3Deafness, congenital with inner ear agenesis, microtia, and microdontiaCongenital deafness with labyrinthine aplasia, microtia, and microdontia (also called LAMM syndrome) is a condition that affects development of the ears and teeth. In people with this condition, the structures that form the inner ear are usually completely absent (labyrinthine aplasia). Rarely, affected individuals have some underdeveloped inner ear structures in one or both ears. The abnormalities of the inner ear cause a form of hearing loss called sensorineural deafness that is present from birth (congenital). Because the inner ear is important for balance as well as hearing, development of motor skills, such as sitting and crawling, may be delayed in affected infants. In addition, people with LAMM syndrome often have abnormally small outer ears (microtia) with narrow ear canals. They can also have unusually small, widely spaced teeth (microdontia).
FGGAfibrinogenemia, congenital; Hypofibrinogenemia, congenitalInherited disorders of fibrinogen affect either the quantity (afibrinogenemia and hypofibrinogenemia; 202400) or the quality (dysfibrinogenemia; 616004) of the circulating fibrinogen or both (hypodysfibrinogenemia; 616004). Afibrinogenemia is characterized by the complete absence of immunoreactive fibrinogen. Bleeding due to afibrinogenemia usually manifests in the neonatal period, with 85% of cases presenting umbilical cord bleeding, but a later age of onst is not unusual. Bleeding may occur in the skin, gastrointestinal tract, genitourinary tract, or the central nervous system, with intracranial hemorrhage being reported as the major cause of death. Patients are susceptible to spontaneous rupture of the spleen. Menstruating women may experience menometrorrhagia. First-trimester abortion is common. Both arterial and venous thromboembolic complications have been reported (Moerloose and Neerman-Arbez, 2009). Hypofibrinogenemia is characterized by reduced amounts of immunoreactive fibrinogen. Patients are often heterozygous carriers of afibrinogenemia mutations and are usually asymptomatic. However, they may bleed when exposed to trauma or if they have a second associated hemostatic abnormality. Women may experience miscarriages. Liver disease occurs in rare cases (Moerloose and Neerman-Arbez, 2009).
FHFumarase deficiencyFumarase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FH gene located on chromosomal region 1q42.1. The age of onset is neonatal/infantile. This disease is characterized by?hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies, although some patients present with only moderate intellectual impairment. The prevalence is below 1,000,000.
FHL1Emery-Dreifuss muscular dystrophy, type 6, X-linkedEmery-Dreifuss muscular dystrophy, type 6, X-linked follows an X-linked pattern of inheritance and is caused by pathogenic variants in the FHL1 gene located on chromosomal region Xq26. ?This is a condition that primarily affects muscles used for movement (skeletal?muscles) and the heart (cardiac muscle). Among the earliest features of this disorder are joint deformities called contractures. Contractures restrict the movement of certain joints, most often the elbows, ankles, and neck, and usually become noticeable in early childhood. Most affected individuals also experience muscle weakness and?wasting?that worsen slowly over time, beginning in muscles of the upper arms and lower legs and later also affecting muscles in the shoulders and hips. Almost all people with Emery-Dreifuss muscular dystrophy develop heart problems by adulthood. The X-linked type of this disorder affects an estimated 1 in 100,000 people.
FIG4Charcot-Marie-Tooth disease, type 4J; Yunis-Varon syndromeCharcot-Marie-Tooth disease, type 4J follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FIG4 gene located on chromosomal region 6q.21. The age of onset is neonatal/infantile. This disease is characterized by rapidly progressive, asymmetric motor neuron degeneration with slow nerve conduction velocities, weakness and paralysis, without sensory loss. The prevalence is 4/100,000 to 8/100,000. Mutations in the FIG4 gene have been also found in patient with Yunis-Varon syndrome. This disease is a severe autosomal recessive disorder characterized by skeletal defects, including cleidocranial dysplasia and digital anomalies, and severe neurologic involvement with neuronal loss. Enlarged cytoplasmic vacuoles are found in neurons, muscle, and cartilage. The disorder is usually lethal in infancy.
FKBP10Bruck syndrome 1Bruck syndrome 1 is characterized by congenital contractures with pterygia, onset of fractures in infancy or early childhood, postnatal short stature, severe limb deformity, and progressive scoliosis (McPherson and Clemens, 1997).
FKRPMuscular dystrophy-dystroglycanopathy, type 5A, 5B and 5CMuscular dystrophy-dystroglycanopathy type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FKRP gene located on chromosomal region 19q13.32. The age of onset is neonatal or early infancy. There are three subtypes of dystroglycanopathies related to FKRP gene: subtype 5A, 5B and 5C. Subtype 5A is the most severe phenotype and is associated with congenital brain and eye anomalies, cobblestone lissencephaly, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. Subtype 5B represents an intermediate phenotype with or without congenital mental retardation, white matter changes and structural brain abnormalities. Finally, subtype 5C is the less severe phenotype characterized by limb-girdle muscular dystrophy, variable age at onset, normal cognition, and no structural brain changes.
FKTNMuscular dystrophy-dystroglycanopathy, type 4A (Walker-Warburg syndrome); Type 4B; Type 4C (limb-girdle muscular dystrophy, type 13 [LGMD R13])Muscular dystrophy-dystroglycanopathy type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FKTN gene located on chromosomal region 9q31.2. The age of onset is neonatal or early infancy. There are three subtypes of dystroglycanopathies related to FKTN gene: subtype 4A, 4B and 4C. Subtype 4A is the most severe phenotype and is associated with congenital brain and eye anomalies, seizures, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. Subtype 4B represents an intermediate phenotype and congenital mental retardation is not a feature. Finally, subtype 4C is the less severe phenotype characterized by limb-girdle muscular dystrophy, onset in early childhood and cognition and brain structure are usually normal.
FLI1Bleeding disorder, platelet-type, type 21Bleeding disorder, platelet-type, type 21 (BDPLT21) is a hematologic disorder characterized by increased risk of bleeding resulting from a functional platelet defect. Platelets have decreased or even absent dense bodies and abnormally enlarged and fused alpha-granules, and they show defective secretion and aggregation responses to agonists. Platelets are usually enlarged, and some patients may have mild to moderate thrombocytopenia (Saultier et al., 2017). One family with a homozygous mutation in the FLI1 gene has been reported (Stevenson et al., 2015).
FLNAFLNA-related disordersMutation in FLNA causes a wide spectrum of disease including skeletal dysplasia, neuronal migration abnormality, cardiovascular malformation, intellectual disability and intestinal obstruction. FLNA-related disorders can be X-linked recessive (XLR) or X-linked dominant (XLD). Frontometaphyseal dysplasia-1 (FMD1;XLR) is 1 of 4 otopalatodigital syndromes caused by mutations in the FLNA gene. The disorders, which include otopalatodigital syndrome-1 (OPD1; XLD; OMIM?311300), otopalatodigital syndrome-2 (OPD2; XLD;?304120), and Melnick-Needles syndrome (MNS; XLD;?309350), constitute a phenotypic spectrum. At the mild end of the spectrum, males with OPD1 have cleft palate and mild skeletal anomalies with conductive deafness caused by ossicular anomalies. FMD1 is characterized by a generalized skeletal dysplasia, deafness, and urogenital defects. Males with OPD2 have disabling skeletal anomalies in addition to variable malformations in the hindbrain, heart, intestines, and kidneys that frequently lead to perinatal death. The most severe phenotype, MNS, is characterized by a skeletal dysplasia in the heterozygote. Affected males exhibit severe malformations similar to those observed in individuals with OPD2, resulting in prenatal lethality or death in the first few months of life (review by?Robertson, 2005).?Verloes et al. (2000)?suggested that these disorders constitute a single entity, which they termed 'frontootopalatodigital osteodysplasia.' Other studies confirm an association between FLNA gene mutation and lung disease, seen in more than 80% of patients with cerebral periventricular nodular heterotopia (PVNH; XLD; 300049); FLNA mutation also cause cardiac valvular dysplasia (XLR; 314400). De novo mutations and mosaic cases have been described.
FLNBSpondylocarpotarsal synostosis syndromeSpondylocarpotarsal synostosis (SCT) syndrome is an inherited syndrome characterized by disproportionate short stature, abnormalities of the vertebrae in the spine, scoliosisand lordosis, carpal and tarsal fusion (fusion of the bones in the hands and feet), clubfoot, and facial abnormalities such as round face, large forehead, and up-turned nostrils. Other features can include cleft palate, deafness, loose joints, and poor formation of tooth enamel.
FLVCR1Posterior column ataxia-retinitis pigmentosa syndromePosterior column ataxia-retinitis pigmentosa follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FLVCR1 gene located on chromosomal region 1q32.3. The age of onset is childhood. This disease is characterized by sensory ataxia, proprioceptive loss and blindness. The prevalence is <1 / 1.000.000.
FLVCR2Proliferative vasculopathy and hydranencephaly-hydrocephaly syndromeThe proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome is a rare autosomal recessive prenatally lethal disorder characterized by hydranencephaly, a distinctive glomerular vasculopathy in the central nervous system and retina, and diffuse ischemic lesions of the brain stem, basal ganglia, and spinal cord with calcifications. It is usually diagnosed by ultrasound between 26 and 33 weeks' gestation (Meyer et al., 2010).
FMN2Mental retardation, autosomal recessive, type 47Mental retardation, autosomal recessive, type 47 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT47 patients show delayed development, with cognition and speech more affected than motor skills.
FMO3TrimethylaminuriaTrimethylaminuria results from the abnormal presence of large amounts of volatile and malodorous trimethylamine within the body. This chemical, a tertiary aliphatic amine, is excreted in the urine, sweat (ichthyohidrosis), and breath, which take on the offensive odor of decaying fish (Mitchell, 1996).
FMR1Fragile X syndromeFragile X syndrome follows an X-linked pattern of inheritance and is caused by pathogenic variants in the FMR1 gene located on chromosomal region Xq27.3. The symptoms are variable depending on the range of CGG triplet expansion. In complete mutation the onset is infantile in men and is characterized by intellectual disability, characteristic appearance (large head, long face, prominent forehead and chin, protruding ears) joint laxity and large testes after puberty. In carrier female, the symptoms are milder and include primary ovarian insufficiency. The prevalence is 1/2,500 (full mutation allele) to 1/4,000 (prevalence of symptomatic cases) for both genders.
FOLR1Neurodegeneration due to cerebral folate transport deficiencyNeurodegeneration due to cerebral folate transport deficiency is an autosomal recessive disorder resulting from brain-specific folate deficiency early in life. Onset is apparent in late infancy with severe developmental regression, movement disturbances, epilepsy, and leukodystrophy. Recognition and diagnosis of this disorder is critical because folinic acid therapy can reverse the clinical symptoms and improve brain abnormalities and function (Steinfeld et al., 2009).
FOXE1Bamforth-Lazarus syndromeBamforth-Lazarus syndrome is a very rare syndrome of congenital hypothyroidism characterized by thyroid dysgenesis (in most cases athyreosis), cleft palate and spiky hair, with or without choanal atresia, and bifid epiglottis. Facial dysmorphism and porencephaly have been reported in isolated cases.
FOXE3Anterior segment dysgenesis, type 2, multiple subtypesAnterior segment dysgeneses (ASGD or ASMD)are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (Cheong et al., 2016).Anterior segment dysgenesis is sometimes divided into subtypes, including aniridia (106210), Axenfeld and Rieger anomalies, iridogoniodysgenesis, Peters anomaly, and posterior embryotoxon (Gould and John, 2002).Some patients with ASGD2 have been reported with a congenital primary aphakia subtype.Congenital primary aphakia is a rare developmental disorder characterized by absence of the lens, the development of which is normally induced during the fourth to fifth week of human embryogenesis. This original failure leads, in turn, to complete aplasia of the anterior segment of the eye, which is the diagnostic histologic criterion for CPAK. In contrast, in secondary aphakia, lens induction occurs and the lens vesicle develops to some degree, but is progressively resorbed perinatally, resulting in less severe ocular defects (Valleix et al., 2006).
FOXN1T-cell immunodeficiency, congenital alopecia and nail dystrophyT-cell immunodeficiency, congenital alopecia and nail dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FOXN1 gene located on chromosomal region 17q11.2. The age of onset is infantile. This disease is characterized by T-cell immunodeficiency, the skin disorder congenital alopecia, and nail dystrophy. The prevalence is <1:1,000,000.
FOXP3Immunodysregulation, polyendocrinopathy, and enteropathy, X-linkedImmunodysregulation, polyendocrinopathy, and enteropathy, X-linked (IPEX) is an X-linked recessive immunologic disorder characterized by onset in infancy of severe diarrhea due to enteropathy, type 1 diabetes mellitus, and dermatitis. Other features may include hypothyroidism, autoimmune hemolytic anemia, thrombocytopenia, lymphadenopathy, hepatitis, and nephritis. The disorder may be fatal before age 2 years if not aggressively treated. Long-term therapeutic options include immunosuppression and hematopoietic stem cell transplantation (d'Hennezel et al., 2012).
FOXRED1Mitochondrial complex I deficiency, nuclear type 19Mitochondrial complex I deficiency, nuclear type 19 (MC1DN19) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN19 transmission pattern is consistent with autosomal recessive inheritance.
FRAS1Fraser syndrome, type 1Fraser syndrome, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the gene FRAS1 located on chromosomal region 4q21.21. The age of onset is early infancy. Twenty-five per cent of affected infants are stillborn, while 20 % die before the age of 1 year. This disease is characterized mainly by cryptophthalmos and syndactyly, besides urinary and genital anormalities. The prevalence is <1:1,000,000.
FREM1Manitoba oculotrichoanal syndromeManitoba-oculo-tricho-anal (MOTA) syndrome is a rare condition defined by eyelid colobomas, cryptophthalmos, and anophthalmia/microphthalmia, an aberrant hairline, a bifid or broad nasal tip, and gastrointestinal anomalies such as omphalocele and anal stenosis. Autosomal recessive inheritance was assumed because of consanguinity in the Oji-Cre population of Manitoba in which the syndrome was first described (Slavotinek et al., 2011).
FREM2Fraser syndrome, type 2Fraser syndrome, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the gene FREM2 located on chromosomal region 13q13.3. The age of onset is early infancy. Twenty-five per cent of affected infants are stillborn, while 20 % die before the age of 1 year. This disease is characterized mainly by cryptophthalmos and syndactyly, besides urinary and genital anormalities. The prevalence is <1:1,000,000.
FRMD7Nystagmus 1, congenital, X-linked; Nystagmus, infantile periodic alternating, X-linkedClassic congenital or infantile nystagmus presents as conjugate, horizontal oscillations of the eyes, in primary or eccentric gaze, often with a preferred head turn or tilt. Other associated features may include mildly decreased visual acuity, strabismus, astigmatism, and occasionally head nodding. Eye movement recordings reveal that infantile nystagmus is predominantly a horizontal jerk waveform, with a diagnostic accelerating velocity slow phase. However, pendular and triangular waveforms may also be present. The nystagmus may rarely be vertical. As these patients often have normal visual acuity, it is presumed that the nystagmus represents a primary defect in the parts of the brain responsible for ocular motor control; thus the disorder has sometimes been termed 'congenital motor nystagmus' (Tarpey et al., 2006; Shiels et al., 2007).Congenital nystagmus may also be a feature of other ocular diseases, such as albinism (see, e.g., OCA1A, 203100), achromatopsia (see, e.g., ACHM3, 262300), and Leber congenital amaurosis (see, e.g., LCA1, 204000). Congenital nystagmus is associated with at least 3 X-linked disorders: Nettleship-Falls ocular albinism (OA1; 300500), which maps to Xp22.3; complete congenital stationary night blindness (CSNB1; 310500), which maps to Xp11.4; and blue-cone monochromatism (CBBM; 303700), which maps to Xq28.
FRMPD4Mental retardation, X-linked, type 104Mental retardation, X-linked, type 104 (MRX104) is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
FSHBHypogonadotropic hypogonadism, type 24, without anosmiaHypogonadotropic hypogonadism, type 24 (HH24) without anosmia is a form of hypogonadotropic hypogonadism, a group of disorders characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic- pituitary axis. HH24 is characterized by primary amenorrhea in women, oligo or azoospermia with low to normal testosterone levels in men, and infertility.
FSHROvarian dysgenesis 1Hypergonadotropic ovarian failure is a heterogeneous disorder that, in the most severe forms, is a result of ovarian dysgenesis 1. Ovarian dysgenesis 1 accounts for about half the cases of primary amenorrhea (Timmreck and Reindollar, 2003), variable development of secondary sex characteristics, poorly developed streak ovaries, and high serum levels of follicle-stimulating hormone (FSH) and luteinizing hormone (LH).
FTCDGlutamate formiminotransferase deficiencyGlutamate formiminotransferase deficiency is an autosomal recessive disorder and the second most common inborn error of folate metabolism. Features of a severe phenotype include elevated levels of formiminoglutamate (FIGLU) in the urine in response to histidine administration, megaloblastic anemia, and mental retardation. Features of a mild phenotype include high urinary excretion of FIGLU in the absence of histidine administration, mild developmental delay, and no hematologic abnormalities (Hilton et al., 2003).
FTLL-ferritin deficiencyL-ferritin deficiency is a condition characterized by low levels of ferritin in serum and tissues in the absence of other hematological symptoms. Seizures and mild neuropsychologic impairment may manifest in individuals with complete ferritin deficiency.
FTOGrowth retardation, developmental delay, facial dysmorphismGrowth retardation, developmental delay, and facial dysmorphism (GDFD) is an autosomal recessive multiple congenital anomaly syndrome characterized by severe psychomotor retardation, poor overall growth, and dysmorphic facial features. Additional features may include cardiac malformations and deafness (Daoud et al., 2016).
FUCA1FucosidosisFucosidosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the FUCA1 gene located on chromosomal region 1p36.11. The age of onset is infantile. This disease is characterized by facial dysmorphism, dysostosis multiplex, moderate hepatomegaly, severe intellectual deficit, deafness, and according to age, angiokeratomas. The prevalence is <1:1,000,000.
FUT8Congenital disorder of glycosylation with defective fucosylation, type 1Congenital disorder of glycosylation with defective fucosylation, type 1 is an autosomal recessive multisystemic disorder apparent from birth. Affected infants have poor growth, failure to thrive, hypotonia, skeletal anomalies, and delayed psychomotor development with intellectual disability. Additional highly variable congenital defects may be observed (Ng et al., 2018).
FXNFriedreich ataxiaFriedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by progressive gait and limb ataxia with associated limb muscle weakness, absent lower limb reflexes, extensor plantar responses, dysarthria, and decreased vibratory sense and proprioception. Onset is usually in the first or second decade, before the end of puberty. It is one of the most common forms of autosomal recessive ataxia, occurring in about 1 in 50,000 individuals. Other variable features include visual defects, scoliosis, pes cavus, and cardiomyopathy (Delatycki et al., 2000). Pandolfo (2008) provided an overview of Friedreich ataxia, including pathogenesis, mutation mechanisms, and genotype/phenotype correlation.
FYCO1Cataract 18, autosomal recessiveMutations in the FYCO1 gene have been identified in families with autosomal recessive cataract described as congenital and congenital nuclear.
FZD6Nail disorder, nonsyndromic congenital, type 10 (claw-shaped nails)Nonsyndromic congenital nail disorder, type 10 is characterized by onychauxis (thick nails), hyponychia, and onycholysis of all nails, with claw-shaped fingernails in some individuals (Frojmark et al., 2011).
G6PCGlycogen storage disease, type 1AGlycogen storage disease, type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the G6PC gene located on chromosomal region 17q21.31. The age of onset is infantile. This disease is characterized by poor tolerance to fasting, significant hepatomegaly and growth retardation. The incidence is 1/100,000.
G6PC3Dursun syndromeDursun syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the G6PC3 gene located on chromosomal region 17q21.31. This disease is characterized by familial pulmonary arterial hypertension, cardiac abnormalities including atrial septal defect, leukopenia including intermittent neutropenia, lymphopenia, monocytosis, and anemia. The prevalence is 1:100,000.
G6PDHemolytic anemia, G6PD deficient (favism)Hemolytic anemia, G6PD deficient (favism) is the most common genetic cause of chronic and drug-, food-, or infection-induced hemolytic anemia. G6PD catalyzes the first reaction in the pentose phosphate pathway, which is the only NADPH-generation process in mature red cells; therefore, defense against oxidative damage is dependent on G6PD. Most G6PD-deficient patients are asymptomatic throughout their life, but G6PD deficiency can be life-threatening. The most common clinical manifestations of G6PD deficiency are neonatal jaundice and acute hemolytic anemia, which in most patients is triggered by an exogenous agent, e.g., primaquine or fava beans. Acute hemolysis is characterized by fatigue, back pain, anemia, and jaundice. Increased unconjugated bilirubin, lactate dehydrogenase, and reticulocytosis are markers of the disorder. The striking similarity between the areas where G6PD deficiency is common and Plasmodium falciparum malaria (611162) is endemic provided evidence that G6PD deficiency confers resistance against malaria (Cappellini and Fiorelli, 2008).
GAAGlycogen storage disease, type 2Glycogen storage disease, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GAA gene located on chromosomal region 17q25.3. There are two forms: adult and infantile.The age of onset in this last form is before the age of three months. This disease is characterized by severe hypotonia, hypertrophic cardiomyopathy and progressive hepatomegaly. The incidence is 1/57,000 for the adult form and 1/138,000 for infantile form.
GALCKrabbe diseaseKrabbe disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GALC gene located on chromosomal region 14q31.3. There are two forms of the disease: infantile form (2-6 months onset) more severe and adult form less severe. It is a degenerative disorder that affects the nervous system characterized by a muscle stiffness, blindness, deafness, and eventually death. The incidence is 1/100,000-1/250,000 and the prevalence is 1/100,000.
GALEGalactose epimerase deficiencyEpimerase-deficiency galactosemia was originally described as a benign condition in which GALE impairment is restricted to circulating red and white blood cells (Gitzelmann, 1972). Fibroblasts, liver, phytohemagglutinin-stimulated leukocyes, and Epstein Barr virus-transformed lymphoblasts from these patients all demonstrated normal or near-normal levels of GALE, leading to the designation 'peripheral' (or 'isolated') epimerase deficiency. A second form of epimerase deficiency became apparent in which a patient, despite normal GALT activity, presented with symptoms reminiscent of classic galactosemia and demonstrated severely impaired GALE activity in both red blood cells and fibroblasts (Holton et al., 1981). This form was designated 'generalized' epimerase deficiency. Openo et al. (2006) demonstrated that epimerase deficiency is in fact not a binary condition but is, rather, a continuum disorder. GALE encodes the third enzyme in the Leloir pathway of galactose metabolism. Galactosemia 1 is classic galactosemia (230400), caused by deficiency of the second enzyme in the Leloir pathway, galactose-1-phosphate uridylyl-transferase (GALT; 606999). Galactosemia 2 (230200) is caused by deficiency of the first enzyme in the Leloir pathway, galactokinase (GALK; 604313).
GALK1Galactokinase deficiency with cataractsGalactokinase deficiency is an autosomal recessive disorder that causes cataract formation in children not maintained on a lactose-free diet. Cataract formation is the result of osmotic phenomena caused by the accumulation of galactitol in the lens (Asada et al., 1999).
GALNSMucopolysaccharidosis, type 4AMucopolysaccharidosis, type 4A is an autosomal recessive lysosomal storage disease characterized by intracellular accumulation of keratan sulfate and chondroitin-6-sulfate. Key clinical features include short stature, skeletal dysplasia, dental anomalies, and corneal clouding. Intelligence is normal and there is no direct central nervous system (CNS) involvement, although the skeletal changes may result in neurologic complications. There is variable severity, but patients with the severe phenotype usually do not survive past the second or third decade of life (Montano et al., 2008).McKusick (1972) noted that between 1929 and 1959, a miscellany of skeletal disorders was included in the Morquio category, including various types of spondyloepiphyseal dysplasia (183900) and multiple epiphyseal dysplasia (132400). Nelson et al. (1988) proposed the division of MPS IVA into 3 subgroups: severe classic, intermediate, and mild, reflecting clinical variability observed in 12 enzymatically proven cases. Those who were only mildly affected showed a relatively high residual enzyme activity.
GALNT3Tumoral calcinosis, hyperphosphatemic, familial, type 1Hyperphosphatemic familial tumoral calcinosis (HFTC) is a condition characterized by an increase in the levels of phosphate in the blood (hyperphosphatemia) and abnormal deposits of phosphate and calcium (calcinosis) in the body's tissues. Calcinosis typically develops in early childhood to early adulthood. Calcinosis usually occurs in and just under skin tissue around the joints, most often the hips, shoulders, and elbows. Calcinosis may also develop in the soft tissue of the feet, legs, and hands. Rarely, calcinosis occurs in blood vessels or in the brain and can cause serious health problems. The deposits develop over time and vary in size. Larger deposits form masses that are noticeable under the skin and can interfere with the function of joints and impair movement. These large deposits may appear tumor-like (tumoral), but they are not tumors or cancerous. The number and frequency of deposits varies among affected individuals; some develop few deposits during their lifetime, while others may develop many in a short period of time.
GALTGalactosemiaGalactosemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GALT gene located on chromosomal region 9p13.3. The age of onset is neonatal. This disease is characterized by feeding difficulties, lethargy, and severe liver disease. Long-term complications appear including cognitive impairments, motor deficits, and ovarian dysfunction with reduced fertility in women and diminished bone density. The prevalence is 1/40,000-1/60,000.
GAMTCerebral creatine deficiency syndrome type 2Cerebral creatine deficiency syndrome type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GAMT gene located on chromosomal region 19p13.3. The age of onset is infantile. This disease is characterized by intellectual disability, seizures and behavioral problems, often in conjunction with pyramidal and/or extrapyramidal manifestations with muscular hypotony. Biochemical symptoms are also included with high urinary excretion of guanidinoacetate, low urinary excretion of creatinine and creatine depletion in brain and muscles.
GANGiant axonal neuropathy, type 1Giant axonal neuropathy, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GAN gene located on chromosomal region 16q23.2. The age of onset is infantile. This disease is characterized by a progressive motor and sensitive peripheral and central nervous system neuropathy. Twenty families have been reported with this disease but the frequency is likely to be under-estimated.
GATA1Anemia, X-linked, with/without neutropenia and/or platelet abnormalities; Thrombocytopenia with beta-thalassemia, X-linked; Thrombocytopenia, X-linked, with or without dyserythropoietic anemiaAnemia, X-linked, with/without neutropenia and/or platelet abnormalities (XLANP) is an X-linked recessive hematologic disorder characterized by early-onset anemia and bone marrow erythroid hypoplasia with variable neutropenia. Some patients may have low platelets or platelet abnormalities. The severity is variable. Some patients have shown a favorable response to corticosteroid treatment (Hollanda et al., 2006; Sankaran et al., 2012). Mutations in the GATA1 gene also cause other phenotypes. Thrombocytopenia with beta-thalassemia, X-linked (XLTT) is an X-linked recessive hematologic disorder characterized by variable thrombocytopenia, hemolytic anemia, splenomegaly, and abnormalities in hemoglobin chain synthesis (Ciovacco et al., 2008 and Millikan et al., 2011). Thrombocytopenia, X-linked, with or without dyserythropoietic anemia (XLTDA) is an X-linked recessive hematologic disorder characterized by thrombocytopenia and abnormal platelet morphology and function due to defective platelet maturation. Some patients have a variable severity of dyserythropoietic anemia (Millikan et al., 2011).
GATMCerebral creatine deficiency syndrome, type 3Cerebral creatine deficiency syndrome, type 3 is an autosomal recessive disorder characterized by developmental delay/regression, mental retardation, severe disturbance of expressive and cognitive speech, and severe depletion of creatine/phosphocreatine in the brain (Schulze, 2003). Most patients develop a myopathy characterized by muscle weakness and atrophy later in life. Oral creatine supplementation can offer symptom improvement (Edvardson et al., 2010).
GBAGaucher diseaseGaucher disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GBA gene located on chromosomal region 1q22. Gaucher disease encompasses a continuum of clinical findings from a perinatal lethal disorder to an asymptomatic type. There are three major clinical types (1, 2, and 3) and two other subtypes (perinatal-lethal and cardiovascular). Type 1 is characterized by the presence of clinical or radiographic evidence of bone disease, hepatosplenomegaly, anemia and thrombocytopenia, lung disease, and the absence of primary central nervous system disease. GD types 2 and 3 are characterized by the presence of primary neurologic disease. Type 2 has an onset before age two years, limited psychomotor development, and a rapidly progressive course with death by age two to four years. Type 3 may have onset before age two years, but often have a more slowly progressive course, with survival into the third or fourth decade. The perinatal-lethal form is associated with ichthyosiform or collodion skin abnormalities or with nonimmune hydrops fetalis. The cardiovascular form is characterized by calcification of the aortic and mitral valves, mild splenomegaly, corneal opacities, and supranuclear ophthalmoplegia. Cardiopulmonary complications have been described with all the clinical subtypes, although varying in frequency and severity. The incidence is 1/60,000 and the prevalence is approximately 1/100,000.
GBE1Glycogen storage disease, type 4Glycogen storage disease, type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GBE1 gene located on chromosomal region 3p12.2. The age of onset is infantile. This disease is characterized by failure to thrive; hepatomegaly, liver dysfunction, and progressive liver cirrhosis; hypotonia; cardiomyopathy and, finally, death.
GCDHGlutaricaciduria, type 1Glutaricaciduria, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GCDH gene located on chromosomal region 19p13.2. The age of onset is infantile or neonatal. This disease is characterized by encephalopathic crises resulting in striatal injury and a severe dystonic dyskinetic movement disorder. The prevalence is 1 in 100,000 births.
GCH1Hyperphenylalaninemia, BH4-deficient, type BHyperphenylalaninemia, BH4-deficient, type B is a disease characterized by malignant hyperphenylalaninemia due to tetrahydrobiopterin deficiency, and defective neurotransmission due to depletion of the neurotransmitters dopamine and serotonin. The principal symptoms include: psychomotor retardation, tonicity disorders, convulsions, drowsiness, irritability, abnormal movements, hyperthermia, hypersalivation, and difficulty swallowing. Some patients may present a phenotype of intermediate severity between severe hyperphenylalaninemia and mild dystonia. In this intermediate phenotype, there is marked motor delay, but no mental retardation and only minimal, if any, hyperphenylalaninemia.
GCKPermanent neonatal diabetes mellitus (PNDM)Permanent neonatal diabetes mellitus (PNDM) is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins.
GCNT2Cataract 13, with adult i phenotypeThe i and I antigens of the I blood group system (110800) are carbohydrate structures carried on glycolipids and glycoproteins and are characterized as straight or branched glycochains composed of repeating N-acetyllactosamine (LacNAc) units, respectively. Conversion of i antigen into an I-active structure requires the activity of the I-branching enzyme, beta-1,6-N-acetylglucosaminyltransferase (GCNT2; 600429), which adds the decisive GlcNAc-beta-1-6 branch onto the straight poly-LacNAc chains. Expression of the i and I antigens on red blood cells (RBCs) is reciprocal and developmentally regulated. Adult human RBCs predominantly express I antigen, whereas fetal and neonatal RBCs predominantly express i antigen. After birth, I antigen levels increase gradually as i antigen levels fall, with the normal Ii status of adult RBCs reached after about 13 to 20 months. Mutations that specifically affect 1 of the 3 variants produced by the GCNT2 gene cause the rare adult i phenotype (110800), in which adult RBCs are rich in i antigen and contain low levels of I antigen. Mutations that eliminate all 3 GCNT2 variants cause the adult i phenotype with congenital cataract (Yu and Lin, 2011).
GDAP1Charcot-Marie-Tooth disease, recessive intermediate, type AAutosomal recessive intermediate Charcot-Marie-Tooth disease type A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GDAP1 gene located on chromosomal region 8q21.11. The age of onset is usually in early childhood. This disease is characterized by by distal sensory impairment predominantly affecting the lower limbs and resulting in walking difficulties due to muscle weakness and atrophy. The upper limbs may also be affected. The prevalence is below 1/1,000,000.
GDF1Right atrial isomerism (Ivemark syndrome)Right atrial isomerism is a severe complex congenital heart defect resulting from embryonic disruption of proper left-right axis determination. RAI is usually characterized by complete atrioventricular septal defect with a common atrium and univentricular AV connection, total anomalous pulmonary drainage, and transposition or malposition of the great arteries. Affected individuals present at birth with severe cardiac failure. Other associated abnormalities include bilateral trilobed lungs, midline liver, and asplenia, as well as situs inversus affecting other organs. Left atrial isomerism (LAI) is a related disorder with a somewhat better prognosis. LAI is characterized by bilateral superior vena cava, interruption of the intrahepatic portion of the inferior vena cava, partial anomalous pulmonary venous drainage, and ventricular septal defect. Patients with LAI may have polysplenia and bilateral bilobed lungs, as well as situs inversus affecting other organs. Both RAI and LAI malformation complexes have classically been referred to as Ivemark syndrome (Eronen et al., 2004; Kaasinen et al., 2010).
GDF5Chondrodysplasia, Grebe typeGrebe chondrodysplasia is an autosomal recessive disorder characterized by severe abnormality of the limbs and limb joints. The severity of limb shortening progresses in a proximal-distal gradient, with the hands and feet being most affected. The fingers and toes lack articulation and appear as skin appendages. In contrast, axial skeletal structures and the craniofacial skeleton are not affected. Heterozygous individuals are of average stature and have mild skeletal abnormalities (Thomas et al., 1997).
GDF6Leber congenital amaurosis 17Leber congenital amaurosis 17 is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or almost absent pupillary responses, photophobia, high hyperopia and keratoconus.
GDI1Mental retardation, X-linked, type 41Mental retardation, X-linked, type 41 (MRX41) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
GFERMyopathy, mitochondrial progressive, with congenital cataract, hearing loss, and developmental delayMyopathy, mitochondrial progressive, with congenital cataract, hearing loss and developmental delay is a disease characterized by progressive myopathy and partial combined respiratory-chain deficiency, congenital cataract, sensorineural hearing loss, and developmental delay.
GFM1Combined oxidative phosphorylation deficiency, type 1Combined oxidative phosphorylation deficiency, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GFM1 gene located on chromosomal region 3q25.32. The age of onset is from early infancy until adult. This disease is characterized by ptosis, external ophthalmoplegia, proximal myopathy and exercise intolerance, cardiomyopathy, sensorineural deafness, optic atrophy, pigmentary retinopathy, and diabetes mellitus.
GFPT1Myasthenia, congenital, type 12, with tubular aggregatesCongenital myasthenic syndrome, type 12 is an autosomal recessive neuromuscular disorder characterized by onset of proximal muscle weakness in the first decade. EMG classically shows a decremental response to repeated nerve stimulation. Affected individuals show a favorable response to acetylcholinesterase (AChE) inhibitors (Senderek et al., 2011).
GGCXVitamin K-dependent clotting factors, combined deficiency of, type 1Deficiency of all vitamin K-dependent clotting factors leads to a bleeding tendency that is usually reversed by oral administration of vitamin K. Acquired forms of the disorder can be caused by intestinal malabsorption of vitamin K. Familial multiple coagulation factor deficiency is rare. Clinical symptoms of the disease include episodes of intracranial hemorrhage in the first weeks of life, sometimes leading to a fatal outcome. The pathomechanism is based on a reduced hepatic gamma-carboxylation of glutamic acid residues of all vitamin K-dependent blood coagulation factors, as well as the anticoagulant factors protein C (612283) and protein S (176880). Posttranslational gamma-carboxylation of proteins enables the calcium-dependent attachment of the proteins to the phospholipid bilayer of membranes, an essential prerequisite for blood coagulation. Vitamin K1 acts as a cofactor for the vitamin K-dependent carboxylase in liver microsomes, GGCX.
GH1Growth hormone deficiency, isolated, type 1A; Kowarski syndromeGrowth hormone deficiency, isolated, type IA is an isolated growth hormone deficiency characterized by autosomal recessive inheritance of severe dwarfism with onset by 6 months of age and variable development of antibodies to growth hormone following exogenous supplementation that has material basis in null mutations in the GH1 gene on chromosome 17q23.3. Mutation in the GH1 gene also causes Kowarski syndrome. Kowarski syndrome, or short stature associated with bioinactive growth hormone, is characterized clinically by normal or slightly increased GH secretion, pathologically low IGF1 (147440) levels, and normal catch-up growth on GH replacement therapy (Besson et al., 2005).
GHRHRGrowth hormone deficiency, isolated, type 1BGrowth hormone deficiency, isolated, type 1B is characterized by low but detectable levels of GH, short stature, significantly retarded bone age, and a positive response and immunologic tolerance to GH therapy.
GHSRGrowth hormone deficiency, isolated partialGrowth hormone deficiency, isolated partial is a disorder characterized by partial growth hormone deficiency resulting in growth delay and short stature, sometimes associated with recurrent episodes of abdominal pain, vomiting, ketosis and hypoglycemia.
GIFIntrinsic factor deficiencyIntrinsic factor deficiency, or congenital pernicious anemia (PA), is a rare disorder characterized by the lack of gastric intrinsic factor in the presence of normal acid secretion and mucosal cytology and the absence of GIF antibodies that are found in the acquired form of pernicious anemia (170900).
GIPC3Deafness, autosomal recessive, type 15This form of autosomal recessive deafness is sensorineural and nonsyndromic, and shows prelingual onset (Charizopoulou et al., 2011).
GJA1Craniometaphyseal dysplasia, autosomal recessiveCraniometaphyseal dysplasia, autosomal recessive follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GJA1 gene located on chromosomal region 6q22.31. The age of onset is infantile. This disease is characterized by hyperostosis and sclerosis of the craniofacial bones associated with abnormal modeling of the metaphyses. Sclerosis of the skull may lead to asymmetry of the mandible, as well as to cranial nerve compression, that may finally result in hearing loss and facial pals. The prevalence is below 1/1,000,000.
GJB1Charcot-Marie-Tooth neuropathy, X-linked dominant, type 1Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory peripheral neuropathies. On the basis of electrophysiologic properties and histopathology, CMT has been divided into primary peripheral demyelinating (type 1) and primary peripheral axonal (type 2) neuropathies. The demyelinating neuropathies classified as CMT type 1, also known as HMSN I, are characterized by severely reduced motor nerve conduction velocities (NCV) (less than 38 m/s) and segmental demyelination and remyelination with onion bulb formations on nerve biopsy (CMT1B; 118200). The axonal neuropathies classified as CMT type 2, also known as HMSN II, are characterized by normal or mildly reduced NCVs and chronic axonal degeneration and regeneration on nerve biopsy (CMT2A1; 118210). Distal hereditary motor neuropathy (dHMN) (158590) is a spinal type of CMT characterized by exclusive motor involvement and sparing of sensory nerves (Pareyson, 1999). There are X-linked, autosomal dominant (118200), and autosomal recessive (214400) forms of CMT.The form of Charcot-Marie-Tooth neuropathy that maps to chromosome Xq13 (CMTX1) is X-linked dominant or X-linked intermediate; heterozygous females are more mildly affected than are hemizygous males.
GJB2Deafness, autosomal recessive, type 1AAutosomal recessive nonsyndromic sensorineural deafness type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GJB2 gene located on chromosomal region 13q12.11. The age of onset is infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
GJB6Deafness, autosomal recessive, type 1BAutosomal recessive nonsyndromic sensorineural deafness type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GJB6 gene located on chromosomal region 13q12.11. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment. No other associated medical findings are present.
GJC2Spastic paraplegia, type 44, autosomal recessiveAutosomal recessive spastic paraplegia type 44 (SPG44) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GJC2 gene located on chromosomal region 1q42.13. This disease is characterized by a late-onset, slowly progressive spastic paraplegia associated with mild ataxia and dysarthria, upper extremity involvement (i.e. loss of finger dexterity, dysmetria), and mild cognitive impairment, without the presence of nystagmus. A hypomyelinating leukodystrophy and thin corpus callosum is observed in all cases and psychomotor development is normal or near normal. The prevalence is below 1/1,000,000.
GKGlycerol kinase deficiencyGlycerol kinase deficiency (GKD) is a metabolic disorder manifesting as 3 clinically distinct forms: infantile, juvenile, and adult. The infantile form is the most severe and is associated with severe developmental delay and adrenal insufficiency. Patients with the adult form have no symptoms and are often detected fortuitously. GKD results in hyperglycerolemia, a condition characterized by the accumulation of glycerol in the blood and urine.
GLAFabry diseaseFabry disease is an X-linked inborn error of glycosphingolipid catabolism resulting from deficient or absent activity of the lysosomal enzyme alpha-galactosidase A. This enzymatic defect leads to the systemic accumulation of globotriaoslyceramide (Gb3) and related glycosphingolipids in the plasma and cellular lysosomes of vessels, nerves, tissues, and organs throughout the body (Nance et al., 2006). The disorder is a systemic disease, manifest as progressive renal failure, cardiac disease, cerebrovascular disease, small-fiber peripheral neuropathy, and skin lesions, among other abnormalities (Schiffmann, 2009).An atypical variant of Fabry disease has been reported in which cardiac disease, specifically left ventricular hypertrophy, with or without renal failure, develops in the sixth decade of life. These patients have residual GLA activity (Nakao et al., 1995; Nakao et al., 2003). Although Fabry disease was previously considered to be an X-linked recessive disorder, Wang et al. (2007) found that heterozygous women with Fabry disease experience significant life-threatening conditions requiring medical treatment and intervention. Thus, heterozygous Fabry women should not be called carriers, as this term underestimates the seriousness of the disease in these patients. Clarke (2007) and Schiffmann (2009) provided detailed reviews of Fabry disease.
GLB1GM1-gangliosidosis, types 1-3; Mucopolysaccharidosis, type 4B (Morquio)Gangliosidosis GM1, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GLB1 gene located on chromosomal region 3p22.3. Although the three types differ in severity, their features can overlap significantly. The age of onset in type 1 is infantile, in type 2 is late-infantile or juvenile and adult in type 3. This disease is characterized by arrest/regression of neurological development, hypotonia, visceromegaly, macular cherry-red spots, dysostosis and coarse facial features. The prevalence is 1:100,000 a 200,000 newborn.
GLDCGlycine encephalopathyGlycine encephalopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in GLDC gene located on chromosomal region 9p24.1. The age of onset is neonatal/infantile. This disease is characterized by lethargy or even coma, hypotonia, hiccups, myoclonic jerks, and breathing/swallowing disorders, with subsequent intellectual deficit, spasticity and intractable seizures. The prevalence is 1:1,000,000-9:1,000,000.
GLE1Lethal congenital contracture syndrome, type 1; Congenital arthrogryposis with anterior horn cell diseaseLethal congenital contracture syndrome, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GLE1 gene located on chromosomal region 9q34.11. The age of onset is neonatal. This disease is characterized by total fetal akinesia (detectable since the 13th week of gestation) accompanied by hydrops, micrognathia, pulmonary hypoplasia, pterygia and multiple joint contractures (usually flexion contractures in the elbows and extension in the knees), leading invariably to death before the 32nd week of gestation. Lack of anterior horn motoneurons, severe atrophy of the ventral spinal cord and severe skeletal muscle hypoplasia are characteristic neuropathological findings, with no evidence of other organ structural anomalies. Mutation in the GLE1 gene can also cause congenital arthrogryposis with anterior horn cell disease (CAAHD). CAAHD is an autosomal recessive neuromuscular disorder with highly variable severity. Affected individuals are usually noted to have contractures in utero on prenatal ultrasound studies, and present at birth with generalized contractures manifest as arthrogryposis multiplex congenita (AMC). Patients have severe hypotonia with respiratory insufficiency, often resulting in death in infancy or early childhood. Some patients may survive into later childhood with supportive care, but may be unable to walk or sit independently due to a combination of muscle weakness and contractures. Cognition may be normal. The disorder also includes multiple congenital anomalies associated with AMC and hypotonia, including high-arched palate, myopathic facies, and bulbar weakness. Neuropathologic studies demonstrate severe loss of anterior horn cells in the spinal cord, as well as diffuse motor neuron axonopathy (summary by Smith et al., 2017 and Tan et al., 2017).
GLIS2Nephronophthisis, type 7Nephronophthisis, type 7 is an autosomal recessive disorder resulting in end-stage renal disease during childhood or adolescence. It is a progressive tubulo- interstitial kidney disorder histologically characterized by modifications of the tubules with thickening of the basement membrane, interstitial fibrosis and, in the advanced stages, medullary cysts.
GLIS3Diabetes mellitus, neonatal, with congenital hypothyroidismNeonatal diabetes mellitus with congenital hypothyroidism (NDH) syndrome is characterized by intrauterine growth retardation and onset of nonimmune diabetes mellitus within the first few weeks of life. Other features include renal parenchymal disease, primarily renal cystic dysplasia, and hepatic disease, with hepatitis in some patients and hepatic fibrosis and cirrhosis in others. Facial dysmorphism, when present, consistently involves low-set ears, epicanthal folds, flat nasal bridge, long philtrum, and thin upper lip. Most patients exhibit developmental delay (Dimitri et al., 2015).
GLRA1Hyperekplexia, type 1Hyperekplexia, type 1 is an early-onset neurologic disorder characterized by an exaggerated startle response to sudden, unexpected auditory or tactile stimuli. Affected individuals have brief episodes of intense, generalized hypertonia in response to stimulation. Neonates may have prolonged periods of rigidity and are at risk for sudden death from apnea or aspiration. Many affected infants have inguinal hernias. The symptoms tend to resolve after infancy, but adults may have increased startle-induced falls and/or experience nocturnal muscle jerks (Ryan et al., 1992).
GLRBHyperekplexia, type 2Hyperekplexia, type 2 is a neurologic disorder characterized by muscular rigidity of central nervous system origin, particularly in the neonatal period, and by an exaggerated startle response to unexpected acoustic or tactile stimuli.
GLRX5Anemia, sideroblastic, type 3, pyridoxine-refractory; Spasticity, childhood-onset, with hyperglycinemiaAnemia, sideroblastic, type 3 (SIDBA3), pyridoxine-refractory is an autosomal recessive hematologic disorder characterized by onset of anemia in adulthood. Affected individuals show signs of systemic iron overload, and iron chelation therapy may be of clinical benefit (sLiu et al., 2014). SIDBA3, is caused by homozygous or compound heterozygous mutation in the GLRX5 gene on chromosome 14q32. Mutation in GLRX5 gene also causes spasticity, childhood-onset, with hyperglycinemia (SPAHGC). Childhood-onset spasticity with hyperglycinemia is an autosomal recessive disorder characterized by onset of slowly progressive spasticity that results in impaired gait in the first decade of life. Imaging of the central nervous system shows leukodystrophy and/or lesions in the upper spinal cord. More variable features include visual defects and mild learning disabilities. Serum glycine is increased, but CSF glycine is only mildly increased or normal; serum lactate is normal. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including SPAHGC, appear to result from defects of mitochondrial lipoate biosynthesis (summary by Baker et al., 2014)
GLULGlutamine deficiency, congenitalCongenital glutamine deficiency is a severe autosomal recessive disorder characterized by onset at birth of encephalopathy, lack of normal development, seizures, and hypotonia associated with variable brain abnormalities (Haberle et al., 2011).
GLYCTKD-glyceric aciduriaD-glyceric aciduria is a rare autosomal recessive metabolic disorder with a highly variable phenotype. Some patients have an encephalopathic presentation, with severe mental retardation, seizures, microcephaly, and sometimes early death, whereas others have a mild phenotype with only mild speech delay or even normal development (Sass et al., 2010).
GM2AGM2-gangliosidosis, AB variantGM2-gangliosidosis, AB variant follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GM2A gene located on chromosomal region 5q33.1. The age of onset is infantile. This disease is characterized by a group of neurodegenerative disorders: seizures, blindness, spasticity, eventual total incapacitation, and death. The prevalence is <1:100.000.
GNAT1Night blindness, congenital stationary, type 1GNight blindness, congenital stationary, type 1G is an autosomal recessive form of congenital stationary night blindness, a non-progressive retinal disorder characterized by impaired night vision or in dim light, with good vision only on bright days.
GNAT2Achromatopsia 4Achromatopsia 4 is an autosomal recessive disorder resulting from lack of cone photoreceptor function. Affected individuals present from birth or early infancy with photophobia, nystagmus, severely reduced visual acuity, and color blindness (Kohl et al., 2015).
GNB5Intellectual developmental disorder with cardiac arrhythmia; Language delay and ADHD/cognitive impairment with or without cardiac arrhythmiaIntellectual developmental disorder with cardiac arrhythmia is an autosomal recessive multisystem disorder characterized by delayed psychomotor development, severe intellectual disability with poor or absent speech, and bradycardia and/or cardiac sinus arrhythmias. Additional features include visual abnormalities, seizures, hypotonia, and gastric reflux (Lodder et al., 2016). Biallelic missense mutation in the GNB5 gene can cause language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia (LADCI), a less severe disorder with overlapping features. LADCI is an autosomal recessive neurodevelopmental disorder characterized by severe expressive and receptive language delay apparent from early childhood. Affected individuals have additional developmental or behavioral abnormalities, including attention deficit, hyperactivity, or mild intellectual disability. Some patients develop cardiac arrhythmias reminiscent of sick sinus syndrome (Lodder et al., 2016 and Shamseldin et al., 2016).
GNEInclusion body myopathy, type 2 (Nonaka myopathy)Inclusion body myopathy, type 2 (Nonaka myopathy) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GNE gene located on chromosomal region 9p13.3. The age of onset is adult. This disease is characterized by progressive muscle weakness and joint deformity. The prevalence is 1:500-1:1,000.
GNMTGlycine N-methyltransferase deficiencyGlycine N-methyltransferase deficiency (GNMT deficiency) is a very rare condition characterized by persistent and isolated excess levels of methionine in the blood (hypermethioninemia). The only clinical abnormalities are mild increase of the liver size (hepatomegaly) and chronic elevation of the transaminase levels in the blood without liver disease. Methionine may also be increased in urine. However, because elevated levels of methionine in the blood itself is a risk factor for development of neurological signs and symptoms, people with GNMT deficiency can have neurological problems when methionine levels are greater than 800 μmol/L.
GNPATRhizomelic chondrodysplasia punctata, type 2Rhizomelic chondrodysplasia punctata (RCDP) is a peroxisomal disorder characterized by disproportionately short stature primarily affecting the proximal parts of the extremities, a typical facial appearance including a broad nasal bridge, epicanthus, high-arched palate, dysplastic external ears, and micrognathia, congenital contractures, characteristic ocular involvement, dwarfism, and severe mental retardation with spasticity. Biochemically, plasmalogen synthesis and phytanic acid alpha-oxidation are defective. Most patients die in the first decade of life. RCDP1 (215100) is the most frequent form of RCDP (Wanders and Waterham, 2005). Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency (Waterham and Ebberink, 2012).
GNPTABMucolipidosis 2 alpha/beta; Mucolipidosis 3 alpha/betaMucolipidosis type 2 alpha/beta follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GNPTAB gene located on chromosomal region 12q23.2. The age of onset is infantile. This disease is characterized by growth retardation, short stature, skeletal abnormalities, facial dysmorphism, stiff skin, developmental delay and cardiomegaly and that is lethal in childhood. Mucolipidosis Type 3 is characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates. It is phenotypically less severe than the allelic disorder mucolipidosis type II alpha/beta. The prevalence is 1:123,500-1:625,500.
GNPTGMucolipidosis III gammaMucolipidosis type III gamma is an autosomal recessive disorder characterized clinically by short stature, skeletal abnormalities, cardiomegaly, and developmental delay. The disorder is caused by a defect in proper lysosomal enzyme phosphorylation and localization, which results in accumulation of lysosomal substrates (Raas-Rothschild et al., 2000).
GNRHRHypogonadotropic hypogonadism, type 7, without anosmiaCongenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).
GNSMucopolysaccharidosis, type 3D (Sanfilippo syndrome D)Mucolipidosis type 3D (Sanfilippo disease) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GNS gene located on chromosomal region 12q14.3. The age of onset is infantile. This disease is characterized by joint stiffness and pain initially in the shoulders, hips, and fingers; and gradual mild coarsening of facial features, cardiorespiratory complications and mild cognitive impairment. The incidence is 1:70,000 newborn.
GORABGeroderma osteodysplasticumGeroderma osteodysplastica is an autosomal recessive disorder characterized by lax, wrinkled skin, loose joints and a typical face with a prematurely aged appearance. Skeletal signs include severe osteoporosis leading to frequent fractures, malar and mandibular hypoplasia (underdeveloped cheekbones and jaw) and a variable degree of growth deficiency.
GOSR2Epilepsy, progressive myoclonic, type 6Progressive myoclonic epilepsy-6 is an autosomal recessive neurologic disorder characterized by onset of ataxia in the first years of life, followed by action myoclonus and seizures later in childhood, and loss of independent ambulation in the second decade. Cognition is not usually affected, although mild memory difficulties may occur in the third decade (Corbett et al., 2011).
GP1BABernard-Soulier syndrome, type A1Bernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5.
GP1BBBernard-Soulier syndrome, type BBernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5.
GP6Bleeding disorder, platelet-type, type 11Platelet-type bleeding disorder, type 11 is an autosomal recessive mild to moderate bleeding disorder caused by defective platelet activation and aggregation in response to collagen (Dumont et al., 2009).
GP9Bernard-Soulier syndrome, type CBernard-Soulier syndrome is an autosomal recessive bleeding disorder caused by a defect in or deficiency of the platelet membrane von Willebrand factor (VWF; 613160) receptor complex, glycoprotein Ib (GP Ib). GP Ib is composed of 4 subunits encoded by 4 separate genes: GP1BA, GP1BB, GP9, and GP5.
GPC3Simpson-Golabi-Behmel syndrome, type 1Simpson-Golabi-Behmel syndrome is an X-linked condition characterized by pre- and postnatal overgrowth, coarse facies, congenital heart defects, and other congenital abnormalities (Xuan et al., 1999). It shows phenotypic similarities to Beckwith-Wiedemann syndrome (BWS; 130650), another overgrowth syndrome.
GPC6Omodysplasia, type 1Omodysplasia, type 1 (OMOD1) is a rare autosomal recessive skeletal dysplasia characterized by severe congenital micromelia with shortening and distal tapering of the humeri and femora to give a club-like appearance. Typical facial features include a prominent forehead, frontal bossing, short nose with a depressed broad bridge, short columella, anteverted nostrils, long philtrum, and small chin. Variable findings are cryptorchidism, hernias, congenital heart defects, and cognitive delay (Elcioglu et al., 2004; Albano et al., 2007).
GPD1Hypertriglyceridemia, transient infantileTransient infantile hypertriglyceridemia is an autosomal recessive disorder characterized by onset of moderate to severe transient hypertriglyceridemia in infancy that normalizes with age. The hypertriglyceridemia is associated with hepatomegaly, moderately elevated transaminases, persistent fatty liver, and the development of hepatic fibrosis. The long-term outcome of affected individuals is unclear (Basel-Vanagaite et al., 2012).
GPHNMolybdenum cofactor deficiency CMolybdenum cofactor deficiency C is a form of molybdenum cofactor deficiency, an autosomal recessive metabolic disorder leading to the pleiotropic loss of molybdoenzyme activities. It is clinically characterized by onset in infancy of poor feeding, intractable seizures, severe psychomotor retardation, and death in early childhood in most patients.
GPIHemolytic anemia, nonspherocytic, due to glucose phosphate isomerase deficiencyHemolytic anemia, non-spherocytic, due to glucose phosphate isomerase deficiency is a form of anemia in which there is no abnormal hemoglobin or spherocytosis. It is caused by glucose phosphate isomerase deficiency.
GPIHBP1Hyperlipoproteinemia, type 1DHyperlipoproteinemia, type 1D (HLPP1D) is an autosomal recessive disorder characterized by hyperlipoproteinemia, decreased plasma LPL levels in some patients, high plasma triglyceride levels, and refractory fasting chylomicronemia.
GPR143Ocular albinism, type 1 (Nettleship-Falls type)X-linked recessive ocular albinism follows an X-linked pattern of inheritance and is caused by pathogenic variants in the GPR143 gene located on chromosomal region Xp22.2. The age of onset is infantile. This condition reduces the coloring (pigmentation) of the iris, which is the colored part of the eye, and the retina, which is the light-sensitive tissue at the back of the eye. Pigmentation in the eye is essential for normal vision. Ocular albinism type I (OA1) is the most common form of ocular albinism. Clinical presentation of OA1 in Caucasians is characterized by nystagmus, impaired visual acuity, iris hypopigmentation with translucency, albinotic fundus, macular hypoplasia, and normally pigmented skin and hair. Carrier females usually have punctate iris translucency and a mottled pattern of fundus pigmentation. In contrast to Caucasian patients, black or Japanese patients with OA1 often have brown irides with little or no translucency and varying degrees of fundus hypopigmentation, the so-called 'nonalbinotic fundus' (summary by Xiao and Zhang, 2009). The prevalence is 1/60,000 to 1/150,000 live male births.
GPR179Night blindness, congenital stationary (complete), type 1E, autosomal recessiveCongenital stationary night blindness type 1E follow an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GPR179 gene located on chromosomal region 17q12. The age of onset is infantile. This disease is characterized by hemeralopia with a moderate loss of visual acuity.
GPR68Amelogenesis imperfecta, type 2A6 (hypomaturation type)Amelogenesis imperfecta, type 2A6 is an autosomal recessive amelogenesis imperfecta pigmented hypomaturation type characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989).
GPSM2Chudley-McCullough syndromeChudley-McCullough syndrome is an autosomal recessive neurologic disorder characterized by early-onset sensorineural deafness and specific brain anomalies on MRI, including hypoplasia of the corpus callosum, enlarged cysterna magna with mild focal cerebellar dysplasia, and nodular heterotopia. Some patients have hydrocephalus. Psychomotor development is normal (Alrashdi et al., 2011).
GPX4Spondylometaphyseal dysplasia, Sedaghatian typeSedaghatian-type spondylometaphyseal dysplasia (SMDS) is a rare lethal disorder characterized by severe metaphyseal chondrodysplasia with mild limb shortening, platyspondyly, delayed epiphyseal ossification, irregular iliac crests, and pulmonary hemorrhage. Affected infants present with severe hypotonia and cardiorespiratory problems; most die within days of birth due to respiratory failure. Cardiac abnormalities include conduction defects, complete heart block, and structural anomalies. Half of infants with SMDS are reported to have central nervous system malformations consistent with abnormal neuronal migration, including agenesis of the corpus callosum, pronounced frontotemporal pachygyria, simplified gyral pattern, partial lissencephaly, and severe cerebellar hypoplasia (Smith et al., 2014).
GRHL2Ectodermal dysplasia/short stature syndromeEctodermal dysplasia/short stature syndrome is a autosomal recessive ectodermal dysplasia syndrome characterized by nail dystrophy and/or loss, oral mucosa and/or tongue pigmentation, abnormal dentition, keratoderma affecting the margins of the palms and soles, focal hyperkeratosis of the dorsal aspects of the hands and feet, and short stature.
GRHPRHyperoxaluria, primary, type 2Primary hyperoxaluria, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GRHPR gene located on chromosomal region 9p13.2. The age of onset is infantile. This disease is characterized by recurrent nephrolithiasis, nephrocalcinosis and end-stage renal disease with subsequent systemic oxalosis.
GRIA3Mental retardation, X-linked, type 94Mental retardation, X-linked, type 94 (MRX94) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX94 patients have moderate mental retardation. Other variable features are macrocephaly, seizures, myoclonic jerks, autistic behavior, asthenic body habitus, distal muscle weakness and hyporeflexia.
GRIK2Mental retardation, autosomal recessive, type, 6Mental retardation, autosomal recessive, type 6 (MRT6) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. In contrast to syndromic or specific mental retardation which also present with associated physical, neurological and/or psychiatric manifestations, intellectual deficiency is the only primary symptom of non-syndromic mental retardation. MRT6 patients display mild to severe mental retardation and psychomotor development delay in early childhood. Patients do not have neurologic problems, congenital malformations, or facial dysmorphism. Body height, weight, and head circumference are normal.
GRIN1Neurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessiveNeurodevelopmental disorder with or without hyperkinetic movements and seizures, autosomal recessive (NDHMSR) is an autosomal recessive neurodevelopmental disorder characterized by severely delayed psychomotor development, severe intellectual disability, and involuntary movements, including stereotypic movements, spasticity, and dystonia. Affected individuals are are usually unable to walk independently and have poor or absent speech. Some patients have intractable seizures (Lemke et al., 2016).
GRIP1Fraser syndrome 3Fraser syndrome is an autosomal recessive malformation disorder characterized by cryptophthalmos, syndactyly, and abnormalities of the respiratory and urogenital tract (van Haelst et al., 2008).
GRM1Spinocerebellar ataxia, autosomal recessive, type 13Spinocerebellar ataxia, autosomal recessive, type 13 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development beginning in infancy. Affected individuals show mild to profound mental retardation with poor or absent speech as well as gait and stance ataxia and hyperreflexia. Most individuals also have eye movement abnormalities. Brain MRI shows cerebellar atrophy and ventriculomegaly (Guergueltcheva et al., 2012).
GRM6Night blindness, congenital stationary (complete), type 1B, autosomal recessiveCongenital stationary night blindness type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GRM6 gene located on chromosomal region 5q35.3. The age of onset is early infancy. This disease is characterized by hemeralopia with a moderate loss of visual acuity.
GRNCeroid lipofuscinosis, neuronal, 11Neuronal ceroid lipofuscinosis, type 11 is an autosomal recessive neurologic disorder characterized by rapidly progressive visual loss due to retinal dystrophy, seizures, cerebellar ataxia, and cerebellar atrophy. Cognitive decline may also occur (Smith et al., 2012).
GRXCR1Deafness, autosomal recessive, type 25Autosomal recessive nonsyndromic sensorineural deafness type 25 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GRXCR1 gene located on chromosomal region 4p13. The age of onset is infantile. This disease is characterized by hearing loss which is not associated visible abnormalities of the external ear or any related medical problems.
GSCShort stature, auditory canal atresia, mandibular hypoplasia, skeletal abnormalitiesShort stature, auditory canal atresia, mandibular hypoplasia, and skeletal abnormalities (SAMS) is an autosomal recessive multiple congenital anomaly syndrome with features of a first and second branchial arch syndrome. Craniofacial abnormalities can lead to conductive hearing loss, respiratory insufficiency, and feeding difficulties. Additional features include rhizomelic skeletal anomalies as well as abnormalities of the shoulder and pelvic joints. Affected individuals may also have some features of a neurocristopathy or abnormal mesoderm development, such as urogenital anomalies, that are distinct from other branchial arch syndromes (Parry et al., 2013).
GSSGlutathione synthetase deficiencyGlutathione synthetase deficiency with 5-oxoprolinuria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GSS gene located on chromosomal region 20q11.22. The severity and age of onset are variable. This disease is characterized by affectation of the neutrophil respiratory burst and can increase host susceptibility to infections, is associated with hemolytic anemia and intellectual disability. The prevalence is <1:1,000,000.
GTF2H5Trichothiodystrophy, type 3, photosensitiveTrichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder. Patients with TTD have not been reported to have a predisposition to cancer (Faghri et al., 2008).
GUCY2CMeconium ileusMeconium ileus refers to intestinal obstruction due to inspissated meconium in the distal ileum and cecum, which develops in utero and presents shortly after birth as a failure to pass meconium (Romi et al., 2012). Meconium ileus is a known clinical manifestation of cystic fibrosis (CF; 219700), and meconium ileus in the absence of CF is a rare phenomenon (Tal et al., 1985).
GUCY2DLeber congenital amaurosis, type 1Leber congenital amaurosis type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GUCY2D gene located on chromosomal region 17p13.1. The age of onset is infantile. This disease is characterized by blindness, nystagmus, roving eye movement and severe visual impairment.
GUSBMucopolysaccharidosis, type 7Mucopolysaccharidosis type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GUSB gene located on chromosomal region 7q11.21. The age of onset is variable. There are prenatal forms with non-immune hydrops fetalis, and severe neonatal forms with dysmorphism, hernias, hepatosplenomegaly, club feet, dysostosis, severe hypotonia and neurological disorders that ultimately lead to profound intellectual deficit and small stature in patients that survive. Finally, there are also very mild cases that are discovered during adolescence or adulthood following presentation with thoracic kyphosis. The prevalence is 1:250,000 in newborn.
GYG1Polyglucosan body myopathy, type 2Polyglucosan body myopathy, type 2 is an autosomal recessive disorder characterized by proximal muscle weakness of the lower limbs resulting in gait disturbances. Some patients also have involvement of the upper limbs and/or distal muscle weakness. The age at onset is highly variable, and the disorder is slowly progressive. Muscle biopsy shows accumulation of polyglucosan, which contains abnormally long and poorly branched glucosyl chains and is variably resistant to digestion by alpha-amylase (Malfatti et al., 2014).
GYS1Glycogen storage disease, type 0, muscleMuscle glycogen storage disease, type 0 is a metabolic disorder caused by the body's inability to form a complex sugar called glycogen in muscles. The signs and symptoms of muscle GSD 0 typically begin in early childhood. Affected individuals often experience muscle pain and weakness or episodes of fainting (syncope) following moderate physical activity, such as walking up stairs. The loss of consciousness that occurs with fainting typically lasts up to several hours. Some individuals with muscle GSD 0 have a disruption of the heart's normal rhythm (arrhythmia) known as long QT syndrome. In all affected individuals, muscle GSD 0 impairs the heart's ability to effectively pump blood and increases the risk of cardiac arrest and sudden death, particularly after physical activity. Sudden death from cardiac arrest can occur in childhood or adolescence in people with muscle GSD 0.
GYS2Glycogen storage disease, type 0, liverGlycogen storage disease type 0?(also known as GSD 0) is a condition caused by the body's inability to form a complex sugar called?glycogen, which is a major source of stored energy in the body. GSD 0 has two types: in muscle GSD 0, glycogen formation in the muscles is impaired, and in liver GSD 0, glycogen formation in?the?liver?is impaired.The signs and symptoms of muscle GSD 0 typically begin in early childhood. Affected individuals often experience muscle pain and weakness or episodes of fainting (syncope) following moderate physical activity, such as walking up stairs. The loss of consciousness that occurs with fainting typically lasts up to several hours. Some individuals with muscle GSD 0 have a disruption of the heart's normal rhythm (arrhythmia) known as long QT syndrome. In all affected individuals, muscle GSD 0 impairs the heart's ability to effectively pump blood and increases the risk of cardiac arrest and sudden death, particularly after physical activity. Sudden death from cardiac arrest can occur in childhood or adolescence in people with muscle GSD 0.
H6PDCortisone reductase deficiency 1Cortisone reductase deficiency (CRD) results from a failure to regenerate the active glucocorticoid cortisol from cortisone via the enzyme 11-beta-hydroxysteroid dehydrogenase (HSD11B1; 600713). The oxoreductase activity of 11-beta-HSD requires the NADPH-regenerating enzyme hexose-6-phosphate dehydrogenase (H6PD; 138090) within the endoplasmic reticulum. Lack of cortisol regeneration stimulates ACTH-mediated adrenal hyperandrogenism, with males manifesting in early life with precocious pseudopuberty and females presenting in midlife with hirsutism, oligomenorrhea, and infertility. Biochemically, CRD is diagnosed through the assessment of urinary cortisol and cortisone metabolites and consists of measuring the tetrahydrocortisol (THF) plus 5-alpha-THF/tetrahydrocortisone (THE) ratio, which in CRD patients is typically less than 0.1 (reference range, 0.7 to 1.2) (Lavery et al., 2008).
HACE1Spastic paraplegia and psychomotor retardation with or without seizuresSpastic paraplegia and psychomotor retardation with or without seizures is an autosomal recessive complex neurodevelopmental disorder with onset in infancy. Affected children show hypotonia followed by severely impaired global development and significant motor disability. Most develop seizures in childhood and have speech delay. Other features, such as ocular abnormalities, foot deformities, hypoplasia of the corpus callosum, and decreased white matter, are more variable (Hollstein et al., 2015).
HADH3-hydroxyacyl-CoA dehydrogenase deficiency3-alpha-hydroxyacyl-CoA dehydrogenase deficiency is an autosomal recessive, metabolic disorder with various clinical presentations including hypoglycemia, hepatoencephalopathy, myopathy or cardiomyopathy, and in some cases sudden death.
HADHALCHAD deficiencyIsolated deficiency of long-chain 3-hydroxyl-CoA dehydrogenase (LCHAD deficiency) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HADHA gene located on chromosomal region 2p23.3. This disease is characterized in infancy/early childhood of hypoketotic hypoglycemia, metabolic acidosis, liver disease, hypotonia and, frequently, cardiac involvement with arrhythmias and/or cardiomyopathy. The prevalence is 1/250,000.
HADHBTrifunctional protein deficiencyMitochondrial trifunctional protein deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in HADHB gene located on chromosomal region 2p23.3. The age of onset is neonatal/infancy. It is characterized by a wide clinical spectrum ranging from severe neonatal manifestations including cardiomyopathy, hypoglycemia, metabolic acidosis, skeletal myopathy and neuropathy, liver disease and death to a mild phenotype with peripheral polyneuropathy, episodic rhabdomyolysis and pigmentary retinopathy. The prevalence is <1 / 1,000,000.
HAMPHemochromatosis, type 2BHemochromatosis, type 2B is an autosomal recessive inborn error of iron metabolism that leads to severe iron loading and organ failure before 30 years of age (Roetto et al., 1999).
HARSUsher syndrome, type 3BUsher syndrome type 3B is characterized by postlingual, progressive hearing loss, variable vestibular dysfunction, and onset of retinitis pigmentosa symptoms, including nyctalopia, constriction of the visual fields, and loss of central visual acuity, usually by the second decade of life (Karjalainen et al., 1985; Pakarinen et al., 1995).
HAX1Neutropenia, severe congenital, type 3, autosomal recessiveNeutropenia, severe congenital, type 3 is an autosomal recessive bone marrow failure disorder characterized by low numbers of neutrophils, increased susceptibility to bacterial and fungal infections, and increased risk of developing myelodysplastic syndrome or acute myeloid leukemia. In addition, patients with HAX1 mutations affecting both isoform A and B of the gene develop neurologic abnormalities (Boztug et al., 2010).The Swedish physician Rolf Kostmann (1956) described an autosomal recessive hematologic disorder, termed infantile agranulocytosis, with severe neutropenia with an absolute neutrophil count below 0.5 x 10(9)/l and early onset of severe bacterial infections. The disorder was later termed Kostmann syndrome (Skokowa et al., 2007). Lekstrom-Himes and Gallin (2000) discussed severe congenital neutropenia in a review of immunodeficiencies caused by defects in phagocytes.In addition to Kostmann agranulocytosis, recessively inherited neutropenic syndromes include congenital neutropenia with eosinophilia (257100), Chediak-Higashi syndrome (214500), and Fanconi pancytopenic syndrome (227650).
HBA1Thalassemia, alpha-Alpha-thalassemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HBA1 gene located on chromosomal region 16p13.3. The age of onset is infantile. It is characterized by impaired synthesis of alpha-globin chains leading to a variable clinical picture depending on the number of affected alleles. The disease can be classified into clinical subtypes of increasing severity: silent alpha thalassemia, alpha thalassemia trait (or alpha thalassemia minor), hemoglobin H disease (HbH), and Hb Bart's hydrops fetalis (see these terms). A rare form called alpha-thalassemia-intellectual deficit syndrome has also been identified (see these terms). Alpha thalassemia trait causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. HbH patients develop moderate hemolytic anemia with variable amounts of HbH along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin with serious developmental implications. Alpha-thalassemia-intellectual deficit syndrome is characterized by very mild to severe anemia associated with developmental abnormalities. The prevalence is 1:10,000-5:10,000.
HBA2Thalassemia, alpha-Alpha-thalassemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HBA2 gene located on chromosomal region 16p13.3. The age of onset is infantile. It is characterized by impaired synthesis of alpha-globin chains leading to a variable clinical picture depending on the number of affected alleles. The disease can be classified into clinical subtypes of increasing severity: silent alpha thalassemia, alpha thalassemia trait (or alpha thalassemia minor), hemoglobin H disease (HbH), and Hb Bart's hydrops fetalis (see these terms). A rare form called alpha-thalassemia-intellectual deficit syndrome has also been identified (see these terms). Alpha thalassemia trait causes microcytosis and hypochromia with absent or mild anemia (often detected on routine blood tests), generally with no other symptoms. HbH patients develop moderate hemolytic anemia with variable amounts of HbH along with occasionally severe splenomegaly, sometimes complicated by hypersplenism. Hb Bart's hydrops fetalis involves a severe deficiency in alpha-globin with serious developmental implications. Alpha-thalassemia-intellectual deficit syndrome is characterized by very mild to severe anemia associated with developmental abnormalities. The prevalence is 1:10,000-5:10,000.
HBBHBB-related hemoglobinopathyDNA variations in the HBB gene result in the production of different versions of beta-globin. Some of these variations may affect a person's health while other variations cause no noticeable signs or symptoms. Two of the most common HBB-related conditions are beta-thalassemia and sickle cell anemia (SCA). Beta thalassemia is caused by HBB gene mutations that prevent or decrease beta-globin production, subunits that make up hemoglobin. A lack of hemoglobin disrupts the normal development of red blood cells. A shortage of mature red blood cells can reduce the amount of oxygen that is delivered to tissues to below what is needed to satisfy the body's energy needs. A lack of oxygen in the body's tissues can lead to poor growth, organ damage, and other health problems associated with beta thalassemia. SCA is a multisystem disease associated with episodes of acute illness and progressive organ damage. SCA-associated mutations cause red blood cells assuming an abnormal, rigid, sickle shape promoting cell break down prematurely, which can lead to anemia. Anemia can cause shortness of breath, fatigue, and delayed growth and development in children.
HCCSLinear skin defects with multiple congenital anomalies, type 1Linear skin defects with multiple congenital anomalies, type 1 is an X-linked dominant disorder characterized by unilateral or bilateral microphthalmia and linear skin defects--which are limited to the face and neck, consisting of areas of aplastic skin that heal with age to form hyperpigmented areas--in affected females and in utero lethality for males (Wimplinger et al., 2006).
HDAC8Cornelia de Lange syndrome 5Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 60% of patients have mutations in the NIPBL gene (608667) on chromosome 5p13 (CDLS1; 122470), and about 4 to 6% of patients have mutations in the X-linked SMC1A gene (300040) (CDLS2; 300590) (Musio et al., 2006, Hoppman-Chaney et al., 2012).
HEPACAMMegalencephalic leukoencephalopathy with subcortical cysts 2AMegalencephalic leukoencephalopathy with subcortical cysts-2A is an autosomal recessive neurodegenerative disorder characterized by infantile-onset macrocephaly and later onset of motor deterioration, with ataxia and spasticity, seizures, and cognitive decline of variable severity. Brain MRI shows typical white matter abnormalities, including swelling of the cerebral white matter and subcortical cysts, in all stages of the disease (Lopez-Hernandez et al., 2011). Heterozygous mutations in the HEPACAM gene can cause a similar, but less severe disorder that shows improvement of MRI changes with age (MLC2B; 613926).
HERC2Mental retardation, autosomal recessive, type 38Mental retardation, autosomal recessive, type 38 (MRT38) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT38 is characterized by global developmental delay affecting motor, speech, adaptive, and social development. Patients manifest autistic features, aggression, self-injury, impulsivity, and distractibility.
HES7Spondylocostal dysostosis, type 4, autosomal recessiveSpondylocostal dysostosis, type 4, autosomal recessive is a rare condition of variable severity characterized by vertebral and costal anomalies. The main feature include dwarfism, vertebral fusion, hemivertebrae, posterior rib fusion, reduced rib number, and other rib malformations.
HESX1Growth hormone deficiency with pituitary anomaliesGrowth hormone deficiency with pituitary anomalies follows an autosomal recessive pattern of inheritance and are caused by pathogenic variants in the HESX1 gene located on chromosomal region 3p14.3. The age of onset is infantile. These diseases are characterized by short stature, cognitive alterations or delayed puberty. The incidence is 1:3,000 and 1:4,000 births.
HEXATay-Sachs diseaseTay-Sachs disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HEXA gene located on chromosomal region 15q23. The age of onset is infantile. There are three forms, type 1 (infantile), with a psychomotor retardation which is associated with hypotonia, amaurosis and megalencephaly. Type 2 is characterized by locomotor ataxia, behavioural disorders, and progressive loss of intellectual capacities. Type three (chronic form) shows spinocerebellar ataxia or spinal amyotrophy. The prevalence is 1 case per 320 000 live births.
HEXBSandhoff disease, infantile, juvenile, and adult formsSandhoff disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HEXB gene located on chromosomal region 5q13.3. The age of onset is adult or infantile. This disease is characterized by central nervous system degeneration, with startle reactions, early blindness, progressive motor and mental deterioration, macrocephaly and cherry-red spots on the macula. The prevalence is 1/130.000.
HGDAlkaptonuriaAlkaptonuria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HGD gene located on chromosomal region 3q13.33. The age of onset is infantile. This disease is characterized by darkening of the urine when it is left exposed to air, grey-blue colouration of the eye sclerae and the ear helix (ochronosis), and a disabling joint disease involving both the axial and peripheral joints (ochronotic arthropathy). The prevalence is 1:250,000-1:1.000.000 newborn.
HGFDeafness, autosomal recessive, type 39Autosomal recessive nonsyndromic sensorineural deafness type 39 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HGF gene located on chromosomal region 7q21.11. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
HGSNATMucopolysaccharidosis type 3C (Sanfilippo syndrome C)Mucopolysaccharidosis type 3C (Sanfilippo C) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HGSNAT gene located on chromosomal region 8p11.21. The age of onset is infantile. This disease is characterized by defective or missing enzymes to break down mucopolysaccharides are missing or are defective. The prevalence is <1:70.000 newborn.
HIBCH3-hydroxyisobutryl-CoA hydrolase deficiency3-Hydroxyisobutryl-CoA hydrolase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HIBCH gene located on chromosomal region 2q32.2. The age of onset is infantile. This disease is characterized by delayed motor development, hypotonia and progressive neurodegeneration. The prevalence is <1:1,000,000.
HK1Charcot-Marie-Tooth disease, type 4GCharcot-Marie-Tooth disease, type 4G (CMT4G), also known as neuropathy, hereditary motor and sensory, Russe type (HMSNR) is an autosomal recessive progressive complex peripheral neuropathy characterized by onset in the first decade of distal lower limb weakness and muscle atrophy resulting in walking difficulties. Distal impairment of the upper limbs usually occurs later, as does proximal lower limb weakness. There is distal sensory impairment, with pes cavus and areflexia. Laboratory studies suggest that it is a myelinopathy resulting in reduced nerve conduction velocities in the demyelinating range as well as a length-dependent axonopathy.
HLCSHolocarboxylase synthetase deficiencyHolocarboxylase synthetase deficiency, a biotin-responsive multiple carboxylase deficiency (MCD), is characterized by metabolic acidosis, lethargy, hypotonia, convulsions, and dermatitis. Most patients present in the newborn or early infantile period, but some become symptomatic in the later infantile period (Suzuki et al., 2005). Care must be taken to differentiate the inherited multiple carboxylase deficiencies from acquired biotin deficiencies, such as those that develop after excessive dietary intake of avidin, an egg-white glycoprotein that binds specifically and essentially irreversibly to biotin (Sweetman et al., 1981) or prolonged parenteral alimentation without supplemental biotin (Mock et al., 1981).
HMGCLHMG-CoA lyase deficiency3-hydroxy-3-methylglutaric aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HMGCL gene located on chromosomal region 1p36.11. The age of onset is infantile. This disease is is an organic aciduria, due to deficiency of 3-hydroxy-3-methylglutaryl-CoA-lyase (a key enzyme in ketogenesis and leucine metabolism) usually presenting in infancy with episodes of metabolic decompensation triggered by periods of fasting or infections, which when left untreated are life-threatening and may lead to neurological sequelae.
HMGCS2HMG-CoA synthase-2 deficiencyMitochondrial HMG-CoA synthase deficiency is an inherited metabolic disorder caused by a defect in the enzyme that regulates the formation of ketone bodies. Patients present with hypoketotic hypoglycemia, encephalopathy, and hepatomegaly, usually precipitated by an intercurrent infection or prolonged fasting (Aledo et al., 2006).
HMX1Oculoauricular syndromeOculoauricular syndrome is a syndrome characterized by microphthalmia, microcornea, anterior segment dysgenesis, cataract, ocular coloboma, retinal pigment epithelium abnormalities, rod-cone dystrophy, and anomalies of the external ear.
HNMTMental retardation, autosomal recessive, type 51Mental retardation, autosomal recessive, type 51 is a form of mental retardation, a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
HOGA1Hyperoxaluria, primary, type 3Hyperoxaluria, primary, type 3 is a disorder phenotypically similar to hyperoxaluria type 1 and type 2. It is characterized by increase in urinary oxalate excretion and mild glycolic aciduria. Clinical manifestations include calcium oxalate urolithiasis, hematuria, pain, and/or urinary tract infection.
HOXA1Athabaskan brainstem dysgenesis syndromeAthabaskan brainstem dysgenesis syndrome is characterized by horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Some patients had swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies.
HPDTyrosinemia, type 3Tyrosinemia type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HPD gene located on chromosomal region 12q24.31. The age of onset is infantile. This disease is characterized by intellectual deficit and ataxia. The prevalence is 1:100,000-1:120,000 newborn.
HPGDHypertrophic osteoarthropathy, primary, type 1 (pachydermoperiostosis)Primary hypertrophic osteoarthropathy is a familial disorder characterized by digital clubbing and osteoarthropathy, with variable features of pachydermia, delayed closure of the fontanels, and congenital heart disease. Secondary hypertrophic osteoarthropathy, or pulmonary hypertrophic osteoarthropathy, is a different disorder characterized by digital clubbing secondary to acquired diseases, most commonly intrathoracic neoplasm (Uppal et al., 2008). Touraine et al. (1935) recognized pachydermoperiostosis as a familial disorder with 3 clinical presentations or forms: a complete form characterized by periostosis and pachydermia; an incomplete form with bone changes but without pachydermia; and a 'forme fruste' with pachydermia and minimal skeletal changes. Isolated digital clubbing (119900) as well as cranioosteoarthropathy can also be caused by homozygous mutation in the HPGD gene.
HPRT1Lesch-Nyhan syndromeLesch-Nyhan syndrome follows an X-linked pattern of inheritance and is caused by pathogenic variants in the HPRT1 gene located on chromosomal region Xq26.2-q26.3. The age of onset is infantile. This disease is characterized by acid overproduction, neurological troubles, and behavioral problems. The prevalence is 1:380,000.
HPS1Hermansky-Pudlak syndrome, type 1Hermansky-Pudlak syndrome, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HPS1 gene located on chromosomal region 10q24.2. The age of onset is early childhood. This disease is characterized by oculocutaneous albinism, bleeding diathesis and, in some cases, neutropenia, pulmonary fibrosis, or granulomatous colitis. The prevalence is 1/500,000 - 1/1,000,000.
HPS3Hermansky-Pudlak syndrome 3Hermansky-Pudlak syndrome 3 (HPS3) is a form of Hermansky-Pudlak syndrome (HPS), a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS.
HPS4Hermansky-Pudlak syndrome 4Hermansky-Pudlak syndrome 4 (HPS4) is characterized by oculocutaneous albinism in association with easy bruising or a bleeding tendency and absence of platelet dense bodies. Some patients also exhibit pulmonary fibrosis and/or granulomatous colitis (Anderson et al., 2003).
HPS5Hermansky-Pudlak syndrome 5Hermansky-Pudlak syndrome 5 (HPS5) is characterized by oculocutaneous albinism, a bleeding diathesis, and lack of platelet dense bodies. HPS5 appears to be a milder form of the syndrome because the complications present in other forms of HPS, such as pulmonary fibrosis, granulomatous colitis, and neutropenia, have not been reported in HPS5 patients (Ringeisen et al., 2013).
HPS6Hermansky-Pudlak syndrome 6Hermansky-Pudlak syndrome 6 (HPS6) is a form of Hermansky-Pudlak syndrome (HPS), a genetically heterogeneous autosomal recessive disorder characterized by oculocutaneous albinism, bleeding due to platelet storage pool deficiency, and lysosomal storage defects. This syndrome results from defects of diverse cytoplasmic organelles including melanosomes, platelet dense granules and lysosomes. Ceroid storage in the lungs is associated with pulmonary fibrosis, a common cause of premature death in individuals with HPS.
HPSE2Urofacial syndrome, type 1Urofacial syndrome (UFS) is a rare autosomal recessive disease characterized by a severe and early-onset form of dysfunctional urinary voiding. Affected individuals usually present prenatally or in early childhood with grossly distorted renal tracts, comprising dysmorphic bladders and dilatation of the ureter and renal pelvis. They are at high risk of vesicoureteral reflux (VUR), with ascending bacterial infection leading to kidney damage, hypertension, and renal failure. One-third of UFS children also experience constipation or fecal soiling, suggesting that the pathophysiology of the syndrome encompasses a broader functional impairment of elimination. In addition, affected individuals have a characteristic facial grimace when trying to smile (Daly et al., 2010).
HRAlopecia universalis; Atrichia with papular lesionsAlopecia universalis congenita is a severe autosomal recessive form of alopecia characterized by a complete absence of hair development affecting all scalp and body hair (Nothen et al., 1998).This rare disorder is clearly distinct from alopecia areata (AA1; 104000), which has an autoimmune basis with probable genetic predisposition. Mutation in HR gene also causes Atrichia with papular lesions (APL), an autosomal recessive disease characterized by papillary lesions over most of the body and almost complete absence of hair.
HSD11B2Apparent mineralocorticoid excessApparent mineralocorticoid excess (AME) is an autosomal recessive form of low-renin hypertension associated with low aldosterone, metabolic alkalosis, hypernatremia, and hypokalemia. The disorder is due to a congenital defect in 11-beta-hydroxysteroid dehydrogenase type 2 (HSD11B2) activity, resulting in decreased conversion of biologically active cortisol to inactive cortisone; this defect allows cortisol to act as a ligand for the mineralocorticoid receptor, resulting in sodium retention and volume expansion. There is a favorable therapeutic response to spironolactone (Ferrari, 2010).
HSD17B10HSD10 mitochondrial diseaseHSD10 mitochondrial disease most commonly presents as an X-linked neurodegenerative disorder with highly variable severity and age at onset ranging from the neonatal period to early childhood. The features are usually multisystemic, consistent with mitochondrial dysfunction. Some affected males have a severe infantile form associated with cardiomyopathy that may result in death in early childhood, whereas other rare patients may have juvenile onset or even atypical presentations with normal neurologic development. More severely affected males show developmental regression in infancy or early childhood, often associated with early-onset intractable seizures, progressive choreoathetosis and spastic tetraplegia, optic atrophy or retinal degeneration resulting in visual loss, and mental retardation. Heterozygous females may show non-progressive developmental delay and intellectual disability, but may also be clinically normal. Although the diagnosis can be aided by the observation of increased urinary levels of metabolites of isoleucine breakdown (2-methyl-3 hydroxybutyrate and tiglylglycine), there is not a correlation between these laboratory features and the phenotype. In addition, patients do not develop severe metabolic crises in the neonatal period as observed in other organic acidurias, but may show persistent lactic acidosis, most likely reflecting mitochondrial dysfunction (Rauschenberger et al., 2010; Zschocke, 2012). In a review of the disorder, Zschocke (2012) noted that although this disorder was originally thought to be an inborn error of branched-chain fatty acid and isoleucine metabolism resulting from decreased HSD17B10 dehydrogenase activity (HSD17B10 'deficiency'), subsequent studies have shown that the HSD17B10 gene product has additional functions and also acts as a component of the mitochondrial RNase P holoenzyme, which is involved in mitochondrial tRNA processing and maturation and ultimately mitochondrial protein synthesis. The multisystemic features of HSD10MD most likely result from the adverse effect of HSD17B10 mutations on mitochondrial function, rather than from the effects on the dehydrogenase activity.
HSD17B346,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency17-b-hydroxysteroid dehydrogenase type 3 (HSD17B3) deficiency is an autosomal recessive disorder that manifests, in males, as undermasculinization characterized by hypoplastic-to-normal internal genitalia (epididymis, vas deferens, seminal vesicles, and ejaculatory ducts) but female external genitalia and the absence of a prostate. This phenotype is caused by inadequate testicular synthesis of testosterone, which, in turn, results in insufficient formation of dihydrotestosterone in the anlage of the external genitalia and prostate during fetal development. At the expected time of puberty, there is a marked increase in plasma leuteinizing hormone and, consequently, in testicular secretion of androstenedione. Hence, a diagnostic hallmark of this disorder is a decreased plasma testosterone-to-androstenedione ratio. Significant amounts of the circulating androstenedione are, however, converted to testosterone, in peripheral tissues, thereby causing virilization (Lindqvist et al., 2001).
HSD17B4D-bifunctional protein deficiencyBifunctional enzyme deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HSD17B4 gene located on chromosomal region 5q23. The age of onset is juvenile. This disease is characterized by slowly progressive cerebellar atrophy and ataxia, intellectual decline, hearing loss, hypogonadism, hyperreflexia, a demyelinating sensorimotor neuropathy.
HSD3B2Adrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiencyAdrenal hyperplasia, congenital, due to 3-beta-hydroxysteroid dehydrogenase 2 deficiency is an autosomal recessive form of CAH characterized by a severe impairment of steroid biosynthesis in both the adrenals and the gonads, resulting in decreased excretion of cortisol and aldosterone and of progesterone, androgens, and estrogens by these tissues. Affected newborns exhibit signs and symptoms of glucocorticoid and mineralocorticoid deficiencies, which may be fatal if not diagnosed and treated early, especially in the severe salt-wasting form. Moreover, male newborns exhibit pseudohermaphroditism with incomplete masculinization of the external genitalia due to an impairment of androgen biosynthesis in the testis. In contrast, affected females exhibit normal sexual differentiation or partial virilization (Rheaume et al., 1992).
HSD3B7Bile acid synthesis defect, congenital, type 1Congenital defects of bile acid synthesis are autosomal recessive disorders characterized by neonatal onset of progressive liver disease with cholestatic jaundice and malabsorption of lipids and lipid-soluble vitamins from the gastrointestinal tract resulting from a primary failure to synthesize bile acids. Affected infants show failure to thrive and secondary coagulopathy. In most forms of the disorder, there is a favorable response to oral bile acid therapy (Cheng et al., 2003).
HSPA9Even-plus syndromeEVEN-PLUS syndrome is characterized by prenatal-onset short stature, vertebral and epiphyseal changes, microtia, midface hypoplasia with flat nose and triangular nares, cardiac malformations, and other findings including anal atresia, hypodontia, and aplasia cutis. The features overlap those reported in patients with CODAS syndrome (Royer-Bertrand et al., 2015).
HSPD1Leukodystrophy, hypomyelinating, type 4Leukodystrophy hypomyelinating, type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HSPD1 gene located on chromosomal region 2q33.1. The age of onset is infantile. A severe autosomal recessive hypomyelinating leukodystrophy. Clinically characterized by infantile-onset rotary nystagmus, progressive spastic paraplegia, neurologic regression, motor impairment, profound mental retardation. Death usually occurs within the first two decades of life.
HSPG2Dyssegmental dysplasia, Silverman-Handmaker typeDyssegmental dysplasia, Silverman-Handmaker type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HSPG2 gene located on chromosomal region 1p36.12. The age of onset is prenatal/neonatal. This disease is characterized by anisospondyly, severe short stature and limb shortening, metaphyseal flaring and distinct dysmorphic features (i.e. flat facial appearance, abnormal ears, short neck, narrow thorax). Additional features may include other skeletal findings (e.g. joint contractures, bowed limbs, talipes equinovarus) and urogenital and cardiovascular abnormalities. The prevalence is below 1/1,000,000.
HTRA1CARASIL syndromeCerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL syndrome) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HTRA1 gene located on chromosomal region 10q26.13. The age of onset is adult. This disease is characterized by early-onset gait disturbances, premature scalp alopecia, ischemic stroke, acute mid to lower back pain and progressive cognitive disturbances leading to severe dementia. About 50 people diagnosed, mainly in Japan and China.
HTRA23-methylglutaconic aciduria, type 83-methylglutaconic aciduria type 8 (MGCA8) is an autosomal recessive metabolic disorder resulting in death in infancy. Features include hypotonia, abnormal movements, respiratory insufficiency with apneic episodes, and lack of developmental progress, often with seizures. Brain imaging is variable, but may show progressive cerebral atrophy. Laboratory studies show increased serum lactate and 3-methylglutaconic aciduria, suggesting a mitochondrial defect (Mandel et al., 2016).
HUWE1Mental retardation, X-linked syndromic, Turner typeMental retardation, X-linked, syndromic, Turner type (MRXST) is a syndrome characterized by the association of mental retardation with macrocephaly and variable contractures.
HYLS1Hydrolethalus syndromeHydrolethalus syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the HYLS1 gene located on chromosomal region 11q24.2. The age of onset is fetal. This disease is characterized by craniofacial dysmorphic features, central nervous system, cardiac, respiratory tract and limb abnormalities. The incidence is 1/20,000 in Finland and the prevalence is <1:1,000,000.
ICKEndocrine-cerebroosteodysplasiaEndocrine-cerebroosteodysplasia syndrome is characterized by various anomalies of the endocrine, cerebral, and skeletal systems resulting in neonatal mortality.
IDH3BRetinitis pigmentosa, type 46Retinitis pigmentosa, type 46 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IDH3B gene located on chromosomal region 20p13. The age of onset is variable. This disease is characterized by night blindness, followed by a progressive loss of peripheral vision in the daylight period and leading to blindness. The prevalence is 1/3,000 to 1/5,000.
IDSMucopolysaccharidosis, type 2Mucopolysaccharidosis, type 2 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the IDS gene located on chromosomal region Xq28. The age of onset is infantile. This disease is characterized by distinctive coarse facial features, short stature, cardio-respiratory involvement and skeletal abnormalities. The prevalence is 1:100,000-1:170,000 mannewborn.
IDUAMucopolysaccharidosis, type 1H; Mucopolysaccharidosis, type 1H/S; Mucopolysaccharidosis, type 1SThe mucopolysaccharidoses type 1 are a group of inherited disorders caused by a lack of specific lysosomal enzymes involved in the degradation of glycosaminoglycans (GAGs), or mucopolysaccharides. The accumulation of partially degraded GAGs causes interference with cell, tissue, and organ function.Deficiency of alpha-L-iduronidase can result in a wide range of phenotypic involvement with 3 major recognized clinical entities: Hurler (MPS1H), Scheie (MPS1S), and Hurler-Scheie (MPS1H/S) syndromes. Hurler and Scheie syndromes represent phenotypes at the severe and mild ends of the MPS1 clinical spectrum, respectively, and the Hurler-Scheie syndrome is intermediate in phenotypic expression (McKusick, 1972). MPS1 is more frequent than MPS2 (Hunter syndrome; 309900), which has no corneal clouding and pursues a slower course.
IER3IP1Microcephaly, epilepsy, and diabetes syndromeMicrocephaly, epilepsy, and diabetes syndrome (MEDS) is an autosomal recessive neurodevelopmental disorder characterized by microcephaly, simplified gyral pattern, severe epilepsy, and infantile diabetes (Poulton et al., 2011).
IFNGR1Immunodeficiency, type 27A, mycobacteriosisImmunodeficiency, type 27A results from autosomal recessive (AR) IFNGR1 deficiency. Patients with complete IFNGR1 deficiency have a severe clinical phenotype characterized by early and often fatal mycobacterial infections. bacillus Calmette-Guerin (BCG) and environmental mycobacteria are the most frequent pathogens, and infection typically begins before the age of 3 years. Plasma from patients with complete AR IFNGR1 deficiency usually contains large amounts of IFNG (147570), and their cells do not respond to IFNG in vitro. In contrast, cells from patients with partial AR IFNGR1 deficiency, which is caused by a specific mutation in IFNGR1, retain residual responses to high IFNG concentrations. Patients with partial AR IFNGR1 deficiency are susceptible to BCG and environmental mycobacteria, but they have a milder clinical disease and better prognosis than patients with complete AR IFNGR1 deficiency. The clinical features of children with complete AR IFNGR1 deficiency are usually more severe than those in individuals with AD IFNGR1 deficiency (IMD27B), and mycobacterial infection often occurs earlier (mean age of 1.3 years vs 13.4 years), with patients having shorter mean disease-free survival. Salmonellosis is present in about 5% of patients with AR or AD IFNGR1 deficiency, and other infections have been reported in single patients (Al-Muhsen and Casanova, 2008).
IFNGR2Immunodeficiency, type 28, mycobacteriosisImmunodeficiency, type 28, mycobacteriosis is caused by autosomal recessive (AR) IFNGR2 deficiency, a rare molecular cause of susceptibility to mycobacterial disease. The clinical presentation of complete AR IFNGR2 deficiency resembles that of complete IFNGR1 deficiency (IMD27A; 209950). The disease manifests early in life, with severe, often fatal, infection. The most commonly encountered pathogens include M. bovis bacillus Calmette-Guerin (BCG), M. avium, and M. fortuitum. Complete AR IFNGR2 deficiency is characterized by an undetectable cellular response to interferon-gamma (IFNG; 147570). There is also a rare, partial form of AR IFNGR2 deficiency, reported in 1 child, who retained a residual cellular response to IFNG and presented with a relatively mild infection by M. bovis BCG and M. abscessus (Al-Muhsen and Casanova, 2008).
IFT122Cranioectodermal dysplasia 1Cranioectodermal dysplasia (CED), also known as Sensenbrenner syndrome, is an autosomal recessive disorder characterized by sagittal craniosynostosis and facial, ectodermal, and skeletal anomalies (Gilissen et al., 2010).
IFT140Retinitis pigmentosa, type 80; Short-rib thoracic dysplasia 9 with or without polydactylyRetinitis pigmentosa is characterized by constriction of the visual fields, night blindness, and fundus changes, including 'bone corpuscle' lumps of pigment. RP unassociated with other abnormalities is inherited most frequently (84%) as an autosomal recessive, next as an autosomal dominant (10%), and least frequently (6%) as an X-linked recessive in the white U.S. population (Boughman et al., 1980). Mutations in IFT140 can also caused short-rib thoracic dysplasia 9 with or without polydactyly. Short-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (Huber and Cormier-Daire, 2012 and Schmidts et al., 2013).
IFT80Short-rib thoracic dysplasia, type 2, with or without polydactylyShort-rib thoracic dysplasia type 2 with or without polydactyly an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IFT80 gene located on chromosomal region 3q25.33. The age of onset is antenatal/neonatal. This is, a group of autosomal recessive ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a trident appearance of the acetabular roof. Polydactyly is variably present. Non-skeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of the disease are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life. Disease spectrum encompasses Ellis-van Creveld syndrome, asphyxiating thoracic dystrophy (Jeune syndrome), Mainzer-Saldino syndrome, and short rib-polydactyly syndrome. The incidence is 1-5/500,000.
IGF1Growth retardation with deafness and mental retardation due to IGF1 deficiencyGrowth retardation with deafness and mental retardation due to IGF1 deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IGF1 gene located on chromosomal region 12q23.2. The age of onset is infantile. This disease is characterized by the association of intrauterine and postnatal growth retardation with sensorineural deafness and intellectual deficit, addition clinical features include microcephaly, adiposity, and insulin resistance. The prevalence is <1:1,000,000.
IGF1RInsulin-like growth factor I, resistance toPatients with mutations in the receptor for insulin-like growth factor I show intrauterine growth retardation and postnatal growth failure, resulting in short stature and microcephaly. Other features may include delayed bone age, developmental delay, and dysmorphic features.
IGFALSAcid-labile subunit deficiencyAcid-labile subunit deficiency is characterized by severely reduced serum insulin-like growth factor I (IGF1; 147440) and IGF-binding protein-3 (IGFBP3; 146732) concentrations that are incongruent with an associated mild growth retardation (height, -2 to -3 SD before and during puberty). Pubertal delay in boys and insulin insensitivity are common findings (Domene et al., 2011).
IGFBP7Retinal arterial macroaneurysm with supravalvular pulmonic stenosisRetinal arterial macroaneurysm is an autosomal recessive condition characterized by the bilateral appearance of 'beading' along the major retinal arterial trunks, with the subsequent formation of macroaneurysms. Affected individuals also have supravalvular pulmonic stenosis, often requiring surgical correction (Abu-Safieh et al., 2011).
IGHMBP2Charcot-Marie-Tooth disease, axonal, type 2SCharcot-Marie-Tooth disease, axonal, type 2S follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IGHMBP2 gene located on chromosomal region 11q13.3. The age of onset can be infancy, childhood, adult or adolescent. This disease is characterized by progressive distal muscle weakness and atrophy of both the lower and upper limbs, absent or reduced deep tendon reflexes, mild sensory loss, foot drop, and pes cavus leading eventually to wheelchair dependence. Some patients present with early hypotonia and delayed motor development. Scoliosis and variable autonomic disturbances may be associated. The prevalence is below 1/1,000,000.
IGLL1Agammaglobulinemia 2Agammaglobulinemia 2 is a rare form of agammaglobulinemia, a primary immunodeficiency disease, and is characterized by variable immune dysfunction with frequent and recurrent bacterial infections and/or chronic diarrhea. Affected individuals develop severe infections in the first years of life.
IHHAcrocapitofemoral dysplasiaAcrocapitofemoral dysplasia is an autosomal recessive disorder characterized by short stature of variable severity with postnatal onset. The most constant radiographic abnormalities are observed in the tubular bones of the hands and in the proximal part of the femur. Cone-shaped epiphyses or a similar epiphyseal configuration with premature epimetaphyseal fusion result in shortening of the skeletal components involved. Cone-shaped epiphyses are also present to a variable extent at the shoulders, knees and ankles.
IKBKGImmunodeficiency, type 33Immunodeficiency, type 33 results from X-linked recessive NEMO deficiency, which is associated with various other diseases, including immunodeficiency with hypohidrotic ectodermal dysplasia (300291), together with osteopetrosis and lymphedema (300301) in some patients, and immunodeficiency without ectodermal dysplasia (300584). In contrast with patients with these other forms of X-linked recessive NEMO deficiency, who display a broad susceptibility to infections, infections in IMD33 patients are mostly limited to mycobacterial disease, with M. avium complex being the most common cause. Furthermore, IMD33 patients lack developmental features suggestive of hypohidrotic ectodermal dysplasia. Monocytes from IMD33 patients have intrinsic defects in T cell-dependent IL12 (161561) production, resulting in impaired IFNG (147570) production. The prognosis of IMD33 patients is variable (Al-Muhsen and Casanova, 2008).
IL10RAInflammatory bowel disease, type 28, early onset, autosomal recessiveInflammatory bowel disease 28 is a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints.
IL10RBInflammatory bowel disease, type 25, early onset, autosomal recessiveInflammatory bowel disease 25 is a chronic, relapsing inflammation of the gastrointestinal tract with a complex etiology. It is subdivided into Crohn disease and ulcerative colitis phenotypes. Crohn disease may affect any part of the gastrointestinal tract from the mouth to the anus, but most frequently it involves the terminal ileum and colon. Bowel inflammation is transmural and discontinuous; it may contain granulomas or be associated with intestinal or perianal fistulas. In contrast, in ulcerative colitis, the inflammation is continuous and limited to rectal and colonic mucosal layers; fistulas and granulomas are not observed. Both diseases include extraintestinal inflammation of the skin, eyes, or joints.
IL11RACraniosynostosis and dental anomaliesThis autosomal recessive disorder is characterized by craniosynostosis, maxillary hypoplasia, and dental anomalies, including malocclusion, delayed and ectopic tooth eruption, and/or supernumerary teeth. Some patients also display minor digit anomalies, such as syndactyly and/or clinodactyly (Nieminen et al., 2011).
IL12BImmunodeficiency, type 29, mycobacteriosisImmunodeficiency, type 29, mycobacteriosis results from autosomal recessive IL12B deficiency and is characterized by undetectable IL12B secretion from leukocytes. IL12B-deficient patients generally present with bacillus Calmette-Guerin (BCG) disease after vaccination in childhood, and at least half also have Salmonella infection. Infections with Mycobacterium tuberculosis and environmental mycobacteria have also been reported in IL12B-deficient patients. The phenotype is relatively mild, and patients have a good prognosis (Al-Muhsen and Casanova, 2008).
IL12RB1Immunodeficiency, type 30Immunodeficiency, type 30 results from autosomal recessive IL12RB1 deficiency and is the most common form of susceptibility to mycobacterial disease. Activated T and natural killer lymphocytes from IMD30 patients do not express IL12RB1 on their surface or, more rarely, express nonfunctional IL12RB1 on their surface. IMD30 patients therefore lack responses to IL12 (161560) and IL23 (605580). The clinical presentation of IL12RB1-deficient patients is similar to that of IL12B-deficient patients (MD29, 614890). Bacillus Calmette-Guerin (BCG) disease and salmonellosis are the most frequent infections. Salmonellosis is present in about half of IL12RB1-deficient patients, and significant numbers of patients present with isolated salmonellosis. Severe tuberculosis has been reported in several unrelated patients, and other infections have been reported in single patients. IMD30 has low penetrance, and patients have relatively mild disease and good prognosis (Al-Muhsen and Casanova, 2008).
IL17RAImmunodeficiency, type 51Immunodeficiency, type 51 is an autosomal recessive primary immune deficiency that is usually characterized by onset of chronic mucocutaneous candidiasis in the first years of life. Most patients also show recurrent Staphylococcal skin infections, and may show increased susceptibility to chronic bacterial respiratory infections. Patient cells show a lack of cellular responses to stimulation with certain IL17 isoforms, including IL17A (603149), IL17F (606496), IL17A/F, and IL17E (IL25; 605658) (Levy et al., 2016).
IL1RAPL1Mental retardation, X-linked, type 21/34This form of nonsyndromic X-linked mental retardation is characterized by a spectrum of cognitive neurologic impairments or disabilities ranging from moderate mental retardation to high-functioning autism. Males are typically severely affected, but some carrier females may manifest milder deficits (Piton et al., 2008).
IL1RNSterile multifocal osteomyelitis with periostitis and pustulosisInterleukin 1 receptor antagonist deficiency is a rare autoinflammatory disease of skin and bone resulting in sterile multifocal osteomyelitis, periostitis, and pustulosis from birth. The term autoinflammatory disease describes a group of disorders characterized by attacks of seemingly unprovoked inflammation without significant levels of autoantibodies and autoreactive T-cells.
IL21RImmunodeficiency, type 56Immunodeficiency, type 56 is an autosomal recessive primary immunodeficiency characterized by B- and T-cell defects and variable dysfunction of NK cells. Patients tend to have normal numbers of lymphocytes, but show defective class-switched B cells, low IgG, defective antibody response, and defective T-cell responses to certain antigens (Kotlarz et al., 2013).
IL2RAImmunodeficiency, type 41 with lymphoproliferation and autoimmunityImmunodeficiency, type 41 is an autosomal recessive complex disorder of immune dysregulation. Affected individuals present in infancy with recurrent viral, fungal, and bacterial infections, lymphadenopathy, and variable autoimmune features, such as autoimmune enteropathy and eczematous skin lesions. Immunologic studies show a defect in T-cell regulation (Goudy et al., 2013).
IL2RGSevere combined immunodeficiency, X-linkedSevere combined immunodeficiency, X-linked follows an X-linked pattern of inheritance and is caused by pathogenic variants in the IL2RG gene located on chromosomal region Xq13.1. The age of onset is infantile. This disease is characterized by absent or markedly reduced numbers of T cells, leading to recurrent infections. The prevalence is 1:50,000-1:100,000.
IL36RNPsoriasis, type 14, pustularGeneralized pustular psoriasis (GPP) is a life-threatening disease characterized by sudden, repeated episodes of high-grade fever, generalized rash, and disseminated pustules, with hyperleukocytosis and elevated serum levels of C-reactive protein (123260) (Marrakchi et al., 2011). GPP often presents in patients with existing or prior psoriasis vulgaris (PV; 177900); however, GPP can develop without a history of PV (Sugiura et al., 2013). Palmoplantar pustulosis and acrodermatitis continua of Hallopeau represent acral forms of pustular psoriasis that have historically been grouped with GPP (Setta-Kaffetzi et al., 2013).GPP in association with sterile multifocal osteomyelitis and periostitis (612852) is caused by mutation in the IL1RN gene (147679). Capon (2013) noted that the percentage of GPP patients reported to be negative for mutation in IL36RN ranges from 51 to 84%, indicative of genetic heterogeneity in the generalized pustular form of psoriasis.
IL7RSevere combined immunodeficiency, T-cell negative, B-cell/natural killer cell-positive typeSevere combined immunodeficiency autosomal recessive T-cell-negative/B-cell-positive/NK-cell-positive is a form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.
ILDR1Deafness, autosomal recessive, type 42Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. Nonsyndromic hearing loss can be classified by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. The characteristics vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear.
IMPAD1Chondrodysplasia with joint dislocations, GPAPP typeChondrodysplasia with joint dislocations, GPAPP type is a condition consisting of congenital joint dislocations, chondrodysplasia with short stature, micrognathia and cleft palate, and a distinctive face.
IMPG2Retinitis pigmentosa, type 56Retinitis pigmentosa type 56 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IMPG2 gene located on chromosomal region 3q12.3. The age of onset is infantile. This disease is characterized by progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades. The prevalence is 1/4.000.
INPP5EJoubert syndrome, type 1Joubert syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the INPP5E gene located on chromosomal region 9q34.3. The age of onset is early infantile. This disease is characterized congenital malformation of the brainstem and agenesis of the cerebellar vermis (molar tooth sign) leading to an abnormal respiratory pattern, nystagmus, hypotonia, mental retardation, ataxia, and delay in achieving motor milestones. Other variable features include retinal dystrophy (manifesting with either Leber congenital amaurosis or progressive retinal dystrophy) and nephronophthisis (usually juvenile). The prevalence is 1:100,000.
INSPermanent neonatal diabetes mellitus (PNDM)Permanent neonatal diabetes mellitus (PNDM) is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins.
INSRDiabetes mellitus, insulin-resistant, with acanthosis nigricans, type ADiabetes mellitus, insulin-resistant, with acanthosis nigricans type A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the INSR gene located on chromosomal region 19p13.2. The age of onset is infantile. This disease is characterized by the triad of hyperinsulinemia, acanthosis nigricans (skin lesions associated with insulin resistance), and signs of hyperandrogenism in females without lipodystrophy and who are not overweight. It is generally diagnosed in young women with marked signs of hyperandrogenism, but insulin resistance and acanthosis nigricans may be observed in men and in childhood. Acromegaloid facies or muscular cramps are sometimes associated. Hyperinsulinemia, a biological marker for insulin resistance, is often associated with glucose tolerance defects over the course of the disease, and diabetes progressively sets in. Hyperandrogenism (associated with polycystic ovarian syndrome (see this term) or ovarian hyperthecoses) leads to fertility problems. The prevalence is <1:1,000,000.
INVSNephronophthisis, type 2, infantileNephronophthisis, type 2, infantile is an autosomal recessive disorder resulting in end-stage renal disease. It is characterized by early onset and rapid progression. Phenotypic manifestations include enlarged kidneys, chronic tubulo-interstitial nephritis, anemia, hyperkalemic metabolic acidosis. Some patients also display situs inversus. Pathologically, it differs from later-onset nephronophthisis by the absence of medullary cysts and thickened tubular basement membranes, and by the presence of cortical microcysts.
IQCB1Senior-Loken syndrome, type 5Senior-Loken syndrome, type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IQCB1 gene located on chromosomal region 3q13.33. The age of onset is infantile. This disease is characterized by the association of nephronophthisis (NPHP), a chronic kidney disease, with retinal dystrophy. The prevalence is 1/1.000.000.
IQSEC2Mental retardation, X-linked, type 1/78Impaired mental functioning occurs as an isolated feature or as part of many syndromes listed in the X-linked catalog. Mental retardation that is not associated with other distinguishing features is referred to as 'nonspecific.
IRAK4IRAK4 deficiencyIRAK-4 deficiency is a condition that affects the immune system (primary immunodeficiency). It causes recurring severe infections by a type of bacteria called pyogenic bacteria. Individuals with IRAK-4 deficiency seem to be particularly susceptible to infections caused by bacteria called Streptococcus pneumoniae.
IRF8Immunodeficiency, type 32B, monocyte and dendritic cell deficiency, autosomal recessiveImmunodeficiency, type 32B, monocyte and dendritic cell deficiency, autosomal recessive results in a life-threatening pediatric syndrome characterized by monocyte and dendritic cell deficiency, myeloproliferation, and susceptibility to severe opportunistic infections, including disseminated BCG infection and oral candidiasis (Hambleton et al., 2011).
IRX5Hamamy syndromeHamamy syndrome is a syndrome characterized by severe hypertelorism, upslanting palpebral fissures, brachycephaly, abnormal ears, sloping shoulders, enamel hypoplasia, and osteopenia with repeated fractures. Additional features include myopia, mild to moderate sensorineural hearing loss, gonadal anomalies and borderline intelligence.
ISCUMyopathy with lactic acidosis, hereditaryHereditary myopathy with lactic acidosis due to ISCU deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ISCU gene located on chromosomal region 12q23.3. The age of onset is infantile. This disease is characterized by myopathy with severe exercise intolerance.
ISPDMuscular dystrophy-dystroglycanopathy, type A7; Muscular dystrophy-dystroglycanopathy, type C7Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A7, which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. It represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Roscioli et al., 2012). Mutation in the ISPD gene can also cause a less severe limb-girdle muscular dystrophy-dystroglycanopathy without brain and eye anomalies, type C7 (MDDGC7).
ITCHAutoimmune disease, multisystem, with facial dysmorphismAutoimmune disease, multisystem, with facial dysmorphism is a disorder characterized by organomegaly, failure to thrive, developmental delay, dysmorphic features and autoimmune inflammatory cell infiltration of the lungs, liver and gut.
ITGA2BGlanzmann thrombastheniaGlanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex resulting from mutations in either the GPIIb or GPIIIa genes (Rosenberg et al., 1997).
ITGA3Interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa, congenitalMutations in the integrin alpha-3 gene are associated with disrupted basement-membrane structures and compromised barrier functions in kidney, lung, and skin. Patients exhibit a multiorgan disorder that includes congenital interstitial lung disease, nephrotic syndrome, and epidermolysis bullosa. The respiratory and renal features predominate, and lung involvement accounts for the lethal course of the disease (Has et al., 2012).
ITGA6Epidermolysis bullosa, junctional, with pyloric stenosisJunctional epidermolysis bullosa with pyloric atresia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ITGA6 gene located on chromosomal region 2q31.1 . The age of onset is early infantile. This disease is characterized by generalized blistering at birth and congenital atresia of the pylorus and rarely of other portions of the gastrointestinal tract.
ITGA7Muscular dystrophy, congenital, due to ITGA7 deficiencyMuscular dystrophy congenital due to integrin alpha-7 deficiency is a form of congenital muscular dystrophy. Patients present at birth, or within the first few months of life, with hypotonia, muscle weakness and often with joint contractures.
ITGB2Leukocyte adhesion deficiencyLeukocyte adhesion deficiency (LAD) is an autosomal recessive disorder of neutrophil function resulting from a deficiency of the beta-2 integrin subunit of the leukocyte cell adhesion molecule. The leukocyte cell adhesion molecule is present on the surface of peripheral blood mononuclear leukocytes and granulocytes and mediates cell-cell and cell-extracellular matrix adhesion. LAD is characterized by recurrent bacterial infections; impaired pus formation and wound healing; abnormalities of a wide variety of adhesion-dependent functions of granulocytes, monocytes, and lymphocytes; and a lack of beta-2/alpha-L, beta-2/alpha-M, and beta-2/alpha-X expression.
ITGB3Glanzmann thrombastheniaGlanzmann thrombasthenia is an autosomal recessive bleeding disorder characterized by failure of platelet aggregation and by absent or diminished clot retraction. The abnormalities are related to quantitative or qualitative abnormalities of the GPIIb/IIIa platelet surface fibrinogen receptor complex resulting from mutations in either the GPIIb or GPIIIa genes (Rosenberg et al., 1997).
ITGB4Epidermolysis bullosa, junctional, with pyloric atresiaJunctional epidermolysis bullosa with pyloric atresia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the ITGB4 gene located on chromosomal region 17q25.1. The age of onset is early infantile. This disease is characterized by generalized blistering at birth and congenital atresia of the pylorus and rarely of other portions of the gastrointestinal tract. More than 100 cases have been reported around the world.
ITKLymphoproliferative syndrome 1Lymphoproliferative syndrome, type 1 is an autosomal recessive primary immunodeficiency characterized by onset in early childhood of Epstein-Barr virus (EBV)-associated immune dysregulation, manifest as lymphoma, lymphomatoid granulomatosis, hemophagocytic lymphohistiocytosis, Hodgkin disease, and/or hypogammaglobulinemia. Autoimmune disorders, such as autoimmune hemolytic anemia or renal disease, may also occur. Patients show a high EBV viral load and decreased invariant natural killer T cells. It is unknown whether patients with ITK mutations are intrinsically susceptible to development of lymphoma or dysgammaglobulinemia in the absence of EBV infection (Stepensky et al., 2011; Linka et al., 2012).
ITPAEpileptic encephalopathy, early infantile, type 35Epileptic encephalopathy, early infantile, type 35 (EIEE35) is an autosomal recessive neurodegenerative disorder characterized by onset of seizures in the first months of life associated with essentially no normal development. Brain imaging shows a characteristic pattern consistent with lack of myelination of early structures, including the posterior limb of the internal capsule, brainstem tracts, and tracts to the primary visual and motor cortices. Many patients die in early childhood (Kevelam et al., 2015).
ITPR1Gillespie syndromeGillespie syndrome is usually diagnosed in the first year of life by the presence of fixed dilated pupils in a hypotonic infant. Affected individuals have a characteristic form of iris hypoplasia in which the pupillary border of the iris exhibits a scalloped or 'festooned' edge, with iris strands extending onto the anterior lens surface at regular intervals. The key extraocular features of Gillespie syndrome are congenital hypotonia, progressive cerebellar hypoplasia, and ataxia, as well as variable cognitive impairment that is usually mild (Gerber et al., 2016; McEntagart et al., 2016). Families with apparent autosomal recessive inheritance of Gillespie syndrome have been reported (Gillespie, 1965; Wittig et al., 1988; Nelson et al., 1997); however, instances of autosomal dominant transmission have also been reported (Verhulst et al., 1993).
IVDIsovaleric acidemiaIsovaleric academia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the IVD gene located on chromosomal region 15q15.1. The age of onset is neonatal. This disease is characterized by vomiting, dehydration, coma and abnormal movements. The prevalence is 1/100,000.
IYDThyroid dyshormonogenesis, type 4Thyroid dyshormonogenesis, type 4 is a disorder due to thyroid dyshormonogenesis, causing severe hypothyroidism, goiter, excessive levels of iodotyrosine in serum and urine, and variable mental deficits derived from unrecognized and untreated hypothyroidism.
JAK3Severe Combined Immunodeficiency, autosomal recessive, T-negative/B-positive typeSevere combined immunodeficiency, T-B+ type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the JAK3 gene located on chromosomal region 19p13.11. The age of onset is infantile. This disease is characterized by chronic diarrhea, failure to thrive, recurrent respiratory infections and/or generalized infections due to opportunistic pathogens. The incidence is 1/100,000 and 1/1,000,000.
JAM3Hemorrhagic destruction of the brain, subependymal calcification, and cataractsHemorrhagic destruction of the brain, subependymal calcification, and cataracts (HDBSCC) is an autosomal recessive disorder with a distinctive phenotype comprising hemorrhagic destruction of the brain, subependymal calcification, and congenital cataracts. Affected individuals have a catastrophic neurologic clinical course resulting in death in infancy (Akawi et al., 2013).
JUPNaxos diseaseNaxos disease is an autosomal recessive disorder characterized by the association of diffuse non-epidermolytic palmoplantar keratoderma with woolly hair and cardiac abnormalities such as dilated cardiomyopathy and arrhythmogenic right ventricular dysplasia.
KARSDeafness, autosomal recessive, type 89Deafness, autosomal recessive, type 89 (DFNB89) is a form of non-syndromic deafness characterized by bilateral, prelingual, moderate to severe hearing loss affecting all frequencies.
KCNE1Jervell and Lange-Nielsen syndrome 2Jervell and Lange-Nielsen syndrome, type 2 is an autosomal recessive disorder characterized by congenital deafness, prolongation of the QT interval, syncopal attacks due to ventricular arrhythmias, and a high risk of sudden death.
KCNJ1Bartter syndrome, type 2Bartter syndrome, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the KCNJ1 gene located on chromosomal region 11q24.3. The age of onset is antenatal. This disease is characterized by severe polyhydramnios in mother leading to premature delivery, postnatally newborns suffer from recurrent episodes of severe dehydration and electrolyte imbalance which can lead to fatal outcome.
KCNJ10SESAME syndromeSeizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance syndrome (SESAMES) is a complex disorder characterized by generalized seizures with onset in infancy, delayed psychomotor development, ataxia, sensorineural hearing loss, hypokalemia, metabolic alkalosis, and hypomagnesemia.
KCNJ11Hyperinsulinemic hypoglycemia, type 2 (congenital hyperinsulinism); Permanent neonatal diabetes mellitus (PNDM)Hyperinsulinemic hypoglycemia, also referred to as congenital hyperinsulinism, nesidioblastosis, or familial hyperinsulinism, is the most common cause of persistent hypoglycemia in infancy and is due to defective negative feedback regulation of insulin secretion by low glucose levels. Unless early and aggressive intervention is undertaken, brain damage from recurrent episodes of hypoglycemia may occur (Thornton et al., 1998). More than 30 mutations in the KCNJ1 gene have been found to cause congenital hyperinsulinism.
Futhermore, around 30 mutations in the KCNJ1 gene have been found to cause permanent neonatal diabetes mellitus (PNDM). Permanent neonatal diabetes mellitus is a type of diabetes that first appears within the first 6 months of life and persists throughout the lifespan. This form of diabetes is characterized by high blood sugar levels (hyperglycemia) resulting from a shortage of the hormone insulin. Individuals with PNDM experience slow growth before birth (intrauterine growth retardation). Affected infants have hyperglycemia and an excessive loss of fluids (dehydration) and are unable to gain weight and grow at the expected rate (failure to thrive). In some cases, people with PNDM also have certain neurological problems, including developmental delay and recurrent seizures (epilepsy). This combination of developmental delay, epilepsy, and neonatal diabetes is called DEND syndrome. Intermediate DEND syndrome is a similar combination but with milder developmental delay and without epilepsy. A small number of individuals with PNDM have an underdeveloped pancreas. Because the pancreas produces digestive enzymes as well as secreting insulin and other hormones, affected individuals experience digestive problems such as fatty stools and an inability to absorb fat-soluble vitamins.
KCNJ13Leber congenital amaurosis, type 16Leber congenital amaurosis, type 16 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the KCNJ13 gene located on chromosomal region 2q37.1. The age of onset is early infantile. This disease is characterized by retinal dystrophy defined by blindness, nystagmus, roving eye movement, leading to severe visual impairment within the first year of life.
KCNV2Retinal cone dystrophy, type 3BRetinal cone dystrophy, type 3B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the KCNV2 gene located on 9p24.2. The age of onset is in the first or second decade of life. This disease is characterized by is characterized by onset in the first or second decade of life of very marked photophobia, myopia, reduced color vision along the red-green axis with relatively preserved tritan discrimination, and central scotomata with peripheral widespread sensitivity loss predominating in the superior visual field. Nyctalopia is a later feature of the disorder. There is often retinal pigment epithelium disturbance at the macula with a normal retinal periphery.
KCTD7Epilepsy, progressive myoclonic, type 3, with or without intracellular inclusionsMutations in the KCTD7 gene cause a severe neurodegenerative phenotype characterized by onset of intractable myoclonic seizures before age 2 years and accompanied by developmental regression. The initial description was consistent with a form of progressive myoclonic epilepsy (designated here as EPM3), whereas a later report identified intracellular accumulation of autofluorescent lipopigment storage material, consistent with neuronal ceroid lipofuscinosis (designated CLN14). Ultrastructural findings on skin biopsies thus appear to be variable. However, clinical features are generally consistent between reports (Staropoli et al., 2012).
KDM5CMental retardation, X-linked, syndromic, Claes-Jensen typeMental retardation, X-linked, syndromic, Claes-Jensen type (MRXSCJ) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRXSCJ patients manifest mental retardation associated with variable features such as slowly progressive spastic paraplegia, seizures, facial dysmorphism.
KDM6AKabuki syndrome, type 2Kabuki syndrome is a congenital mental retardation syndrome with additional features, including postnatal dwarfism, a peculiar facies characterized by long palpebral fissures with eversion of the lateral third of the lower eyelids (reminiscent of the make-up of actors of Kabuki, a Japanese traditional theatrical form), a broad and depressed nasal tip, large prominent earlobes, a cleft or high-arched palate, scoliosis, short fifth finger, persistence of fingerpads, radiographic abnormalities of the vertebrae, hands, and hip joints, and recurrent otitis media in infancy (Niikawa et al., 1981).
KERACornea plana 2, autosomal recessiveCornea plana is clinically characterized by reduced corneal curvature leading in most cases to hyperopia, hazy corneal limbus, and arcus lipoides at an early age. CNA2 is a severe form of the disorder, which is frequently associated with additional ocular manifestations (Tahvanainen et al., 1996).
KHDC3LHydatidiform mole, recurrent, type 2A hydatidiform mole is an abnormal pregnancy characterized by hydropic placental villi, trophoblastic hyperplasia, and poor fetal development. Familial recurrent hydatidiform mole is an autosomal recessive condition in which women experience recurrent pregnancy losses, predominantly complete hydatidiform mole (CHM). However, unlike sporadic CHMs, which are androgenetic with 2 paternal chromosome complements, CHMs associated with familial recurrence are genetically biparental in origin with both a maternal and a paternal contribution to the genome. Other pregnancy losses in this condition include partial hydatidiform mole, stillbirths, ectopic pregnancies, early neonatal deaths, and miscarriages, some of which may be undiagnosed molar pregnancies. Normal pregnancies are extremely rare in families with this condition (Fallahian et al., 2013).
KIF1ANeuropathy, hereditary sensory, type 2C; Spastic paraplegia, type 30, autosomal recessiveNeuropathy, hereditary sensory, type 2C (HSN2C) is an autosomal recessive disorder characterized by onset in the first decade of progressive distal sensory loss leading to ulceration and amputation of the fingers and toes. Affected individuals also develop distal muscle weakness, primarily affecting the lower limbs (Riviere et al., 2011). HSN2C is caused by homozygous or compound heterozygous mutation in the KIF1A gene on chromosome 2q37. Mutation in the KIF1A gene can also cause hereditary spastic paraplegia 30 (SPG30). SPG30 is an autosomal recessive form of slowly progressive spastic paraplegia characterized by onset in the first or second decades of unsteady spastic gait and hyperreflexia of the lower limbs. Mildly impaired sensation and cerebellar involvement has been reported in 1 putatively affected family (Erlich et al., 2011).
KIF1BPGoldberg-Shprintzen megacolon syndromeGoldberg-Shprintzen syndrome is an autosomal recessive multiple congenital anomaly syndrome characterized by intellectual disability, microcephaly, and dysmorphic facial features. Most patients also have Hirschsprung disease and/or gyral abnormalities of the brain, consistent with defects in migration of neural crest cells and neurons. Other features, such as megalocornea or urogenital anomalies, may also be present. Goldberg-Shprintzen syndrome has some resemblance to Mowat-Wilson syndrome (MOWS; 235730) but is genetically distinct (Drevillon et al., 2013).Yomo et al. (1991) referred to this disorder as Goldberg-Shprintzen syndrome, which should not be confused with Shprintzen-Goldberg craniosynostosis syndrome (182212) or 2 other Shprintzen syndromes (192430, 82210).
KIF7Acrocallosal syndrome; Joubert syndrome, type 12Acrocallosal syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the KIF7 gene located on chromosomal region 15q26.1. The age of onset is infantile. This disease is considered a ciliopathy and is characterized by mental retardation, brain abnormalities such as corpus callosum agenesis and/or Dandy-Walker malformation as well as dysmorphic features, postaxial polydactyly of the hands, and preaxial polydactyly of the feet. The prevalence is below 1/1,000,000.
Mutations in KIF7 gene are also associated with Joubert syndrome type 12, a disorder with an acrocallosal syndrome overlapping phenotype characterized by the hallmark finding of the molar tooth sign (MTS) on brain MRI.
KISS1RHypogonadotropic hypogonadism, type 8, with or without anosmiaCongenital idiopathic hypogonadotropic hypogonadism (IHH) is a disorder characterized by absent or incomplete sexual maturation by the age of 18 years, in conjunction with low levels of circulating gonadotropins and testosterone and no other abnormalities of the hypothalamic-pituitary axis. Idiopathic hypogonadotropic hypogonadism can be caused by an isolated defect in gonadotropin-releasing hormone (GNRH; 152760) release, action, or both. Other associated nonreproductive phenotypes, such as anosmia, cleft palate, and sensorineural hearing loss, occur with variable frequency. In the presence of anosmia, idiopathic hypogonadotropic hypogonadism has been called 'Kallmann syndrome (KS),' whereas in the presence of a normal sense of smell, it has been termed 'normosmic idiopathic hypogonadotropic hypogonadism (nIHH)' (Raivio et al., 2007). Because families have been found to segregate both KS and nIHH, the disorder is here referred to as 'hypogonadotropic hypogonadism with or without anosmia (HH).
KLHL3Pseudohypoaldosteronism, type 2DFamilial hyperkalemic hypertension, also known as type II pseudohypoaldosteronism (PHAII) or Gordon syndrome, is a rare autosomal dominant disease in which a net positive sodium ion balance is associated with renal potassium ion retention, resulting in hypertension, hyperkalemia, and hyperchloremic metabolic acidosis (Louis-Dit-Picard et al., 2012).
KLHL7Cold-induced sweating syndrome 3Cold-induced sweating syndrome 3 is an autosomal recessive disorder characterized by infantile-onset hyperthermia and abnormal paroxysmal contractions of the facial and oropharyngeal muscles, resulting in feeding and respiratory difficulties. Cold-induced sweating usually has onset at 3 years of age. Other features include joint contractures and camptodactyly. Death in infancy may occur, and those that survive may develop retinitis pigmentosa later in childhood (Angius et al., 2016).
KLK4Amelogenesis imperfecta, type 2A1Amelogenesis imperfecta, type 2A1 is an autosomal recessive amelogenesis imperfecta pigmented hypomaturation type characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989).
KLKB1Fletcher factor (prekallikrein) deficiencyPrekallikrein deficiency is a blood condition that usually causes no health problems. In people with this condition, blood tests show a prolonged activated partial thromboplastin time (PTT), a result that is typically associated with bleeding problems; however, bleeding problems generally do not occur in prekallikrein deficiency. The condition is usually discovered when blood tests are done for other reasons.
KNL1Microcephaly 4, primary, autosomal recessiveMicrocephaly 4, primary, autosomal recessive is a clinical diagnosis made when an individual has a head circumference more than 3 standard deviations below the age- and sex-matched population mean and mental retardation, with no other associated malformations and with no apparent etiology. Most cases of primary microcephaly show an autosomal recessive mode of inheritance (Woods et al., 2005).
KRT10Epidermolytic hyperkeratosisEpidermolytic hyperkeratosis (EHK), also termed bullous congenital ichthyosiform erythroderma (BCIE), is a keratinization disorder with an incidence of approximately 1 in 200,000 in the USA. The clinical phenotype of EHK is characterized by erythema and widespread formation of epidermal blisters developing at birth. Later in life, bullous erythema is replaced by progressive hyperkeratosis, involving thickening of the cornified layer of the epidermis (Muller et al., 2006). Goldsmith (1976) used the designation of epidermolytic hyperkeratosis for the condition that is called bullous congenital ichthyosiform erythroderma (BCIE) when generalized, and ichthyosis hystrix (146600) when localized. They are presumably distinct entities. A form of epidermolytic hyperkeratosis that is limited to the palms and soles, designated palmoplantar keratoderma (EPPK; 144200), is caused by mutation in the keratin gene KRT9 (607606), and a mild form of EPPK can also be caused by mutation in KRT1.
KRT14Epidermolysis bullosa simplex, autosomal recessive, type 1Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous group of disorders characterized by recurrent blistering and cleavage within basal keratinocytes. Most forms show autosomal dominant inheritance (see, e.g., 131800, 131760, and 131900), but autosomal recessive inheritance has been described (Fine et al., 2008).
KRT5Epidermolysis bullosa simplex, autosomal recessive, type 1Epidermolysis bullosa simplex (EBS) is a clinically and genetically heterogeneous group of disorders characterized by recurrent blistering and cleavage within basal keratinocytes. Most forms show autosomal dominant inheritance (see, e.g., 131800, 131760, and 131900), but autosomal recessive inheritance has been described (Fine et al., 2008).
KYNUVertebral, cardiac, renal, and limb defects syndrome, type 2Vertebral, cardiac, renal, and limb defects syndrome, type 2 (VCRL2) is an autosomal recessive congenital malformation syndrome characterized by vertebral segmentation abnormalities, congenital cardiac defects, renal, and distal mild limb defects. Additional features are variable (Shi et al., 2017).
L1CAML1 SyndromeL1 syndrome?describes a group of conditions that primarily affect the nervous system and occur almost exclusively in males. These conditions vary in severity and include, from most severe to least, X-linked hydrocephalus with stenosis of the aqueduct of Sylvius (HSAS), MASA syndrome, spastic paraplegia type 1, and X-linked complicated corpus callosum agenesis. HSAS is an acronym for the characteristic features of the condition: fluid in the brain (hydrocephalus), muscle stiffness (spasticity), thumbs that are permanently bent toward the palms (adducted thumbs), and narrowing (stenosis) of the aqueduct of Sylvius in the brain. Individuals with HSAS often have severe intellectual disability and may have seizures. MASA syndrome include intellectual disability (mental retardation), mild to moderate, delayed speech (aphasia), spasticity, and adducted thumbs. Individuals with MASA syndrome may have mild enlargement of the ventricles. Spastic paraplegia type 1 is characterized by progressive muscle stiffness (spasticity) and the development of paralysis of the limbs (paraplegia). Affected individuals also have mild to moderate intellectual disability. X-linked complicated corpus callosum agenesis is defined by underdevelopment (hypoplasia) or absence (agenesis) of the tissue that connects the left and right halves of the brain (the corpus callosum). The life expectancy of individuals with L1 syndrome varies depending on the severity of the signs and symptoms.
L2HGDHL-2-hydroxyglutaric aciduriaL-2-hydroxyglutaric aciduria is an inheritedmetabolic condition that is associated with progressive brain damage. Signs and symptoms of this condition typically begin during infancy or early childhood and may include developmental delay, seizures, speech difficulties, macrocephaly and abnormalities in a part of the brain called the cerebellum, which is involved in coordinating movement (i.e. balance and muscle coordination).
LAMA1Poretti-Boltshauser syndromePoretti-Boltshauser syndrome is an autosomal recessive disorder characterized by cerebellar dysplasia, cerebellar vermis hypoplasia, cerebellar cysts in most patients, high myopia, variable retinal dystrophy, and eye movement abnormalities. Affected individuals have delayed motor development and often have speech delay. Cognitive function can range from normal to intellectually disabled (Aldinger et al., 2014).
LAMA2LAMA2-related muscular dystrophyLAMA2-related muscular dystrophy 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LAMA2 gene located on chromosomal region 6q22.33. LAMA2-related muscular dystrophy is a disorder that causes weakness and atrophy of skeletal muscles. This condition varies in severity, from a severe, early-onset type to a milder, late-onset form. Early-onset LAMA2-related muscular dystrophy is apparent at birth or within the first few months of life, called merosin-deficient congenital muscular dystrophy type 1A (607855). Patients show hypotonia, poor suck and cry, and delayed motor development; most never achieve independent ambulation. Most patients also have periventricular white matter abnormalities on brain imaging, but mental retardation and/or seizures occur only rarely. Symptoms of late-onset LAMA2-related muscular dystrophy become evident later in childhood or adulthood, and are similar to those of a group of muscle disorders classified as autosomal recessive limb-girdle muscular dystrophies, type 23. This group is characterized by slowly progressive proximal muscle weakness primarily affecting the lower limbs and resulting in gait difficulties. Additional features include white matter abnormalities on brain imaging, increased serum creatine kinase, and dystrophic features, with partial LAMA2 deficiency on muscle biopsy. Some patients may have additional neurologic features, including executive deficits, seizures, and peripheral neuropathy. Patients remain ambulatory well into adulthood. The prevalence is 1/30,000.
LAMA3Junctional epidermolysis bullosa (JEB) Herlitz type; JEB non-Herlitz typeJunctional epidermolysis bullosa (JEB) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LAMA3 gene located on chromosomal region 18q11.2. The age of onset is neonatal/infancy. JEB is a group of genetic conditions that cause the skin to be very fragile and to blister easily. Blisters and skin erosions form in response to minor injury or friction, such as rubbing or scratching. Researchers classify junctional epidermolysis bullosa into two main types based on severity: Herlitz JEB and non-Herlitz JEB. Herlitz type is more severe phenotype characterized by blisters and erosions, localized to the skin and mucous membranes and often results in early death. More than 30 mutations in the LAMA3 gene have been identified in people with Herlitz JEB. Other LAMA3 gene mutations cause the milder form non-Herlitz JEB, phenotype characterized by generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.
LAMB1Lissencephaly, type 5Lissencephaly, type 5 is an autosomal recessive brain malformation characterized by cobblestone changes in the cortex, more severe in the posterior region, and subcortical band heterotopia. Affected individuals have hydrocephalus, seizures, and severely delayed psychomotor development (Radmanesh et al., 2013).
LAMB2Pierson syndrome; Nephrotic syndrome, type 5, with or without ocular abnormalitiesPierson syndrome is an autosomal recessive disorder comprising congenital nephrotic syndrome with diffuse mesangial sclerosis and distinct ocular abnormalities, including microcoria and hypoplasia of the ciliary and pupillary muscles, as well as other anomalies. Many patients die early, and those who survive tend to show neurodevelopmental delay and visual loss (Zenker et al., 2004).Mutations in the LAMB2 gene also cause nephrotic syndrome type 5 with or without mild ocular anomalies (NPHS5). Nephrotic syndrome type 5 is an autosomal recessive disorder characterized by very early onset of progressive renal failure manifest as proteinuria with consecutive edema starting in utero or within the first 3 months of life. A subset of patients may develop mild ocular anomalies, such as myopia, nystagmus, and strabismus (Hasselbacher et al., 2006).
LAMB3Junctional epidermolysis bullosa (JEB) Herlitz type; JEB non-Herlitz typeJunctional epidermolysis bullosa (JEB) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LAMB3 gene located on chromosomal region 1q32.2. The age of onset is neonatal/infancy. JEB is a group of genetic conditions that cause the skin to be very fragile and to blister easily. Blisters and skin erosions form in response to minor injury or friction, such as rubbing or scratching. Researchers classify junctional epidermolysis bullosa into two main types based on severity: JEB Herlitz type and JEB non-Herlitz type. Herlitz type is more severe phenotype characterized by blisters and erosions, localized to the skin and mucous membranes and often results in early death. More than 80 mutations in the LAMB3 gene have been identified in people with JEB Herlitz type. Other LAMB3 gene mutations cause the milder form JEB non-Herlitz type, disease characterized by generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.
LAMC2Junctional epidermolysis bullosa (JEB) Herlitz type; JEB non-Herlitz typeJunctional epidermolysis bullosa (JEB) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LAMC2 gene located on chromosomal region 1q25.3. The age of onset is neonatal/infancy. JEB is a group of genetic conditions that cause the skin to be very fragile and to blister easily. Blisters and skin erosions form in response to minor injury or friction, such as rubbing or scratching. Researchers classify junctional epidermolysis bullosa into two main types based on severity: Herlitz JEB and non-Herlitz JEB. Herlitz type is more severe phenotype characterized by blisters and erosions, localized to the skin and mucous membranes and often results in early death. More than 30 mutations in the LAMC2 gene have been identified in people with Herlitz JEB. Other LAMC2 gene mutations cause the milder form non-Herlitz JEB, disease characterized by generalized skin blistering, atrophic scarring, nail dystrophy or nail absence, and enamel hypoplasia, with extracutaneous involvement.
LAMC3Cortical malformations, occipitalOccipital cortical malformations (OCCM) is an autosomal recessive condition in which affected individuals develop seizures, sometimes associated with transient visual changes. Brain MRI shows both pachygyria and polymicrogyria restricted to the lateral occipital lobes (Barak et al., 2011).
LAMP2Danon diseaseDanon disease is an X-linked dominant disorder predominantly affecting cardiac muscle. Skeletal muscle involvement and mental retardation are variable features. The accumulation of glycogen in muscle and lysosomes originally led to the classification of Danon disease as a variant of glycogen storage disease II (Pompe disease; 232300) with 'normal acid maltase' or alpha-glucosidase (GAA; 606800) (Danon et al., 1981). However, Nishino et al. (2000) stated that Danon disease is not a glycogen storage disease because glycogen is not always increased. Sugie et al. (2005) classified Danon disease as a form of autophagic vacuolar myopathy, characterized by intracytoplasmic autophagic vacuoles with sarcolemmal features. The characteristic vacuole is believed to be an autolysosome surrounded by secondarily-generated membranes containing sarcolemmal proteins, basal lamina, and acetylcholinesterase activity.X-linked myopathy with excessive autophagy (XMEA; 310440) is a distinct disorder with similar pathologic features.
LARGE1Muscular dystrophy-dystroglycanopathy, type 6A and 6BMuscular dystrophy-dystroglycanopathy, type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LARGE1 gene located on chromosomal region 22q12.3. The age of onset is infantile. There are two subtypes of dystroglycanopathies related to LARGE1 gene: subtype 6A and 6B. Subtype 6A is the most severe phenotype and is associated with congenital brain and eye anomalies, cobblestone lissencephaly, profound mental retardation, and death usually in the first years of life. Included diseases are the more severe Walker-Warburg syndrome and the slightly less severe muscle-eye-brain disease. Subtype 6B represents an intermediate phenotype with or without congenital mental retardation, white matter changes and structural brain abnormalities. The prevalence is 1:100,000-9:100,000.
LARS2Perrault syndrome, type 4Perrault syndrome is characterized by premature ovarian failure (POF) in females and by progressive hearing loss in both females and males (Pierce et al., 2013).
LBRGreenberg skeletal dysplasiaGreenberg dysplasia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LBR gene located on chromosomal region 1q42.12. The age of onset is fetal. This disease is characterized by fetal hydrops, short limbs and abnormal chondro-osseous calcification. The prevalence is <1:1,000,000.
LCA5Leber congenital amaurosis, type 5Leber congenital amaurosis 5 is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.
LCATFamilial LCAT deficiency; Fish-eye diseaseFamilial LCAT deficiency is a genetic disorder that affects the body's ability to process (metabolize) cholesterol. It is characterized by cloudiness of the clear front surface of the eye (corneal opacities), a shortage of red blood cells (hemolytic anemia), and kidney failure. Symptoms usually appear in adulthood and may also include enlargement of the liver (hepatomegaly), spleen (splenomegaly), and lymph nodes (lymphadenopathy), as well as an accumulation of fat in the artery walls (atherosclerosis). Familial LCAT deficiency is one of two types of LCAT deficiency; the other type of LCAT deficiency is fish-eye disease. Both types of LCAT deficiency are caused by mutations in the LCAT gene and are inherited in an autosomal recessive manner. The LCAT gene is also mutant in fish-eye disease. At least 18 mutations in the LCAT gene have been identified in people with fish-eye disease, also called partial LCAT deficiency. This disorder causes clouding of the clear covering of the eyes (corneas). Individuals with fish-eye disease have mutations in both copies of the LCAT gene in each cell.
LCTLactase deficiency, congenitalCongenital lactase deficiency is a severe gastrointestinal disorder characterized by watery diarrhea in infants fed with breast milk or other lactose-containing formulas.
LDHAGlycogen storage disease type 11Glycogen storage disease type 11 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LDHA gene located on chromosomal region 11p15.1. The age of onset is infantile. This disease is characterized by hepatic glycogenosis and renal Fanconi syndrome.
LDLRAP1Hypercholesterolemia, familial, autosomal recessiveHypercholesterolemia, familial, autosomal recessive is a rare monogenic disease characterized by very high levels of low-density lipoprotein (LDL) cholesterol (usually above 400 mg/dl) and increased risk of premature atherosclerotic cardiovascular disease (Sanchez-Hernandez et al., 2018).
LEPObesity, morbid, due to leptin deficiencyCongenital leptin deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. Without treatment, the extreme hunger continues and leads to chronic excessive eating (hyperphagia) and obesity. People with congenital leptin deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Without treatment, affected individuals experience delayed puberty or do not go through puberty, and may be unable to conceive children (infertile).
LEPRObesity, morbid, due to leptin receptor deficiencyLeptin receptor deficiency is a condition that causes severe obesity beginning in the first few months of life. Affected individuals are of normal weight at birth, but they are constantly hungry and quickly gain weight. The extreme hunger leads to chronic excessive eating (hyperphagia) and obesity. People with leptin receptor deficiency also have hypogonadotropic hypogonadism, which is a condition caused by reduced production of hormones that direct sexual development. Affected individuals experience delayed puberty or do not go through puberty, and they may be unable to conceive children (infertile).
LHBHypogonadotropic hypogonadism, type 23, with or without anosmiaMale patients with hypogonadotropic hypogonadism due to isolated luteinizing hormone (LH) deficiency have normal sexual differentiation but fail to develop spontaneous puberty. Absence of LH alters Leydig cell proliferation and maturation and impairs the onset of normal spermatogenesis, which requires high levels of intratesticular testosterone. Infertility and very low levels of spermatogenesis generally persist in affected men despite long-term exposure to gonadotropin therapy. Female patients exhibit normal pubertal development and menarche, followed by oligomenorrhea and anovulatory secondary amenorrhea (Basciani et al., 2012).
LHCGRLeydig cell hypoplasiaLeydig cell hypoplasia is an autosomal recessive disorder in which loss of function of the LHCGR gene in the male prevents normal sexual development. Two types of LCH have been defined (Toledo, 1992). Type 1, a severe form caused by complete inactivation of LHCGR, is characterized by complete 46,XY male pseudohermaphroditism, low testosterone and high LH levels, total lack of responsiveness to LH/CG challenge, lack of breast development, and absent development of secondary male sex characteristics. Type 2, a milder form caused by partial inactivation of the gene, displays a broader range of phenotypic expression ranging from micropenis to severe hypospadias. Females with inactivating mutations in the LHCGR gene display a mild phenotype characterized by defective follicular development and ovulation, amenorrhea, and infertility (Themmen and Huhtaniemi, 2000). Arnhold et al. (2009) noted that the clinical manifestations of female patients with hypogonadotropic hypogonadism due to isolated LH deficiency (HH23; 228300) are very similar to those of women with hypergonadotropic hypogonadism due to inactivating mutations of the LH receptor: all have female external genitalia, spontaneous development of normal pubic hair and breasts at puberty, and normal to late menarche followed by oligoamenorrhea and infertility. Pelvic ultrasound shows a small or normal uterus and normal or enlarged ovaries with cysts. However, women with LHB (152780) mutations can be treated with luteinizing hormone or chorionic gonadotropin (CG; 118860) replacement therapy; women with LH receptor mutations are resistant to LH, and no treatment is effective in recovering their fertility.
LHFPL5Deafness, autosomal recessive type 67Autosomal recessive nonsyndromic sensorineural deafness type 67 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LHFPL5 gene located on chromosomal region 6p21.31. The age of onset is infantile, etc/. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
LHX3Pituitary hormone deficiency, combined, type 3Combined pituitary hormone deficiency type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LHX3 gene located on chromosomal region 9q34.3. The age of onset is infantile, etc/. This disease is characterized by somatolactotroph, thyrotroph and gonadotroph deficiencies, limited head and neck rotation associated with spinal abnormalities. The prevalence is <1 /1,000,000.
LIASHyperglycinemia, lactic acidosis, and seizuresHyperglycinemia, lactic acidosis, and seizures is a severe autosomal recessive disorder characterized by onset of hypotonia and seizures associated with increased serum glycine and lactate in the first days of life. Affected individuals develop an encephalopathy or severely delayed psychomotor development, which may result in death in childhood. The disorder represents a form of 'variant' nonketotic hyperglycinemia and is distinct from classic nonketotic hyperglycinemia (NKH, or GCE; 605899), which is characterized by significantly increased CSF glycine. Several forms of 'variant' NKH, including HGCLAS, appear to result from defects of mitochondrial lipoate biosynthesis (Baker et al., 2014).
LIFRStuve-Wiedemann syndrome / Schwartz-Jampel type 2 syndromeSt?ve-Wiedemann syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LIFR gene located on chromosomal region 5p13.1. The age of onset is neonatal. This disease is characterized by small stature, congenital bowing of the long bones and campodactyly.
LIG4LIG4 syndromeLIG4 syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LIG4 gene located on chromosomal region 10p13. The age of onset is infantile. It is associated with impaired DNA double-strand break repair mechanisms and characterized by microcephaly, unusual facial features (''bird-like''), growth and developmental delay, skin anomalies including photosensitivity and psoriatic-like lesions, and pancytopenia. The disease is associated with immunodeficiency. Some patients have been reported as having telangiectasias, leukemia, lymphoma, bone marrow abnormalities, and type 2 diabetes. The prevalence 1-9/1.000.000.
LINS1Mental retardation, autosomal recessive, type 27Mental retardation, autosomal recessive, type 27 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
LIPALysosomal acid lipase deficiencyDeficiency of lysosomal acid lipase causes 2 distinct phenotypes in humans: Wolman disease and cholesteryl ester storage disease (CESD). Wolman disease is an early-onset fulminant disorder of infancy with massive infiltration of the liver, spleen, and other organs by macrophages filled with cholesteryl esters and triglycerides. Death occurs early in life. Wolman disease is very rare, with an incidence of less than one in 100,000 live births. CESD is a milder, later-onset disorder with primary hepatic involvement by macrophages engorged with cholesteryl esters. This slowly progressive visceral disease has a very wide spectrum of involvement ranging from early onset with severe cirrhosis to later onset of more slowly progressive hepatic disease with survival into adulthood (Du et al., 2001).
LIPELipodystrophy, familial partial, type 6Familial partial lipodystrophy, type 6 (FPLD6) is characterized by abnormal subcutaneous fat distribution, with variable excess accumulation of fat in the face, neck, shoulders, axillae, back, abdomen, and pubic region, and reduction in subcutaneous fat of the lower extremities. Progressive adult-onset myopathy is seen in some patients, and there is variable association with diabetes, hypertriglyceridemia, low high-density lipoprotein (HDL) cholesterol, and hepatic steatosis (Zolotov et al., 2017).
LIPHHypotrichosis, type 7 or woolly hair, autosomal recessive, type 2, with or without hypotrichosisHypotrichosis is a condition that affects hair growth. People with this condition have sparse hair (hypotrichosis) on the scalp beginning in infancy. This hair is usually coarse, dry, and tightly curled (often described as woolly hair). Scalp hair may also be lighter in color than expected and is fragile and easily broken. Affected individuals often cannot grow hair longer than a few inches. The eyebrows, eyelashes, and other body hair may be sparse as well. Over time, the hair problems can remain stable or progress to complete scalp hair loss (alopecia) and a decrease in body hair. Mutations in the LIPH gene can also cause a hair condition called autosomal recessive woolly hair. People with this condition have hair that is unusually coarse, dry, fine, and tightly curled. Woolly hair typically affects only scalp hair and is present from birth. In some cases, affected individuals develop hypotrichosis as they get older. Certain LIPH gene mutations cause autosomal recessive woolly hair in some people and autosomal recessive hypotrichosis in others, even among members of the same family. Because of a shared genetic cause and overlapping features, it is uncertain whether these two conditions are separate disorders or part of the same disease spectrum.
LMAN1Combined deficiency of factor V and factor VIII, type 1Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (Zhang and Ginsburg, 2004).
LMBRD1Methylmalonic aciduria and homocystinuria, cblF typeCombined methylmalonic aciduria (MMA) and homocystinuria is a genetically heterogeneous disorder of cobalamin (cbl; vitamin B12) metabolism. The defect causes decreased levels of the coenzymes adenosylcobalamin (AdoCbl) and methylcobalamin (MeCbl), which results in decreased activity of the respective enzymes methylmalonyl-CoA mutase (MUT; 609058) and methyltetrahydrofolate:homocysteine methyltransferase, also known as methionine synthase (MTR; 156570). Different forms of the disorder have been classified according to complementation groups of cells in vitro: cblC (MAHCC; 277400), cblD (MAHCD; 277410), cblF, and cblJ (MAHCJ; 614857).
LMF1Lipase deficiency, combinedCombined lipase deficiency (CLD) is characterized by repeated episodes of pancreatitis, tuberous xanthomas and lipodystrophy and is caused by deficiency of both lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL).
LMNALMNA-related disorders, autosomal recessiveLMNA-related disorders, autosomal recessive, are caused by pathogenic variants in the LMNA gene located on chromosomal region 1q22, and include Charcot-Marie-Tooth disease, type 2B1, Emery-Dreifuss muscular dystrophy type 3, mandibuloacral dysplasia, lethal restrictive dermopathy among others. Charcot-Marie-Tooth disease constitutes a clinically and genetically heterogeneous group of hereditary motor and sensory neuropathies. Emery-Dreifuss muscular dystrophy is characterized classically by the triad of weakness of the shoulder and pelvic girdle muscles, contractures of the elbows, neck, and Achilles tendon, and cardiac involvement, most commonly arrhythmias. Mandibuloacral dysplasia is characterized by growth retardation, craniofacial anomalies with mandibular hypoplasia, skeletal abnormalities with progressive osteolysis of the distal phalanges and clavicles, and pigmentary skin changes. Restrictive dermopathy is a rare, lethal genodermatosis characterized by thin, tightly adherent translucent skin with erosions at flexure sites, superficial vessels, typical facial dysmorphism, and generalized joint ankylosis.
LOXHD1Deafness, autosomal recessive type 77Autosomal recessive nonsyndromic sensorineural deafness type 77 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LOXHD1 gene located on chromosomal region 18q21.1. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
LPAR6Hypotrichosis, type 8 or woolly hair, autosomal recessive, type 1, with or without hypotrichosisHypotrichosis simplex refers to a group of hereditary isolated alopecias characterized by diffuse and progressive hair loss, usually beginning in early childhood (Pasternack et al., 2008). Localized autosomal recessive hypotrichosis (LAH) is characterized by fragile hairs that break easily, leaving short, sparse scalp hairs. The disorder affects the trunk and extremities as well as the scalp, and the eyebrows and eyelashes may also be involved, whereas beard, pubic, and axillary hairs are largely spared. In addition, patients can develop hyperkeratotic follicular papules, erythema, and pruritus in affected areas (Schaffer et al., 2006). Mutations in the LPAR6 gene can also cause a hair condition called autosomal recessive woolly hair. Woolly hair (WH) refers to a group of hair shaft disorders that are characterized by fine and tightly curled hair. Compared to normal curly hair that is observed in some populations, WH grows slowly and stops growing after a few inches. Under light microscopy, WH shows some structural anomalies, including trichorrhexis nodosa and tapered ends (Petukhova et al., 2009). Several families have been reported in which some affected individuals exhibit features of hypotrichosis and others have woolly scalp hair (Khan et al., 2011).Woolly hair is also a feature of several syndromes, such as Naxos disease (601214) and cardiofaciocutaneous syndrome (115150) (Petukhova et al., 2009), or the palmoplantar keratoderma and cardiomyopathy syndrome (601214) (Carvajal-Huerta, 1998). Certain LPAR6 gene mutations cause autosomal recessive woolly hair in some people and autosomal recessive hypotrichosis in others, even among members of the same family. Because of a shared genetic cause and overlapping features, it is uncertain whether these two conditions are separate disorders or part of the same disease spectrum.
LPIN1Myoglobinuria, acute recurrent, autosomal recessiveRecurrent myoglobinuria is characterized by recurrent attacks of rhabdomyolysis associated with muscle pain and weakness and followed by excretion of myoglobin in the urine. Renal failure may occasionally occur. Onset is usually in early childhood under the age of 5 years. Unlike the exercise-induced rhabdomyolyses such as McArdle syndrome (232600), carnitine palmitoyltransferase deficiency (255110), and the Creteil variety of phosphoglycerate kinase deficiency (311800), the attacks in recurrent myoglobinuria no relation to exercise, but are triggered by intercurrent illnesses, commonly upper respiratory tract infections. (Ramesh and Gardner-Medwin, 1992).
LPIN2Majeed syndromeMajeed syndrome is an autosomal recessive syndrome characterized by chronic recurrent multifocal osteomyelitis that is of early onset with a lifelong course, congenital dyserythropoietic anemia that presents as hypochromic, microcytic anemia during the first year of life and ranges from mild to transfusion-dependent, and transient inflammatory dermatosis, often manifesting as Sweet syndrome (neutrophilic skin infiltration).
LPLLipoprotein lipase deficiencyLipoprotein lipase deficiency is a rare genetic disorder is which a person lacks the enzyme lipoprotein lipase, a protein needed to break down fat molecules. Deficiency of this enzyme prevents affected individuals from properly digesting certain fats. This results in the accumulation of fatty droplets called chylomicrons in the blood and an increase in the blood concentration of triglycerides. Symptoms include episodes of abdominal pain, recurrent inflammation of the pancreas (pancreatitis), abnormal enlargement of the liver and/or spleen (hepatosplenomegaly), and the development of skin lesions known as erruptive xanthomas.
LRATLeber congenital amaurosis type 14Leber congenital amaurosis type 14 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LRAT gene located on chromosomal region 4q32.1. The age of onset is infantile. This disease is characterized by blindness, nystagmus, roving eye movement. The prevalence is 2:100,000-3:100,000 newborn.
LRMDAAlbinism, oculocutaneous, type 7Albinism, oculocutaneous, type 7 is a disorder of pigmentation characterized by reduced biosynthesis of melanin in the skin, hair and eyes. Patients show reduced or lacking pigmentation associated with classic albinism ocular abnormalities, including decreased visual acuity, macular hypoplasia, optic dysplasia, atypical choroidal vessels, and nystagmus.
LRP2Donnai-Barrow syndromeDonnai-Barrow syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LRP2 gene located on chromosomal region 2q31.1. The age of onset is infantile. This disease is characterized by diaphragmatic hernia, ocular findings, hipertelorism, agenesis of the corpus callosum, hearing loss and facial dimorphism. The prevalence is <1:1,000,000.
LRP4Cenani-Lenz syndactyly syndromeCenani-Lenz syndactyly syndrome is a congenital malformation syndrome defined as complete and complex syndactyly of the hands combined with malformations of the forearm bones and similar manifestations in the lower limbs. It is characterized by fusion and disorganization of metacarpal and phalangeal bones, radius and ulnar shortening, radioulnar synostosis, and severe syndactyly of hands and feet.
LRP5Osteoporosis-pseudoglioma syndromeOsteoporosis-pseudoglioma syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LRP5 gene located on chromosomal region 11q13.2. The age of onset is infantile. This disease is characterized by congenital or infancy-onset blindness and severe juvenile-onset osteoporosis and spontaneous fractures. The prevalence is 1:2,000,000.
LRPAP1Myopia, type 23, autosomal recessiveMyopia type 23, autosomal recessive or nearsightedness, is a refractive error of the eye. Light rays from a distant object are focused in front of the retina and those from a near object are focused in the retina; therefore distant objects are blurry and near objects are clear (Kaiser et al., 2004).
LRPPRCLeigh syndrome, French-Canadian typeFrench-Canadian type Leigh syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LRPPRC gene located on chromosomal region 2p21. The age of onset is infantile. This disease is characterized by chronic metabolic acidosis, hypotonia, facial dysmorphism and delayed development. The prevalence is 1:2,000 newborn.
LRRC6Ciliary dyskinesia, primary, type 19Ciliary dyskinesia, primary, type 19 (CILD19) is an autosomal recessive ciliopathy characterized by chronic sinopulmonary infections, asthenospermia, and immotile cilia. Respiratory epithelial cells and sperm flagella of affected individuals lack both the inner and outer dynein arms. About 50% of patients have situs inversus (Kott et al., 2012).
LRSAM1Charcot-Marie-Tooth disease, axonal, type 2PCharcot-Marie-Tooth disease, axonal, type 2P is a rare, genetic, axonal hereditary motor and sensory neuropathy disorder characterized by adulthood-onset of slowly progressive, occasionally asymmetrical, distal muscle weakness and atrophy (predominantly in the lower limbs), pan-modal sensory loss, muscle cramping in extremities and/or trunk, pes cavus and absent or reduced deep tendon reflexes.
LRTOMTDeafness, autosomal recessive type 63Autosomal recessive nonsyndromic sensorineural deafness type 63 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the LRTOMT gene located on chromosomal region 11q13.4. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
LTBP2Microspherophakia and/or megalocornea, with ectopia lentis and with or without secondary glaucomaMicrospherophakia (MSP) is a rare disease characterized by smaller and more spherical lenses than normal bilaterally, an increased anteroposterior thickness of the lens, and highly myopic eyes. Lens dislocation or subluxation may occur, leading to defective accommodation (Ben Yahia et al., 2009).Microspherophakia may occur in association with ectopia lentis and glaucoma, Marfan syndrome (MFS; 154700), and Weill-Marchesani syndrome (WMS; 277600).
LTBP3Dental anomalies and short statureDental anomalies and short stature (DASS) is characterized by significant short stature with brachyolmia as well as hypoplastic amelogenesis imperfecta with almost absent enamel (Huckert et al., 2015). Some patients exhibit valvular and/or vascular defects, including mitral valve prolapse, aortic root dilation, and aortic as well as other arterial aneurysms (Dugan et al., 2015; Guo et al., 2018). Inter- and intrafamilial variability has been reported.
LTBP4Cutis laxa, autosomal recessive, type 1CCutis laxa is a collection of disorders that are typified by loose and/or wrinkled skin that imparts a prematurely aged appearance. Face, hands, feet, joints, and torso may be differentially affected. The skin lacks elastic recoil, in marked contrast to the hyperelasticity apparent in classic Ehlers-Danlos syndrome (130000). These properties are nearly always attributable to loss, fragmentation, or severe disorganization of dermal elastic fibers (Davidson and Giro, 2002).Patients with autosomal recessive cutis laxa type 1C exhibit generalized cutis laxa in association with impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development (Callewaert et al., 2013).For general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive cutis laxa, see ARCL1A (219100).
LYSTChediak-Higashi syndromeChediak-Higashi syndrome (CHS) is a rare autosomal recessive disorder characterized by hypopigmentation, severe immunologic deficiency, a bleeding tendency, neurologic abnormalities, abnormal intracellular transport to and from the lysosome, and giant inclusion bodies in a variety of cell types. Most patients die at an early age unless they receive an allogeneic hematopoietic stem cell transplant.
LZTFL1Bardet-Biedl syndrome, type 17Bardet-Biedl syndrome 17 (BBS17) is an autosomal recessive ciliopathy characterized by retinitis pigmentosa, cognitive impairment, obesity, renal dysfunction, and hypogenitalism. Polydactyly, most often postaxial, is also a primary feature of BBS; in BBS17 mesoaxial polydactyly, with fused or Y-shaped metacarpals, is a distinct manifestation (Deffert et al., 2007; Schaefer et al., 2014).
MAGI2Nephrotic syndrome, type 15Nephrotic syndrome, type 15 (NPHS15) is an autosomal recessive renal disorder characterized by onset of impaired kidney function with proteinuria in the first months of life. The disease course and severity varies widely. Some patients show rapid progression to end-stage renal failure necessitating transplant, whereas others have a more benign course that can be managed with medication. Renal biopsy tends to show glomerular sclerosis and effacement of podocyte foot processes (Bierzynska et al., 2017).
MAGT1Immunodeficiency, X-linked, with magnesium defect, Epstein-Barr virus infection and neoplasiaX-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (typically known by the acronym XMEN) is a disorder that affects the immune system in males. In XMEN, certain types of immune system cells called T cells are reduced in number or do not function properly. Normally these cells recognize foreign invaders, such as viruses, bacteria, and fungi, and are then turned on (activated) to attack these invaders in order to prevent infection and illness. Because males with XMEN do not have enough functional T cells, they have frequent infections, such as ear infections, sinus infections, and pneumonia.In particular, affected individuals are vulnerable to the Epstein-Barr virus (EBV). EBV is a very common virus that infects more than 90 percent of the general population and in most cases goes unnoticed. Normally, after initial infection, EBV remains in the body for the rest of a person's life. However, the virus is generally inactive (latent) because it is controlled by T cells. In males with XMEN, however, the T cells cannot control the virus, and EBV infection can lead to cancers of immune system cells (lymphomas). The word "neoplasia" in the condition name refers to these lymphomas; neoplasia is a general term meaning abnormal growths of tissue.
MAKRetinitis pigmentosa type 62Retinitis pigmentosa type 62 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MAK gene located on chromosomal region 6p24.2. The age of onset is infantile. This disease is characterized by progressive loss of the photoreceptors and retinal pigment epithelium and resulting in blindness usually after several decades.
MAMLD1Hypospadias 2, X-linkedHypospadias 2, X-linked (HYSP2) is a common malformation in which the urethra opens on the ventral side of the penis, due to developmental arrest of urethral fusion. The opening can be located glandular, penile, or even more posterior in the scrotum or perineum. Hypospadias is a feature of several syndromic disorders, including the androgen insensitivity syndrome and Opitz syndrome.
MAN1B1Mental retardation, autosomal recessive, type 15Mental retardation, autosomal recessive, type 15 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
MAN2B1Mannosidosis, alpha-, types I and IIAlpha-mannosidosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MAN2B1 gene located on chromosomal region 19p13.2. The age of onset is infantile. This disease is characterized by immunodeficiency, facial and skeletal abnormalities, hearing impairment and intellectual disability. The prevalence is 1:1,000,000-9:1,000,000.
MANBAMannosidosis, betaBeta-mannosidosis is an autosomal recessive lysosomal storage disease of glycoprotein catabolism caused by a deficiency of lysosomal beta-mannosidase activity. The most severely affected patients show developmental delay and mental retardation, but there are differing levels of severity and some patients may have comparatively mild disease (Bedilu et al., 2002) The disorder was first described in goats (Jones and Dawson, 1981), who have a more severe neurodegenerative disorder than that seen in humans.
MAOABrunner syndromeBrunner syndrome is a recessive X-linked disorder characterized by impulsive aggressiveness and mild mental retardation associated with MAOA deficiency (Brunner et al., 1993).
MAPTSupranuclear palsy, progressive atypical (parkinsonism syndrome)Progressive supranuclear palsy 1 (PSNP1) is characterized by akinetic-rigid syndrome, supranuclear gaze palsy, pyramidal tract dysfunction, pseudobulbar signs and cognitive capacities deterioration. Neurofibrillary tangles and gliosis but no amyloid plaques are found in diseased brains. Most cases appear to be sporadic, with a significant association with a common haplotype including the MAPT gene and the flanking regions. Familial cases show an autosomal dominant pattern of transmission with incomplete penetrance; genetic analysis of a few cases showed the occurrence of tau mutations, including a deletion of Asn-613.
MARS2Spastic ataxia, type 3, autosomal recessiveSpastic ataxia, type 3, autosomal recessive is a neurologic disorder characterized by cerebellar ataxia, ataxic gait, spasticity, and hyperreflexia. Other variable features include dysarthria, dysmetria, mild cognitive impairment, urinary urgency and dystonic positioning.
MARVELD2Deafness, autosomal recessive type 49Autosomal recessive nonsyndromic sensorineural deafness type 49 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MARVELD2 gene located on chromosomal region 5q13.2. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
MASP13MC syndrome 1The term '3MC syndrome' encompasses 4 rare autosomal recessive disorders that were previously designated the Carnevale, Mingarelli, Malpuech, and Michels syndromes, respectively. The main features of these syndromes are facial dysmorphism that includes hypertelorism, blepharophimosis, blepharoptosis, and highly arched eyebrows, which are present in 70 to 95% of cases. Cleft lip and palate, postnatal growth deficiency, cognitive impairment, and hearing loss are also consistent findings, occurring in 40 to 68% of cases. Craniosynostosis, radioulnar synostosis, and genital and vesicorenal anomalies occur in 20 to 30% of cases. Rare features include anterior chamber defects, cardiac anomalies, caudal appendage, umbilical hernia (omphalocele), and diastasis recti (Rooryck et al., 2011).
MAT1AMethionine adenosyltransferase deficiency, autosomal recessiveMethionine adenosyltransferase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MAT1A gene located on chromosomal region 10q23.1. This disease is characterized by brain demyelination (rarely leading to neurological disorders) and isolated hepatic hypermethioninemia. The prevalence is <1:1,000,000.
MBTPS2IFAP/BRESHECK syndrome; Osteogenesis imperfecta, type 19IFAP/BRESHECK syndrome and Osteogenesis imperfecta, type 19 follow an X-linked pattern of inheritance and are caused by pathogenic variants in the MBTPS2 gene located on chromosomal region Xp22.12-p22.11. IFAP/ BRESHECK syndrome's age of onset is infantile and it is characterized by the triad of ichthyosis follicularis, alopecia, and photophobia. Some patients have additional features, including mental retardation, brain anomalies, Hirschsprung disease, corneal opacifications, kidney dysplasia, cryptorchidism, cleft palate, and skeletal malformations, which constitutes BRESHECK syndrom . The prevalence of this syndrome is 1:200,000. Osteogenesis imperfecta type 19 is characterized by prenatal fractures and generalized osteopenia, with severe short stature in adulthood, as well as variable scoliosis and pectal deformity, and marked anterior angulation of the tibia.
MC2RGlucocorticoid deficiency, due to ACTH unresponsivenessFamilial glucocorticoid deficiency is an autosomal recessive disorder resulting from defects in the action of adrenocorticotropic hormone (ACTH) to stimulate glucocorticoid synthesis in the adrenal. Production of mineralocorticoids by the adrenal is normal. Patients present in early life with low or undetectable cortisol and, because of the failure of the negative feedback loop to the pituitary and hypothalamus, grossly elevated ACTH levels (Clark et al., 2009).
MCCC13-Methylcrotonyl-CoA carboxylase type 1 deficiency3-methylcrotonyl-CoA carboxylase deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MCCC1 gene located on chromosomal region 3q27.1. The age of onset is neonatal. This disease is characterized by a highly variable clinical picture ranging from neonatal onset with severe neurological involvement to asymptomatic adults. The prevalence is 1:75,000 newborn.
MCCC23-Methylcrotonyl-CoA carboxylase type 2, deficiency3-methylcrotonyl-CoA carboxylase deficiency type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MCCC2 gene located on chromosomal region 5q13.2. The age of onset is neonatal. This disease is characterized by a highly variable clinical picture ranging from neonatal onset with severe neurological involvement to asymptomatic adults. The prevalence is 1:75,000 newborn.
MCEEMethylmalonyl-CoA epimerase deficiencyMethylmalonic acidemia due to methylmalonyl-CoA epimerase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MCEE gene located on chromosomal region 2p13.3. The age of onset is neonatal. This disease is characterized by lethargy, vomiting, hypotonia, hypothermia, respiratory distress, severe ketoacidosis, hyperammonemia, neutropenia, and thrombocytopenia. The prevalence is 1:50,000-1:80,000.
MCFD2Combined deficiency of factor V and factor VIII, type 2Combined deficiency of factor V (612309) and factor VIII (300841) is characterized by bleeding symptoms similar to those in hemophilia (306700) or parahemophilia (227400), caused by single deficiency of FV or FVIII, respectively. The most common symptoms are epistaxis, menorrhagia, and excessive bleeding during or after trauma. Plasma FV and FVIII antigen and activity levels are in the range of 5 to 30%. Inheritance of F5F8D is autosomal recessive and distinct from the coinheritance of FV deficiency and FVIII deficiency (Zhang and Ginsburg, 2004).
MCM3APPeripheral neuropathy, autosomal recessive, with or without impaired intellectual developmentAutosomal recessive peripheral neuropathy with or without impaired intellectual development is an early childhood-onset neurologic disorder characterized by slowly progressive distal motor impairment resulting in gait difficulties, often with loss of ambulation, and difficulties using the hands in most patients. Most affected individuals also have impaired intellectual development, although some have normal cognition. Electrophysiologic testing and sural nerve biopsy are most compatible with an axonal motor neuropathy; some patients may show signs of demyelination. Additional features may include eye movement abnormalities, claw hands, foot deformities, and scoliosis (Ylikallio et al., 2017).
MCOLN1Mucolipidosis type 4Mucolipidosis type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MCOLN1 gene located on chromosomal region 19p13.2. The age of onset is infantile. This disease is characterized by psychomotor retardation and visual abnormalities including corneal clouding, retinal degeneration, or strabismus. The prevalence is 1:40,000.
MCPH1Microcephaly type 1, primary, autosomal recessiveAutosomal recessive primary microcephaly type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MCPH1 gene located on chromosomal region 8p23.1. The age of onset is neonatal. This disease is characterized by reduced head circumference at birth with no gross anomalies of brain architecture and variable degrees of intellectual impairment. The incidence is 1/1,000,000.
MECP2Encephalopathy, neonatal severeEncephalopathy, neonatal severe follows an X -linked pattern of inheritance and is caused by pathogenic variants in the MECP2 gene located on chromosomal region Xq28. The age of onset is neonatal. This neurological disorder primarily affects males and causes brain dysfunction (encephalopathy). Affected males have microcephaly, poor muscle tone (hypotonia), movement disorders, rigidity, and seizures. Individuals with MECP2-related severe neonatal encephalopathy have severe to profound intellectual disability. Genetic heterogeneity: Many of the mutations causing male's phenotype also cause Rett syndrome, a severe neurodevelopmental disorder that almost always occurs in females. Most severe neonatal encephalopathy cases are surviving male sibs of patients with Rett syndrome. Males with non-Rett syndrome mutations in the MECP2 gene can demonstrate a wide variety of phenotypes. Note: other conditions are also associated to the MECP2 gene, like MECP2 duplication syndrome, a condition characterized by intellectual disability, delayed development, and seizures. It is caused by a duplication of the MECP2 gene and surrounding DNA; this duplication is not tested in the CGT analysis.
MED12Lujan-Fryns syndromeLujan-Fryns syndrome follows an X-linked pattern of inheritance and is caused by pathogenic variants in the MED12 gene located on chromosomal region Xq13.1. The age of onset is neonatal. It is characterized by mild to moderate intellectual disability, behavioral problems (such as hyperactivity, aggressiveness, extreme shyness, and excessive attention-seeking), and certain physical features such as tall, thin body and an unusually large head (macrocephaly). Almost all people with this condition have weak muscle tone (hypotonia).
MED23Mental retardation, autosomal recessive, type 18Mental retardation, autosomal recessive, type 18 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
MED25Basel-Vanagait-Smirin-Yosef syndromeBasel-Vanagait-Smirin-Yosef syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MED25 gene located on chromosomal region 19q13.33. The age of onset neonatal/infantile. This syndrome is characterized by eye, brain, cardiac and palatal abnormalities as well as growth retardation, microcephaly and severe intellectual disability.
MEFVFamilial Mediterranean feverFamilial Mediterranean fever follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MEFV gene located on chromosomal region 16p13.3. The age of onset is infantile or adult (before the age of 30). This disease is characterized by recurrent short episodes of fever and serositis resulting in pain in the abdomen, chest, joints and muscles. In rare cases, this condition appears to be inherited in an autosomal dominant pattern. The prevalence is 1:10,000-5:10,000.
MEGF10Myopathy, areflexia, respiratory distress, and dysphagia, early-onsetMyopathy, areflexia, respiratory distress, and dysphagia, early-onset (EMARDD) is a congenital myopathy characterized by proximal and generalized muscle weakness, respiratory difficulties, joint contractures, and scoliosis. More variable features include cleft palate and feeding difficulties. There is variable severity: some patients become ventilator-dependent, never achieve walking, and die in childhood, whereas others have a longer and more favorable course (Logan et al., 2011; Boyden et al., 2012).
MERTKRetinitis pigmentosa type 38Retinitis pigmentosa type 38 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MERTK gene located on chromosomal region 2q13. The age of onset is infantile. This disease is characterized by. This disease is characterized by night blindness, followed by a progressive loss of peripheral vision in the daylight period and leading to blindness.
MESP2Spondylocostal dysostosis, type 2, autosomal recessiveThe spondylocostal dysostoses are a heterogeneous group of axial skeletal disorders characterized by multiple segmentation defects of the vertebrae (SDV), malalignment of the ribs with variable points of intercostal fusion, and often a reduction in rib number. The term 'spondylocostal dysostosis' is best applied to those phenotypes with generalized SDV and a broadly symmetric thoracic cage (Gucev et al., 2010).
MFFEncephalopathy due to defective mitochondrial and peroxisomal fission, type 2Encephalopathy due to defective mitochondrial and peroxisomal fission, type 2 is an autosomal recessive disorder characterized by delayed psychomotor development, severe hypotonia with inability to walk, microcephaly, and abnormal signals in the basal ganglia. More variable features include early-onset seizures, optic atrophy, and peripheral neuropathy (Koch et al., 2016).
MFN2Charcot-Marie-Tooth disease, axonal, type 2A2BCharcot-Marie-Tooth disease, axonal, type 2A2B is a neurologic disorder characterized by onset of peripheral neuropathy in the first years of life. Patients have difficulty walking due to distal muscle weakness; upper limbs may also be affected. Sensory impairment is more variable. Patients often have optic atrophy (Polke et al., 2011).
MFRPMicrophthalmia, isolated type 5Microphthalmia, isolated type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MFRP gene located on chromosomal region 11q23.3. The age of onset is infantile. This disease is characterized by posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disk drusen.
MFSD2AMicrocephaly 15, primary, autosomal recessiveMicrocephaly 15, primary, autosomal recessive is a form of microcephaly, a disease defined as a head circumference more than 3 standard deviations below the age, sex and ethnically matched mean. Brain weight is markedly reduced and the cerebral cortex is disproportionately small.
MFSD8Ceroid lipofuscinosis, neuronal, type 7Neuronal ceroid lipofuscinosis type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MFSD8 gene located on chromosomal region 4q28.2. The age of onset is late infantile. This disease is characterized by decline of mental and motor capacities, epilepsy, and vision loss through retinal degeneration. The prevalence is 0.56:100,000-3.9:100,000.
MGAT2Congenital disorder of glycosylation, type 2aCongenital disorder of glycosylation type 2a follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MGAT2 gene located on chromosomal region 14q21.3. The age of onset is infantile. This disease is characterized by severe psychomotor delay, postnatal growth retardation, facial dysmorphology and bleeding tendency. It has been described in four children.
MGPKeutel syndromeKeutel syndrome is an autosomal recessive disorder characterized by multiple peripheral pulmonary stenoses, brachytelephalangy, inner ear deafness, and abnormal cartilage ossification or calcification (Khosroshahi et al., 2014).
MID1Opitz GBBB syndrome, type 1Opitz GBBB syndrome is a congenital midline malformation syndrome characterized by hypertelorism, hypospadias, cleft lip/palate, laryngotracheoesophageal abnormalities, imperforate anus, developmental delay, and cardiac defects (So et al., 2005).This disorder was first reported as 2 separate entities, BBB syndrome and G syndrome; subsequent reports of families in which the BBB and G syndromes segregated within a single kindred suggested that they represent a single entity.
MITFCOMMAD syndromeCOMMAD syndromeis an autosoma recessive disease characterized by a coloboma, osteoporosis, microphthalmia, macrocephaly, albinosm and deafness.
MKKSBardet-Biedl syndrome type 6Bardet-Biedl syndrome type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MKKS gene located on chromosomal region 20p12.2. The age of onset is antenatal or infacy. This disease is characterized by a combination of clinical signs: obesity, pigmentary retinopathy, post-axial polydactyly, polycystic kidneys, hypogenitalism, and learning disabilities, many of which appear several years after disease onset. Clinical expression is variable but most patients manifest the majority of clinical signs during the disease course.
MKS1Bardet-Biedl syndrome type 13; Meckel syndrome, type 1Bardet-Biedl syndrome type 13 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MKS1 gene located on chromosomal region 17q22. The age of onset is antenatal or infacy. This disease is characterized by a combination of clinical signs: obesity, pigmentary retinopathy, post-axial polydactyly, polycystic kidneys, hypogenitalism, and learning disabilities, many of which appear several years after disease onset. Clinical expression is variable but most patients manifest the majority of clinical signs during the disease course. Meckel syndrome, type 1 is a disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly.
MLC1Megalencephalic leukoencephalopathy with subcortical cystsMegalencephalic leukoencephalopathy with subcortical cysts follows an autosomal recessive patternof inheritance and is caused by pathogenic variants in the MLC1 gene located on chromosomal region 22q13.33. The age of onset is infantile. This disease is characterized by ataxia followed by progressive signs of pyramidal tract involvement and mental deterioration.
MLPHGriscelli syndrome, type 3Griscelli syndrome, type 3 is a rare autosomal recessive disorder characterized by pigmentary dilution of the skin and hair, the presence of large clumps of pigment in hair shafts, and an accumulation of melanosomes in melanocytes, without other clinical manifestations.
MLYCDMalonyl-CoA decarboxylase deficiencyMalonyl-CoA decarboxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MLYCD gene located on chromosomal region 16q23.3. The age of onset is early infantile. This disease is characterized by developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea. The prevalence is <1:1,000,000.
MMAAMethylmalonic aciduria, vitamin B12-responsiveVitamin B12-responsive methylmalonic acidemia type cblA follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MMAA gene located on chromosomal region 4q31.21. The age of onset is early infantile. This disease is characterized by developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea. The prevalence is <1:1,000,000.
MMABMethylmalonic aciduria, vitamin B12-responsive, type cblBVitamin B12-responsive methylmalonic acidemia type cbl B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MMAB gene located on chromosomal region 12q24.31. The age of onset is early infantile. This disease is characterized by developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea. The prevalence is <1:1,000,000.
MMACHCMethylmalonic aciduria and homocystinuria, cblC typeVitamin B12-responsive methylmalonic acidemia type cbl B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MMAB gene located on chromosomal region 12q24.31. The age of onset is early infantile. This disease is characterized by developmentally delayed with other features that include hypotonia, seizures, hypoglycaemia, metabolic acidosis, cardiomyopathy and diarrhoea. The prevalence is <1:1,000,000.
MMADHCHomocystinuria, cblD type, variant 1Homocystinuria, cblD type, variant 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MMADHC gene located on chromosomal region 2q23.2. The age of onset is variable (infantile to adult). This disease is characterized by developmental delay, severe learning difficulties, seizures, movement and gait abnormalities, behavioral problems and signs of megaloblastic anemia (pallor, fatigue, anorexia). The prevalence is 1:50,000-1:80,000.
MMECharcot-Marie-Tooth disease, axonal, type 2TCharcot-Marie-Tooth disease, axonal, type 2T is a slowly progressive autosomal recessive sensorimotor peripheral neuropathy with onset in middle age (Higuchi et al., 2016).
MMP13Metaphyseal dysplasia, Spahr typeMetaphyseal dysplasia, Spahr type is an autosomal recessive, rare disease characterized by moderate short stature, mild genua vara, and radiographic signs of metaphyseal dysplasia, but no biochemical signs of rickets.
MMP2Multicentric osteolysis, nodulosis, and arthropathyMulticentric osteolysis, nodulosis, and arthropathy, also known as Torg syndrome, is characterized by the presence of multiple, painless, subcutaneous nodules and mild to moderate osteoporosis and osteolysis that is usually limited to the hands and feet. Radiographically, the osteolysis is accompanied by a characteristic widening of the metacarpal and metatarsal bones. Winchester syndrome presents with severe osteolysis in the hands and feet and generalized osteoporosis and bone thinning, similar to NAO, but subcutaneous nodules are characteristically absent. Various additional features including coarse face, corneal opacities, gum hypertrophy, and EKG changes have been reported. NAO syndrome, which has only been described in patients from Saudi Arabia, is generally more severe, with multiple prominent and painful subcutaneous nodules, massive osteolysis in the hands and feet, and generalized osteoporosis. Coarse face and body hirsutism are additional features.
MMP20Amelogenesis imperfecta, type 2A2Amelogenesis imperfecta, type 2A2 is an autosomal recessive amelogenesis imperfecta pigmented hypomaturation type characterized by enamel of normal thickness that is hypomineralized and has a mottled appearance. The slightly soft enamel detaches easily from the dentin, and radiographs show a lack of contrast between enamel and dentin (Witkop, 1989).
MMUTMethylmalonic aciduria, mut(0) typeMethylmalonic acidemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MUT gene located on chromosomal region 6p12.3. The age of onset is very early infantile. This disease is characterized by recurrent ketoacidotic comas or transient vomiting, dehydration, hypotonia and intellectual deficit, which does not respond to administration of vitamin B12.
MOCOSXanthinuria, type 2Xanthinuria, type 2 is an autosomal recessive inborn error of metabolism resulting from a defect in the synthesis of the molybdenum cofactor, which is necessary for the 2 enzymes that degrade xanthine: XDH (607633) and AOX1 (602841). Most individuals with type II xanthinuria are asymptomatic, but some develop urinary tract calculi, acute renal failure, or myositis due to tissue deposition of xanthine. Laboratory studies show increased serum and urinary hypoxanthine and xanthine and decreased serum and urinary uric acid (Ichida et al., 2001).Two clinically similar but distinct forms of xanthinuria are recognized. In type 1 xanthinuria (XAN1; 278300), there is an isolated deficiency of xanthine dehydrogenase resulting from mutation in the XDH gene; in type 2, there is a dual deficiency of xanthine dehydrogenase and aldehyde oxidase. Type 1 patients can metabolize allopurinol, whereas type 2 patients cannot (Simmonds et al., 1995).
MOCS1Molybdenum cofactor deficiency AMolybdenum cofactor deficiency type A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MOCS1 gene located on chromosomal region 6p21.2. The age of onset is infantile. This disease is characterized by severe neurological abnormalities, dislocated ocular early death.
MOCS2Molybdenum cofactor deficiency BMolybdenum cofactor deficiency type B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MOCS2 gene located on chromosomal region 5q11.2. This disease is characterized by severe neurological abnormalities, dislocated ocular early death.
MOGSCongenital disorder of glycosylation, type 2BCongenital disorder of glycosylation, type 2B (CDG2B) is characterized by marked generalized hypotonia and hypomotility of the neonate, dysmorphic features, including a prominent occiput, short palpebral fissures, retrognathia, high arched palate, generalized edema, and hypoplastic genitalia.
MPDU1Congenital disorder of glycosylation, type 1FCongenital disorders of glycosylation (CDGs) are metabolic deficiencies in glycoprotein biosynthesis that usually cause severe mental and psychomotor retardation. Different forms of CDGs can be recognized by altered isoelectric focusing (IEF) patterns of serum transferrin.
MPDZHydrocephalus, congenital, type 2, with or without brain or eye anomaliesHydrocephalus, congenital, type 2, with or without brain or eye anomalies is a disease characterized by a disturbance of cerebrospinal fluid circulation causing accumulation of ventricular cerebrospinal fluid, which results in progressive ventricular dilatation with onset in utero. Affected individuals may have neurologic impairment.
MPICongenital disorder of glycosylation, type 1bCongenital disorder of glycosylation type 1b follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MPI gene located on chromosomal region 15q24.1. The age of onset is infantile. This disease is characterized by hepatic-intestinal manifestations (diarrhoea, vomiting, and hepatomegaly associated with hepatic fibrosis).
MPLThrombocytopenia, congenital amegakaryocyticCongenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies (Muraoka et al., 1997). King et al. (2005) proposed a new classification of CAMT based on the course and outcome of the disease, as exemplified by 20 patients: CAMT type 1 (11 patients) was characterized by early onset of severe pancytopenia, decreased bone marrow activity, and very low platelet counts. CAMT type 2 (9 patients) was somewhat milder and characterized by transient increases of platelet counts up to nearly normal values during the first year of life and an onset of bone marrow failure at age 3 or later. Also, a family with thrombocythemia was reported by Ding et al. (2004) with an autosomal dominant inheritance pattern due to a heterozygous mutation in the MPL gene.
MPLKIPTrichothiodystrophy, type 4, nonphotosensitiveTrichothiodystrophy is a rare autosomal recessive disorder in which patients have brittle, sulfur-deficient hair that displays a diagnostic alternating light and dark banding pattern, called 'tiger tail banding,' under polarizing microscopy. TTD patients display a wide variety of clinical features, including cutaneous, neurologic, and growth abnormalities. Common additional clinical features are ichthyosis, intellectual/developmental disabilities, decreased fertility, abnormal characteristics at birth, ocular abnormalities, short stature, and infections. There are both photosensitive and nonphotosensitive forms of the disorder (Faghri et al., 2008).
MPOMyeloperoxidase deficiencyMyeloperoxidase deficiency is a disorder characterized by decreased myeloperoxidase activity in neutrophils and monocytes that results in disseminated candidiasis.
MPV17Mitochondrial DNA depletion syndrome type 6 (hepatocerebral); Charcot-Marie-Tooth disease, axonal, type 2EEMitochondrial DNA depletion syndrome type 6 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MPV17 gene located on chromosomal region 2p23.3. The age of onset is infantile. It is a disease due to mitochondrial dysfunction. It is characterized by infantile onset of progressive liver failure, often leading to death in the first year of life, peripheral neuropathy, corneal scarring, acral ulceration and osteomyelitis leading to autoamputation, cerebral leukoencephalopathy, failure to thrive, and recurrent metabolic acidosis with intercurrent infections. Charcot-Marie-Tooth disease type 2EE (CMT2EE) is an autosomal recessive sensorimotor peripheral axonal neuropathy with onset in the first or second decades of life. The disorder primarily affects the lower limbs and is slowly progressive, sometimes resulting in loss of ambulation, with later onset of upper limb involvement. There is significant distal muscle weakness and atrophy, usually with foot or hand deformities. Skeletal muscle biopsy shows findings of disturbed mitochondrial maintenance. Cognition is unaffected, and chronic liver disease is absent (summary by Baumann et al., 2019).
MRAPGlucocorticoid deficiency, type 2Familial glucocorticoid deficiency is an autosomal recessive disorder resulting from resistance to the action of adrenocorticotropin (ACTH) on the adrenal cortex, which stimulates glucocorticoid production. Affected individuals are deficient in cortisol and, if untreated, are likely to succumb to hypoglycemia or overwhelming infection in infancy or childhood (Metherell et al., 2005).
MRE11Ataxia-telangiectasia-like disorder 1Ataxia-telangiectasia-like disorder1 is an autosomal recessive disorder characterized clinically by progressive cerebellar degeneration resulting in ataxia and oculomotor apraxia. Laboratory studies of patient cells showed increased susceptibility to radiation, consistent with a defect in DNA repair. The disorder shares some phenotypic features of ataxia-telangiectasia (AT; 208900), but telangiectases and immune deficiency are not present in ATLD1 (Hernandez et al., 1993; Stewart et al., 1999).
MRPS16Combined oxidative phosphorylation deficiency 2Combined oxidative phosphorylation defect type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MRPS16 gene located on chromosomal region 10q22.2. The age of onset is infantile. This disease is characterized by agenesis of corpus callosum, dismorphism and fatal lactic acidosis.
MRPS22Combined oxidative phosphorylation deficiency type 5Combined oxidative phosphorylation defect type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MRPS22 gene located on chromosomal region 3q23. The age of onset is infantile. This disease is characterized by evere hypotonia, lactic academia and congenital hyperammonaemia.
MSH3Familial adenomatous polyposis, type 4Familial adenomatous polyposis, type 4 is an autosomal recessive tumor predisposition syndrome characterized by the development of multiple colonic adenomas in adulthood, often with progression to colorectal cancer. Proliferative lesions in other tissues may also occur (Adam et al., 2016).
MSMO1Microcephaly, congenital cataract, and psoriasiform dermatitisMicrocephaly, congenital cataract, and psoriasiform dermatitis, also known as SC4MOL deficiency, represents an inborn error of cholesterol metabolism that is characterized by accumulation of a large amount of methylsterols, particularly dimethylsterols, in affected patients. The associated features of immune dysregulation, skin disease, and growth delay can be at least partially corrected with cholesterol and statin supplements (He et al., 2014).
MSRB3Deafness, autosomal recessive, type 74Nonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. Nonsyndromic hearing loss can be classified by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. The characteristics vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear.
MTFMTCombined oxidative phosphorylation deficiency 15Combined oxidative phosphorylation deficiency 15 (COXPD15) is an autosomal recessive multisystem disorder with variable manifestations resulting from a defect in the mitochondrial oxidative phosphorylation (OXPHOS) system. Onset occurs at or soon after birth, and features can include growth retardation, microcephaly, hypertonicity, axial hypotonia, encephalopathy, cardiomyopathy, and liver dysfunction. Death usually occurs in the first weeks or years of life (Smits et al., 2011)
MTHFD1Combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemiaCombined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia is an inborn error of folate metabolism due to deficiency of methylenetetrahydrofolate dehydrogenase-1. Manifestations may include hemolytic uremic syndrome, macrocytosis, epilepsy, hearing loss, retinopathy, mild mental retardation, lymphopenia involving all subsets, and low T-cell receptor excision circles. Folinic acid supplementation is an effective treatment (Ramakrishnan et al., 2016).
MTM1Myotubular myopathy, X-linkedX-linked centronuclear myopathy follows an X-linked pattern of inheritance and is caused by pathogenic variants in the MTM1 gene located on chromosomal region Xq28. The age of onset is infantile, etc/. This disease is characterized by severe phenotype in males presenting at birth with marked weakness, hypotonia and respiratory failure. The incidence is 1/50,000 newborn man.
MTMR2Charcot-Marie-Tooth disease, type 4B1Charcot-Marie-Tooth disease type 4B1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MTMR2 gene located on chromosomal region 11q21. The age of onset is early infantile. This disease is characterized by distal and proximal muscular weakness starting in the lower extremities, sensory loss and cranial nerve involvement, foot deformities and diaphragmatic and facial involvement.
MTO1Combined oxidative phosphorylation deficiency 10Combined oxidative phosphorylation deficiency 10 (COXPD10) is an autosomal recessive disorder resulting in variable defects of mitochondrial oxidative respiration. Affected individuals present in infancy with hypertrophic cardiomyopathy and lactic acidosis. The severity is variable, but can be fatal in the most severe cases (Ghezzi et al., 2012).
MTRHomocystinuria-megaloblastic anemia, cblG complementation typeHomocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase. Clinical features are somewhat variable, but include delayed psychomotor development, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE (236270) and CblG (Watkins and Rosenblatt, 1988). Most patients present in early infancy, but some patients with CblG have shown later onset (Outteryck et al., 2012). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (Leclerc et al., 1996).CblE is caused by mutation in the MTRR gene (602568). Watkins and Rosenblatt (1989) commented on the clinical and biochemical heterogeneity in patients with cblE and cblG.
MTRRHomocystinuria-megaloblastic anemia, cbl E typeHomocystinuria and megaloblastic anemia is an autosomal recessive inborn error of metabolism resulting from defects in the cobalamin (vitamin B12)-dependent pathway that converts homocysteine to methionine, which is catalyzed by methionine synthase (MTR; 156570). Clinical features are somewhat variable, but include delayed psychomotor development, hypotonia, megaloblastic anemia, homocystinuria, and hypomethioninemia, all of which respond to cobalamin supplementation. Methylmalonic aciduria is not present. Two complementation groups have been described based on fibroblast studies: CblE and CblG (250940) (Watkins and Rosenblatt, 1988). Cells from patients with CblE fail to incorporate methyltetrahydrofolate into methionine in whole cells, but cell extracts show normal methionine synthase activity in the presence of a reducing agent. Cells from patients with CblG have defects in the methionine synthase enzyme under both conditions (Leclerc et al., 1996).CblG is caused by mutation in the MTR gene.
MTTPAbetalipoproteinemiaAbetalipoproteinemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MTTP gene located on chromosomal region 4q23. The age of onset is infantile. This disease is characterized by growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations. The prevalence is <1:1,000,000.
MUSKFetal akinesia deformation sequence, type 1; Myasthenic syndrome, congenital, type 9, associated with acetylcholine receptor deficiencyThe fetal akinesia deformation sequence (FADS) refers to a clinically and genetically heterogeneous constellation of features including fetal akinesia, intrauterine growth retardation, arthrogryposis, and developmental anomalies, including lung hypoplasia, cleft palate, and cryptorchidism (Vogt et al., 2009). It shows phenotypic overlap with the lethal form of multiple pterygium syndrome. Mutation in the MUSK gene can also cause a form of congenital myasthenic syndrome (CMS9). Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity. Electrophysiologic studies show low amplitude of the miniature endplate potential (MEPP) and current (MEPC) resulting from deficiency of AChR at the endplate. Patients may show a favorable response to amifampridine (Engel et al., 2015).
MVKMevalonic aciduriaMevalonic aciduria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MVK gene located on chromosomal region 12q24.11. The age of onset is infantile. This disease is characterized by psychomotor retardation, failure to thrive, progressive cerebellar ataxia, dysmorphic features, progressive visual impairment and recurrent febrile crises. The prevalence is <1:1,000,000.
MYBPC1Lethal congenital contracture syndrome, type 4Lethal congenital contracture syndrome 4 (LCCS4) is a form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy and congenital non- progressive joint contractures. The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth.
MYD88Pyogenic bacterial infections, recurrent, due to MYD88 deficiencyMyD88 deficiency is an inherited disorder of the immune system (primary immunodeficiency). This primary immunodeficiency affects the innate immune response, which is the body's early, nonspecific response to pathogens. MyD88 deficiency leads to abnormally frequent and severe infections by pyogenic bacteria. However, affected individuals have normal resistance to other common bacteria, viruses, fungi, and parasites. The most common infections in MyD88 deficiency are caused by the Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa bacteria. Most people with this condition have their first bacterial infection before age 2, and the infections can be life-threatening in infancy and childhood. Infections become less frequent by about age 10.
MYH2Proximal myopathy and ophthalmoplegiaProximal myopathy and ophthalmoplegia is a relatively mild muscle disorder characterized by childhood onset of symptoms. The disorder is either slowly progressive or nonprogressive, and affected individuals retain ambulation, although there is variable severity. MYPOP can show both autosomal dominant and autosomal recessive inheritance; the phenotype is similar in both forms (Lossos et al., 2005; Tajsharghi et al., 2014).
MYO15ADeafness, autosomal recessive type 3Deafness autosomal recessive type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MYO15A gene located on chromosomal region 17p11.2. The age of onset is infantile, etc/. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
MYO18BKlippel-Feil syndrome, type 4, autosomal recessive, with myopathy and facial dysmorphismKlippel-Feil syndrome, type 4, with nemaline myopathy and facial dysmorphism is an autosomal recessive disorder characterized mainly by severe hypotonia apparent from infancy. Klippel-Feil anomaly is primarily defined by fusion of the cervical spine, with associated low posterior hairline and limited neck mobility being observed in about half of patients (Alazami et al., 2015).
MYO3ADeafness, autosomal recessive type 30Deafness autosomal recessive type 30 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MYO3A gene located on chromosomal region 10p12.1. The age of onset is infantile. This disease is characterized by mild-to-profound sensorineural hearing impairment with no associated visible abnormalities of the external ear or any related medical problems.
MYO5AGriscelli syndrome, type 1Griscelli disease type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MYO5A gene located on chromosomal region 15q21.2. The age of onset is infantile. This disease is characterized by is characterised by silvery gray sheen of the hair and hypopigmentation of the skin which can be associated to neurological impairment. The prevalence is <1:1,000,000.
MYO5BMicrovillus inclusion diseaseMicrovillus inclusion disease (MVID) is characterized by onset of intractable life-threatening watery diarrhea during infancy. Two forms are recognized: early-onset MVID with diarrhea beginning in the neonatal period, and late-onset, with first symptoms appearing after 3 or 4 months of life. Definite diagnosis is made by transmission electron microscopy demonstrating shortening or absence of apical microvilli with pathognomonic microvillus inclusions in mature enterocytes and peripheral accumulation of periodic acid-Schiff (PAS)-positive granules or vesicles in immature enterocytes (Muller et al., 2008). The natural course of MVID is often fatal, but partial or total weaning from parenteral nutrition has been described.
MYO7AUsher syndrome, type 1B; Deafness, autosomal recessive, type 2Usher syndrome type 1B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the MYO7A gene located on chromosomal region 11q13.5. The age of onset is infantile. This disease is characterized by congenital, bilateral, profound sensorineural hearing loss, vestibular areflexia, and adolescent-onset retinitis pigmentosa. The prevalence is 1:100,000-9:100,000. Mutation in the MYO7A gene can also cause deafness autosomal recesive, type 2 which involves changes in both the inner ear and the middle ear. This combination is called mixed hearing loss.
MYPNNemaline myopathy, type 11, autosomal recessiveNemaline myopathy, type 11 (NEM11) is an autosomal recessive congenital myopathy characterized by onset of slowly progressive muscle weakness in the first decade. Affected individuals present with gait difficulties due to proximal muscle weakness and atrophy mainly affecting the lower limbs and neck. Muscle biopsy shows nemaline bodies. Some patients may have mild cardiac or respiratory involvement, but they do not have respiratory failure (Miyatake et al., 2017).
NAA10Ogden syndromeOgden syndrome is an X-linked neurodevelopmental disorder characterized by postnatal growth failure, severely delayed psychomotor development, variable dysmorphic features, and hypotonia. Most patients also have cardiac malformations or arrhythmias (Popp et al., 2015).
NAGASchindler disease, type ISchindler disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NAGA gene located on chromosomal region 22q13.2. The age of onset is infantile. This disease is characterized by early-onset neuroaxonal dystrophy and neurological signs (convulsion during fever, epilepsy, psychomotor retardation and hypotonia). NAGA deficiency is typically classified in three main phenotypes: NAGA deficiency type I (Schindler disease or Schindler disease type I) with severe manifestations; NAGA deficiency type II (Kanzazi disease or Schindler disease type II) which is mild; NAGA deficiency type III (Schindler disease type III) characterized by mild-to-moderate neurologic manifestations. NAGA deficiency results in the increased urinary excretion of glycopeptides and oligosaccharides containing alpha-N-acetylgalactosaminyl moieties.
NAGLUMucopolysaccharidosis, type 3B (Sanfilippo B)Mucopolysaccharidosis, type 3B, also known as Sanfilippo syndrome B, is an autosomal recessive lysosomal storage disorder characterized by the accumulation of heparan sulfate. Clinically, patients have progressive neurodegeneration, behavioral problems, mild skeletal changes, and shortened life span. The clinical severity ranges from mild to severe (Chinen et al., 2005).
NAGSN-acetylglutamate synthase deficiencyN-acetylglutamate synthetase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NAGS gene located on chromosomal region 17q21.31. The age of onset is infantile, etc/. This disease is characterized by hyperammonemia, vomiting, hyperactivity or lethargy, diarrhoea, poor feeding, seizures, hypotonia, delayed psychomotor development and respiratory distress. The prevalence is <1:1,000,000.
NARS2Combined oxidative phosphorylation deficiency 24Combined oxidative phosphorylation deficiency 24 (COXPD24) is an autosomal recessive mitochondrial disorder with wide phenotypic variability. Some patients have a milder form affecting only skeletal muscle, whereas others may have a more severe infantile-onset neurodegenerative disorder (Vanlander et al., 2015; Sofou et al., 2015).
NBASInfantile liver failure syndrome, type 2; Short stature, optic nerve atrophy, and Pelger-Huet anomalyInfantile liver failure syndrome, type 2 (ILFS2) is an autosomal recessive disorder characterized by recurrent episodes of acute liver failure during intercurrent febrile illness. Patients first present in infancy or early childhood, and there is complete recovery between episodes with conservative treatment (Haack et al., 2015). ILFS2 is caused by homozygous or compound heterozygous mutation in the NBAS gene. Among the Yakuts, an Asian population isolate that is located in the northeastern part of Siberia, Maksimova et al. (2010) ascertained a short stature syndrome involving autosomal recessive postnatal growth failure, small hands and feet, loss of visual acuity with abnormalities of color vision, abnormal nuclear shape in neutrophil granulocytes, and normal intelligence due to mutation in NBAS gene.
NBEAL2Gray platelet syndromeThe gray platelet syndrome (GPS) is a rare inherited disorder characterized by mild to moderate bleeding tendency, moderate thrombocytopenia, and a marked decrease or absence of platelet alpha-granules and of the proteins contained in alpha-granules. The platelets are enlarged, but not giant, and have a gray appearance on light microscopy of Wright-stained peripheral blood smears due to decreased granules. Many patients with gray platelet syndrome develop a stable myelofibrosis (Nurden and Nurden, 2007).Cases suggesting autosomal dominant and autosomal recessive inheritance have been described, indicating that GPS is probably a genetically heterogeneous disorder with more than one molecular cause.
NBNNijmegen breakage syndromeThe Nijmegen breakage syndrome and the phenotypically indistinguishable Berlin breakage syndrome are autosomal recessive chromosomal instability syndromes characterized by microcephaly, growth retardation, immunodeficiency, and predisposition to cancer. Ataxia-telangiectasia variant-1 is the designation applied to the Nijmegen breakage syndrome and AT variant-2 is the designation for the Berlin breakage syndrome, which differ only in complementation studies. Cells from NBS/BBS patients are hypersensitive to ionizing radiation with cytogenetic features indistinguishable from those of ataxia-telangiectasia (AT; 208900), but NBS/BBS patients have a distinct clinical phenotype.The clinical features of LIG4 syndrome (606593), caused by mutation in the LIG4 gene (601837), resemble those of NBS.
NCF1Chronic granulomatous disease due to deficiency of NCF-1Chronic granulomatous disease due to deficiency of NCF-1 is a disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.
NCF2Chronic granulomatous disease due to deficiency of NCF-2Chronic granulomatous disease due to deficiency of NCF-2 is a disorder characterized by the inability of neutrophils and phagocytes to kill microbes that they have ingested. Patients suffer from life-threatening bacterial/fungal infections.
NDE1Lissencephaly, type 4 (with microcephaly)Lissencephaly, type 4 is an autosomal recessive neurodevelopmental disorder characterized by lissencephaly, severe brain atrophy, extreme microcephaly (head circumference of more than 10 standard deviations (SD) below the mean), and profound mental retardation. It has also been referred to as 'microlissencephaly' (Bakircioglu et al., 2011; Alkuraya et al., 2011).
NDPNorrie diseaseNorrie disease is an X-linked recessive disorder characterized by very early childhood blindness due to degenerative and proliferative changes of the neuroretina. Approximately 50% of patients show some form of progressive mental disorder, often with psychotic features, and about one-third of patients develop sensorineural deafness in the second decade. In addition, some patients have more complex phenotypes, including growth failure and seizures (Berger et al., 1992). Warburg (1966) noted confusion of the terms 'pseudoglioma' and microphthalmia with Norrie disease in the literature. 'Pseudoglioma' is a nonspecific term for any condition resembling retinoblastoma and can have diverse causes, including inflammation, hemorrhage, trauma, neoplasia, or congenital malformation, and often shows unilateral involvement. Thus, 'pseudoglioma' is not an acceptable clinical or pathologic diagnosis (Duke-Elder, 1958).
NDRG1Charcot-Marie-Tooth disease, type 4DCharcot-Marie-Tooth disease type 4D follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NDRG1 gene located on chromosomal region 8q24.22. The age of onset is infantile, etc/. This disease is characterized by demyelination and hearing loss.
NDST1Mental retardation, autosomal recessive, type 46Mental retardation, autosomal recessive, type 46 (MRT46) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. MRT46 manifestations include delayed psychomotor development apparent from infancy or early childhood, delayed or absent expressive speech, hypotonia, and therapy-responsive seizures in some patients. Behavioral abnormalities are variable and include aggression, self- injurious behavior, and sleep disturbances.
NDUFA10Mitochondrial complex I deficiency, nuclear type 22Mitochondrial complex I deficiency, nuclear type 22 (MC1DN22) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN22 transmission pattern is consistent with autosomal recessive inheritance.
NDUFA11Mitochondrial complex I deficiency, nuclear type 14Mitochondrial complex I deficiency, nuclear type 14 (MC1DN14) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN14 transmission pattern is consistent with autosomal recessive inheritance.
NDUFA12?Mitochondrial complex I deficiency, nuclear type 23Mitochondrial complex I deficiency, nuclear type 23 (MC1DN23) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN23 transmission pattern is consistent with autosomal recessive inheritance.
NDUFAF1Mitochondrial complex I deficiency, nuclear type 11Mitochondrial complex I deficiency, nuclear type 11 (MC1DN11) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN11 transmission pattern is consistent with autosomal recessive inheritance.
NDUFAF2Mitochondrial complex I deficiency, nuclear type 10Mitochondrial complex I deficiency, nuclear type 10 (MC1DN10) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN10 transmission pattern is consistent with autosomal recessive inheritance.
NDUFAF3Mitochondrial complex I deficiency, nuclear type 18Mitochondrial complex I deficiency, nuclear type 18 (MC1DN18) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN18 transmission pattern is consistent with autosomal recessive inheritance.
NDUFAF5Mitochondrial complex I deficiency, nuclear type 16Mitochondrial complex I deficiency, nuclear type 16 (MC1DN16) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN16 transmission pattern is consistent with autosomal recessive inheritance.
NDUFAF6Mitochondrial complex I deficiency, nuclear type 17Mitochondrial complex I deficiency, nuclear type 17 (MC1DN17) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN17 transmission pattern is consistent with autosomal recessive inheritance.
NDUFB3Mitochondrial complex I deficiency, nuclear type 25Mitochondrial complex I deficiency, nuclear type 25 (MC1DN25) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN25 transmission pattern is consistent with autosomal recessive inheritance.
NDUFS1Mitochondrial complex I deficiency, nuclear type 5Mitochondrial complex I deficiency, nuclear type 5 (MC1DN5) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN5, transmission pattern is consistent with autosomal recessive inheritance.
NDUFS2Mitochondrial complex I deficiency, nuclear type 6Mitochondrial complex I deficiency, nuclear type 6 (MC1DN6) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN6 transmission pattern is consistent with autosomal recessive inheritance.
NDUFS3Mitochondrial complex I deficiency, nuclear type 8Mitochondrial complex I deficiency, nuclear type 8 (MC1DN8) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN8 transmission pattern is consistent with autosomal recessive inheritance.
NDUFS4Mitochondrial complex I deficiency, nuclear type 1Mitochondrial complex I deficiency, nuclear type 10 (MC1DN10) is the most common enzymatic defect of the oxidative phosphorylation disorders (McFarland et al., 2004; Kirby et al., 2004). It causes a wide range of clinical disorders, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, nonspecific encephalopathy, hypertrophic cardiomyopathy, myopathy, liver disease, Leigh syndrome (see 256000), Leber hereditary optic neuropathy (535000), and some forms of Parkinson disease (556500) (Loeffen et al., 2000; Pitkanen et al., 1996; Robinson, 1998).
NDUFS6Mitochondrial complex I deficiency, nuclear type 9Mitochondrial complex I deficiency, nuclear type 9 (MC1DN9) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN9 transmission pattern is consistent with autosomal recessive inheritance.
NDUFS7Mitochondrial complex I deficiency, nuclear type 3Mitochondrial complex I deficiency, nuclear type 3 (MC1DN3) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN3 transmission pattern is consistent with autosomal recessive inheritance.
NDUFS8Mitochondrial complex I deficiency, nuclear type 2Mitochondrial complex I deficiency, nuclear type 2 (MC1DN2) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN2 inheritance is autosomal recessive.
NDUFV1Mitochondrial complex I deficiency, nuclear type 4Mitochondrial complex I deficiency, nuclear type 4 (MC1DN4) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN4 transmission pattern is consistent with autosomal recessive inheritance.
NEBNemaline myopathy type 2, autosomal recessiveNemaline myopathy type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NEB gene located on chromosomal region 2q23.3. The age of onset is infantile or adult. This disease is characterized by hypotonia, weakness and depressed or absent deep tendon reflexes, with pathologic evidence of nemaline bodies (rods) on muscle biopsy. The prevalence is 1:100,000-9:100,000 and the incidence is 1/50.000 newborn.
NECTIN1Cleft lip/palate-ectodermal dysplasia syndrome; Orofacial cleft 7Cleft lip/palate-ectodermal dysplasia syndrome is an autosomal recessive form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. It is a syndrome characterized by the association of cleft lip/palate, ectodermal dysplasia (sparse short and dry scalp hair, sparse eyebrows and eyelashes), and partial syndactyly of the fingers and/or toes. Two thirds of the patients do not manifest oral cleft but present with abnormal teeth and nails. Mutation in the PVRL1 gene has also been found in a form of orofacial cleft (OFC7). OFC7 is a birth defect consisting of cleft lips with or without cleft palate. Cleft lips are associated with cleft palate in two-third of cases. A cleft lip can occur on one or both sides and range in severity from a simple notch in the upper lip to a complete opening in the lip extending into the floor of the nostril and involving the upper gum.
NECTIN4Ectodermal dysplasia-syndactyly syndrome, type 1Ectodermal dysplasia-syndactyly syndrome (EDSS) is characterized by sparse to absent scalp hair, eyebrows, and eyelashes, hypoplastic nails, tooth enamel hypoplasia, conical-shaped teeth, palmoplantar keratoderma, and partial cutaneous syndactyly (Raza et al., 2015).
NEFLCharcot-Marie-Tooth disease, type 1FCharcot-Marie-Tooth disease type 1F follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NEFL gene located on chromosomal region 8p21.2. The age of onset is infantile. This disease is characterized by a progressive peripheral motor and sensory neuropathy with variable clinical, distal weakness and wasting of the muscles of the lower limbs. The prevalence is 15:100,000-20:100,000.
NEK1Short-rib thoracic dysplasia, type 6, with or without polydactylyShort-rib thoracic dysplasia (SRTD) with or without polydactyly refers to a group of autosomal recessive skeletal ciliopathies that are characterized by a constricted thoracic cage, short ribs, shortened tubular bones, and a 'trident' appearance of the acetabular roof. SRTD encompasses Ellis-van Creveld syndrome (EVC) and the disorders previously designated as Jeune syndrome or asphyxiating thoracic dystrophy (ATD), short rib-polydactyly syndrome (SRPS), and Mainzer-Saldino syndrome (MZSDS). Polydactyly is variably present, and there is phenotypic overlap in the various forms of SRTDs, which differ by visceral malformation and metaphyseal appearance. Nonskeletal involvement can include cleft lip/palate as well as anomalies of major organs such as the brain, eye, heart, kidneys, liver, pancreas, intestines, and genitalia. Some forms of SRTD are lethal in the neonatal period due to respiratory insufficiency secondary to a severely restricted thoracic cage, whereas others are compatible with life (Huber and Cormier-Daire, 2012; Schmidts et al., 2013).
NEK8Renal-hepatic-pancreatic dysplasia, type 2Renal-hepatic-pancreatic dysplasia, type 2 (RHPD2) is an autosomal recessive multisystemic disorder with severe abnormalities apparent in utero and often resulting in fetal death or death in infancy. The main organs affected include the kidney, liver, and pancreas, although other abnormalities, including cardiac, skeletal, and lung defects, may also be present. Affected individuals often have situs inversus. The disorder results from a defect in ciliogenesis and ciliary function, as well as in cell proliferation and epithelial morphogenesis; thus, the clinical manifestations are highly variable (Grampa et al., 2016).
NEU1Sialidosis, type 1 and type 2Sialidosis is an autosomal recessive disorder characterized by the progressive lysosomal storage of sialylated glycopeptides and oligosaccharides caused by a deficiency of the enzyme neuraminidase. Common to the sialidoses is the accumulation and/or excretion of sialic acid (N-acetylneuraminic acid) covalently linked ('bound') to a variety of oligosaccharides and/or glycoproteins (Lowden and O'Brien, 1979). The sialidoses are distinct from the sialurias in which there is storage and excretion of 'free' sialic acid, rather than 'bound' sialic acid; neuraminidase activity in sialuria is normal or elevated. Salla disease (604369) is a form of 'free' sialic acid disease. Lowden and O'Brien (1979) provided a logical nosology of neuraminidase deficiency into sialidosis type 1 and type 2. Type 1 is the milder form, also known as the 'normosomatic' type or the cherry red spot-myoclonus syndrome. Sialidosis type 2 is the more severe form with an earlier onset, and is also known as the 'dysmorphic' type. Type 2 has been subdivided into juvenile and infantile forms. Other terms for sialidosis type 2 are mucolipidosis type 1 and lipomucopolysaccharidosis.
NEUROG3Diarrhea type 4, malabsorptive, congenitalCongenital malabsorptive diarrhea type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NEUROG3 gene located on chromosomal region 10q22.1. The age of onset is early infantile. This disease is characterized by severe, life-threatening watery diarrhea associated with generalized malabsorption and a paucity of enteroendocrine cells. The prevalence is <1:1,000,000.
NFU1Multiple mitochondrial dysfunctions syndrome 1Multiple mitochondrial dysfunctions syndrome, type 1 (MMDS1) is a severe autosomal recessive disorder of systemic energy metabolism, resulting in weakness, respiratory failure, lack of neurologic development, lactic acidosis, and early death (Seyda et al., 2001).
NGFNeuropathy, hereditary sensory and autonomic, type 5Neuropathy, hereditary sensory and autonomic, type 5 (HSAN5) is a form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN5 patients manifest loss of pain perception and impaired temperature sensitivity, ulcers, and in some cases self-mutilation. The autonomic involvement is variable.
NHEJ1Severe combined immunodeficiency with microcephaly, growth retardation, and sensitivity to ionizing radiationSevere combined immunodeficiency (SCID) due to NHEJ1 deficiency of a form of SCID, a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia and low or absent antibody levels. Patients with SCID present in infancy with recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. NHEJ1-SCID is characterized by a profound T- and B-lymphocytopenia associated with increased cellular sensitivity to ionizing radiation, microcephaly and growth retardation.
NHLRC1Epilepsy, progressive myoclonic, type 2B (Lafora)The Lafora type of progressive myoclonic epilepsy is an autosomal recessive disorder characterized by insidious onset of progressive neurodegeneration between 8 and 18 years of age. Initial features can include headache, difficulties in school work, myoclonic jerks, generalized seizures, and often visual hallucination. The myoclonus, seizures, and hallucinations gradually worsen and become intractable. This is accompanied by progressive cognitive decline, resulting in dementia. About 10 years after onset, affected individuals are in near-continuous myoclonus with absence seizures, frequent generalized seizures, and profound dementia or a vegetative state. Histologic studies of multiple tissues, including brain, muscle, liver, and heart show intracellular Lafora bodies, which are dense accumulations of malformed and insoluble glycogen molecules, termed polyglucosans (Ramachandran et al., 2009).
NHP2Dyskeratosis congenita, autosomal recessive type 2Dyskeratosis congenita type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NHP2 gene located on chromosomal region 5q35.3. The age of onset is variable from infancy to adult. It is a multisystem disorder caused by defective telomere maintenance. Clinical manifestations include mucocutaneous abnormalities, bone marrow failure, and an increased predisposition to cancer, among other variable features.
NHSCataract 40, X-linkedCataract 40 is a disease characterized by an opacification of the crystalline lens of the eye that frequently results in visual impairment or blindness. Opacities vary in morphology, are often confined to a portion of the lens, and may be static or progressive. CTRCT40 manifests as a congenital nuclear opacity with severe visual impairment in affected males. Heterozygous females have suture cataracts and only slight reduction in vision. In some cases, cataract is associated with microcornea without any other systemic anomaly or dysmorphism. Microcornea is defined by a corneal diameter inferior to 10 mm in both meridians in an otherwise normal eye.
NIPAL4Ichthyosis, congenital, autosomal recessive, type 6Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
NKX2-6Conotruncal heart malformationsConotruncal heart malformations (CTHM) is a group of congenital heart defects involving the outflow tracts. Examples include truncus arteriosus communis, double-outlet right ventricle and transposition of great arteries. Truncus arteriosus communis is characterized by a single outflow tract instead of a separate aorta and pulmonary artery. In transposition of the great arteries, the aorta arises from the right ventricle and the pulmonary artery from the left ventricle. In double outlet of the right ventricle, both the pulmonary artery and aorta arise from the right ventricle.
NLGN4XMental retardation, X-linkedAutism, the prototypic pervasive developmental disorder (PDD), is usually apparent by 3 years of age. It is characterized by a triad of limited or absent verbal communication, a lack of reciprocal social interaction or responsiveness, and restricted, stereotypic, and ritualized patterns of interests and behavior (Bailey et al., 1996; Risch et al., 1999). 'Autism spectrum disorder,' sometimes referred to as ASD, is a broader phenotype encompassing the less severe disorders Asperger syndrome (SPG1; 608638) and pervasive developmental disorder, not otherwise specified (PDD-NOS). 'Broad autism phenotype' includes individuals with some symptoms of autism, but who do not meet the full criteria for autism or other disorders. Mental retardation coexists in approximately two-thirds of individuals with ASD, except for Asperger syndrome, in which mental retardation is conspicuously absent (Jones et al., 2008). Genetic studies in autism often include family members with these less stringent diagnoses (Schellenberg et al., 2006).
NLRP1Autoinflammation with arthritis and dyskeratosisAutoinflammation with arthritis and dyskeratosis is characterized by recurrent fever, widespread skin dyskeratosis, arthritis, elevated biologic markers of inflammation, and mild autoimmunity with a high transitional B-cell level (Grandemange et al., 2016).
NLRP7Hydatidiform mole, recurrent, type 1A hydatidiform mole is an abnormal pregnancy characterized by hydropic placental villi, trophoblastic hyperplasia, and poor fetal development. Familial recurrent hydatidiform mole is an autosomal recessive condition in which women experience recurrent pregnancy losses, predominantly complete hydatidiform mole (CHM). However, unlike sporadic CHMs, which are androgenetic with 2 paternal chromosome complements, CHMs associated with familial recurrence are genetically biparental in origin with both a maternal and a paternal contribution to the genome. Other pregnancy losses in this condition include partial hydatidiform mole, stillbirths, ectopic pregnancies, early neonatal deaths, and miscarriages, some of which may be undiagnosed molar pregnancies. Normal pregnancies are extremely rare in families with this condition (Fallahian et al., 2013).
NME8Ciliary dyskinesia, primary, type 6Ciliary dyskinesia, primary, type 6 (CILD6) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit randomization of left-right body asymmetry and situs inversus, due to dysfunction of monocilia at the embryonic node.
NMNAT1Leber congenital amaurosis type 9Leber congenital amaurosis type 9 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NMNAT1 gene located on chromosomal region 1p36.22. The age of onset is early infantile. This disease is characterized by blindness, nystagmus, roving eye movement, leading to severe visual impairment.
NOP10Dyskeratosis congenita, autosomal recessive type 1Dyskeratosis congenita autosomal recessive type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NOP10 gene located on chromosomal region 15q14. The age of onset is infantile. This disease is characterized by the mucocutaneous triad of abnormal skin pigmentation, nail dystrophy and mucosal leucoplakia. The prevalence is 1:1,000,000.
NPC1Niemann-Pick disease, type C1Niemann-Pick disease type C1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPC1 gene located on chromosomal region 18q11.2. The age of onset varies between the perinatal period and the age of 50 years or more. This disease is characterized by hepatosplenomegaly and progressive neurological involvement. The prevalence is 1/130,000.
NPC2Niemann-pick disease, type C2Niemann-Pick disease type C2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPC2 gene located on chromosomal region 14q24.3. The age of onset varies between the perinatal period and the age of 50 years or more. This disease is characterized by hepatosplenomegaly and progressive neurological involvement. The prevalence is 1/130,000.
NPHP1Joubert syndrome type 4Joubert syndrome type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPHP1 gene located on chromosomal region 2q13. This is a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Additional variable features include retinal dystrophy and renal disease. Joubert syndrome type 4 is a phenotypically mild form.
NPHP3Meckel syndrome type 7Meckel syndrome type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPHP3 gene located on chromosomal region 3q22.1. The age of onset is infantile. This is a disorder characterized by a combination of renal cysts and variably associated features including developmental anomalies of the central nervous system (typically encephalocele), hepatic ductal dysplasia and cysts, and polydactyly.
NPHP4Nephronophthisis type 4Nephronophthisis type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPHP4 gene located on chromosomal region 1p36.31. The age of onset is infantile. This disease results in end-stage renal disease at age ranging between 6 and 35 years. It is a progressive tubulo-interstitial kidney disorder characterized by polydipsia, polyuria, anemia and growth retardation. The prevalence is 1:1,000,000-9:1,000,000.
NPHS1Nephrotic syndrome, type 1Nephrotic syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NPHS1 gene located on chromosomal region 19q13.12. The age of onset is fetal- infantile. This disease is characterized by fetal proteinuria and nephritic infantile syndrome. The prevalence is 1 in 8 200 births.
NPHS2Nephrotic syndrome, type 2Nephrotic syndrome, type 2 (NPHS2) is an autosomal recessive disorder characterized clinically by childhood onset of proteinuria, hypoalbuminemia, hyperlipidemia, and edema. Kidney biopsies show nonspecific histologic changes such as minimal change, focal segmental glomerulosclerosis (FSGS), and diffuse mesangial proliferation. The disorder is resistant to steroid treatment and progresses to end-stage renal failure in the first or second decades (Fuchshuber et al., 1996). Some patients show later onset of the disorder (Tsukaguchi et al., 2002).
NPR2Acromesomelic dysplasia, Maroteaux typeAcromesomelic dysplasia, Maroteaux type is an autosomal recessive disorder characterized by severe dwarfism (height below 120 cm) with shortening of the middle and distal segments of the limbs. This condition is usually diagnosed at birth and becomes more obvious in the first 2 years of life. X-rays show short broad fingers, square flat feet, and shortening of the long bones (particularly the forearms). The radius is bowed; the ulna is shorter than the radius, and its distal end is occasionally hypoplastic. The skull is dolichocephalic and a shortness of the trunk, with decreased vertebral height and narrowing of the lumbar interpedicular distances, is consistently observed. Facial appearance and intelligence are normal (Faivre et al., 2000).
NR0B1Adrenal hypoplasia, congenitalCongenital adrenal hypoplasia follows an X-linked pattern of inheritance and is caused by pathogenic variants in the NR0B1 gene located on chromosomal region Xp21.2. The age of onset is infantile. This disease is characterized by adrenal insufficiency with vomiting, feeding difficulty, dehydration, and shock caused by a salt-wasting episode and hypoglycemia.
NR1H4Cholestasis, progressive familial intrahepatic, type 5Cholestasis, progressive familial intrahepatic, type 5(PFIC5) is an autosomal recessive severe liver disorder characterized by onset of intralobular cholestasis in the neonatal period. The disease is rapidly progressive, leading to liver failure and death if liver transplant is not performed. Other features include abnormal liver enzymes, low to normal gamma-glutamyl transferase (GGT) activity, increased alpha-fetoprotein, and a vitamin K-independent coagulopathy (Gomez-Ospina et al., 2016).
NR2E3Enhanced S-cone syndrome (Goldmann-Favre); Retinitis pigmentosa, type 37Enhaced S-Cone Syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NR2E3 gene located on chromosomal region 15q23. The age of onset is infantile. This disease is characterized by night blindness, reduced bilateral visual acuity, and typical fundus findings (progressive pigmentary degenerative changes, macular edema, retinoschisis). Mutations in the NR2E3 gene can also cause retinitis pigmentosa 37 (RP37). RP37 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision.
NRLRetinal degeneration, autosomal recessive, clumped pigment typeRetinal degeneration autosomal recessive clumped pigment type (RDCP) is a retinopathy characterized by night blindness since early childhood, consistent with a severe reduction in rod function. Color vision is normal although there is a relatively enhanced function of short-wavelength-sensitive cones in the macula. Signs of retinal degeneration and clusters of clumped pigment deposits in the peripheral fundus at the level of the retinal pigment epithelium are present. One family with a clinical diagnosis of clumped pigment-type retinal degeneration has been reported with compound heterozygous mutation in the NPL gene.
NRXN1Pitt-Hopkins-like syndrome, type 2Pitt-Hopkins-like syndrome 2 (PTHSL2) is a syndrome characterized by severe mental retardation and variable additional symptoms, such as impaired speech development, autistic behavior, breathing anomalies and a broad mouth, resembling Pitt-Hopkins syndrome. Other features include decreased reflexes in the upper extremities, constipation, strabismus, and protruding tongue with drooling. In contrast to patients with Pitt-Hopkins syndrome, PTHSL2 patients present with normal or only mildly to moderately delayed motor milestones.
NSDHLCHILD syndromeCHILD syndrome is an acronym for an X-linked dominant disorder characterized by congenital hemidysplasia with ichythyosiform erythrodema and limb defects. The mutations are lethal in hemizygous males (Happle et al., 1980).CK syndrome (300275), an X-linked recessive mental retardation syndrome, is an allelic disorder with a less severe phenotype.
NSUN2Mental retardation, autosomal recessive, type 5Mental retardation, autosomal recessive, type 5 (MRT5) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
NT5C3AAnemia, hemolytic, due to UMPH1 deficiencyDeficiency of pyrimidine 5-prime nucleotidase, also called uridine 5-prime monophosphate hydrolase, causes an autosomal recessive hemolytic anemia characterized by marked basophilic stippling and the accumulation of high concentrations of pyrimidine nucleotides within the erythrocyte. The enzyme is implicated in the anemia of lead poisoning and is possibly associated with learning difficulties. Hirono et al. (1988) suggested that this deficiency is the third most common RBC enzymopathy--after G6PD (300908) and pyruvate kinase (266200) deficiencies--causing hemolysis (Marinaki et al., 2001).
NT5ECalcification of joints and arteriesAdult-onset calcification of the lower extremity arteries, including the iliac, femoral, and tibial arteries, and hand and foot capsule joints is an autosomal recessive condition that represents only the second mendelian disorder of isolated calcification. Age of onset has been reported as early as the second decade of life, usually involving intense joint pain or calcification in the hands (St. Hilaire et al., 2011).
NTHL1Familial adenomatous polyposis, type 3Familial adenomatous polyposis, type 3 is an autosomal recessive cancer predisposition syndrome characterized by the development of multiple colonic adenomas, often with progression to colorectal cancer. Carcinomas affecting other tissues may also occur, and the carcinomas tend to develop in middle age or late adulthood (Weren et al., 2015).
NTRK1Insensitivity to pain, congenital, with anhidrosisInsensitivity to pain, congenital, with anhidrosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NTRK1 gene located on chromosomal region 1q23.1. The age of onset is infantile. This disease is characterized by anhidrosis, insensitivity to pain, self-mutilating behavior and episodes of fever.
NUBPLMitochondrial complex I deficiency, nuclear type 21Mitochondrial complex I deficiency, nuclear type 21 (MC1DN21) is a form of mitochondrial complex I deficiency, the most common biochemical signature of mitochondrial disorders, a group of highly heterogeneous conditions characterized by defective oxidative phosphorylation, which collectively affects 1 in 5-10000 live births. Clinical disorders have variable severity, ranging from lethal neonatal disease to adult-onset neurodegenerative disorders. Phenotypes include macrocephaly with progressive leukodystrophy, non-specific encephalopathy, cardiomyopathy, myopathy, liver disease, Leigh syndrome, Leber hereditary optic neuropathy, and some forms of Parkinson disease. MC1DN21 transmission pattern is consistent with autosomal recessive inheritance.
NUP62Striatonigral degeneration, infantileInfantile striatal degeneration follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the NUP62 gene located on chromosomal region 19q13.33. The age of onset is infantile. This disease is characterized by choreoathetosis, dystonia, rigidity, spasticity, dysphagia, optic atrophy, intellectual deficit, developmental regression of motor and verbal skills, failure to thrive, myoclonus, quadriparesis, cerebellar ataxia and nystagmus. The prevalence is <1:1,000,000.
NYXNight blindness, congenital stationary (complete), type 1A, X-linkedCongenital stationary night blindness follows an X-linked pattern of inheritance and is caused by pathogenic variants in the NYX gene located on chromosomal region Xp11.4. The age of onset is infantile. This disease is characterized by hemeralopia with a moderate loss of visual acuity.
OATGyrate atrophy of choroid and retinaGyrate atrophy of choroid and retina follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OAT gene located on chromosomal region 10q26.13. The age of onset is infantile. This disease is characterized by gyrate atrophy of the choroid and retina that begins during childhood with myopia and night blindness, followed by concentric shrinking of the visual field (tunnel vision) and a peculiar aspect of retinopathy on the funduscopy. Patients can also present with ornithinemia.
OBSL13-M syndrome 23M syndrome 2 is an autosomal recessive disorder characterized by low birth weight and short stature, relative macrocephaly, lumbar hyperlordosis, and prominent heels. Dysmorphic facial features include triangular face with frontal bossing and midface hypoplasia, anteverted nares with fleshy nasal tip, and full fleshy lips (Hanson et al., 2009)
OCA2Oculocutaneous albinism type 2Oculocutaneous albinism type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OCA2 gene located on chromosomal region 15q12-q13. The age of onset is infantile. This disease is characterized by variable hypopigmentation of the skin and hair, numerous characteristic ocular changes and misrouting of the optic nerves at the chiasm. The prevalence is 1/38,000-1/40,000
OCLNPseudo-TORCH syndrome, type 1Pseudo-TORCH syndrome, type 1 is an autosomal recessive neurologic disorder with characteristic clinical and neuroradiologic features that mimic intrauterine TORCH infection in the absence of evidence of infection. Affected individuals have congenital microcephaly, intracranial calcifications, severe developmental delay, simplified gyration and polymicrogyria, and severe developmental delay (Reardon et al., 1994; O'Driscoll et al., 2010). Crow et al. (2000, 2003) called attention to the phenotypic overlap of pseudo-TORCH syndrome and Aicardi-Goutieres syndrome (AGS; 225750), and even suggested that some cases may represent the same disorder. Congenital microcephaly, thrombocytopenia, hepatic dysfunction, and hepatosplenomegaly are usually associated with pseudo-TORCH syndrome and not with AGS, but some patients with AGS have shown these features.
OCRLLowe Syndrome; Dent disease type 2Dent disease type 2 and Lowe syndrome follow an X-linked pattern of inheritance and are caused by pathogenic variants in the OCRL gene located on chromosomal region Xq25-q26. Dent disease type 2 is a type of Dent disease in which patients have the manifestations of Dent disease type 1 associated with extra-renal features: hypercalciuria and low-molecular-weight (LMW) proteinuria. In addition, these patients may also have nephrocalcinosis, nephrolithiasis, hematuria, hypophosphatemia and/or renal insufficiency. The features of Lowe syndrome are hydrophthalmia, cataract, mental retardation, vitamin D-resistant rickets, amino aciduria, and reduced ammonia production by the kidney.
OFD1Joubert syndrome type 10; Orofaciodigital syndrome type 1Joubert syndrome type 10 and Orofaciodigital syndrome type 1 follow an X-linked pattern of inheritance and are caused by pathogenic variants in the OFD1 gene located on chromosomal region Xp22.2. Joubert syndrome type 10 is a disorder presenting with cerebellar ataxia, oculomotor apraxia, hypotonia, neonatal breathing abnormalities and psychomotor delay. Neuroradiologically, it is characterized by cerebellar vermian hypoplasia/aplasia, thickened and reoriented superior cerebellar peduncles, and an abnormally large interpeduncular fossa, giving the appearance of a molar tooth on transaxial slices (molar tooth sign). Additional variable features include retinal dystrophy and renal disease. Orofaciodigital syndrome type 1 is characterized by malformations of the face, oral cavity, and digits and is transmitted as an X-linked dominant condition with lethality in males. The central nervous system may also be involved in as many as 40% of cases.
OPA1Behr syndromeBehr syndrome is a clinical term that refers to the constellation of early-onset optic atrophy accompanied by neurologic features, including ataxia, pyramidal signs, spasticity, and mental retardation (Behr, 1909; Thomas et al., 1984).Patients with mutations in genes other than OPA1 can present with clinical features reminiscent of Behr syndrome.
OPA33-methylglutaconic aciduria, type 33-methylglutaconic aciduria type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OPA3 gene located on chromosomal region 19q13.32. The age of onset is infantile. This disease is characterized by the association of optic atrophy and choreoathetosis with 3-methylglutaconic aciduria. The prevalence is 1:10,000-5:10,000.
OPHN1Mental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearanceMental retardation, X-linked, with cerebellar hypoplasia and distinctive facial appearance is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. This patients manifest mental retardation associated with a neurological condition in which the cerebellum is not completely developed or is smaller than it should be (cerebellar hypoplasia) and distinctive facial dysmorphism.
OPTNAmyotrophic lateral sclerosis, type 12Amyotrophic lateral sclerosis, type 12 is a neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates.
ORC1Meier-Gorlin syndrome, type 1The Meier-Gorlin syndrome is a rare disorder characterized by severe intrauterine and postnatal growth retardation, microcephaly, bilateral microtia, and aplasia or hypoplasia of the patellae (Shalev and Hall, 2003). While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal (Bicknell et al., 2011).
ORC4Meier-Gorlin syndrome, type 2Meier-Gorlin syndrome 2 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.
ORC6Meier-Gorlin syndrome, type 3Meier-Gorlin syndrome 3 is a syndrome characterized by bilateral microtia, aplasia/hypoplasia of the patellae, and severe intrauterine and postnatal growth retardation with short stature and poor weight gain. Additional clinical findings include anomalies of cranial sutures, microcephaly, apparently low-set and simple ears, microstomia, full lips, highly arched or cleft palate, micrognathia, genitourinary tract anomalies, and various skeletal anomalies. While almost all cases have primordial dwarfism with substantial prenatal and postnatal growth retardation, not all cases have microcephaly, and microtia and absent/hypoplastic patella are absent in some. Despite the presence of microcephaly, intellect is usually normal.
OSTM1Osteopetrosis, autosomal recessive type 5Osteopetrosis, autosomal recessive type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OSTM1 gene located on chromosomal region 6p21. The age of onset is infantile. This disease is characterized by osteopetrosis, agenesis del cuerpo calloso, atrofia cerebral e hipocampo peque?o.
OTCOrnithine transcarbamylase deficiencyOrnithine transcarbamylase deficiency follows an X-linked pattern of inheritance and is caused by pathogenic variants in the OTC gene located on chromosomal region Xp11.4. The age of onset is infantile. This disease is characterized by severe neonatal hyperammonemic coma that generally proves to be fatal, in males. Females may be also affected by symptoms with various degrees of intensity, ranging from dislike for proteins to chronic vomiting, growth retardation, hypotonia, psychomotor retardation, hyperammonemic coma, or psychiatric disorders. The prevalence is 1:80,000.
OTOADeafness, autosomal recessive type 22Deafness, autosomal recessive type 22 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OTOA gene located on chromosomal region 16p12.2. The age of onset is infantile. This disease is characterized by hearing loss with no associated visible abnormalities of the external ear or any related medical problems.
OTOFAuditory neuropathy, autosomal recessive, type 1Auditory neuropathy, autosomal recessive type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the OTOF gene located on chromosomal region 2p23.3. Patients can have varying degrees of hearing loss with poor speech reception out of proportion to the degree of hearing loss.
OXCT1Succinyl CoA:3-oxoacid CoA transferase deficiencyKetone bodies are major vectors of energy transfer from the liver to extrahepatic tissues and are the main source of lipid-derived energy for the brain. Mitchell et al. (1995) reviewed medical aspects of ketone body metabolism, including the differential diagnosis of abnormalities. As the first step of ketone body utilization, succinyl-CoA:3-oxoacid CoA transferase (SCOT, or OXCT1; EC 2.8.3.5) catalyzes the reversible transfer of CoA from succinyl-CoA to acetoacetate.
P2RY12Bleeding disorder, platelet-type, type 8Bleeding disorder, platelet-type, type 8 is an autosomal recessive condition characterized by mild to moderate mucocutaneous bleeding and excessive bleeding after surgery or trauma. The defect is due to the inability of ADP to induce platelet aggregation (Cattaneo, 2011).
P3H1Osteogenesis imperfecta, type 8Osteogenesis imperfecta type 8 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the P3H1 gene located on chromosomal region 1p34.2. The age of onset is infantile. This disease is characterized by bone fragility, low bone mass and susceptibility to bone fractures. The prevalence is 6:100,000-7:100,000.
P3H2Myopia, high, with cataract and vitreoretinal degenerationMyopia, high, with cataract and vitreoretinal degeneration is a disorder characterized by severe myopia with variable expressivity of cataract and vitreoretinal degeneration. Some patients manifest lens subluxation, lens instability and retinal detachment.
PAHPhenylketonuriaPhenylketonuria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PAH gene located on chromosomal region 12q23.2. The age of onset is neonatal. This disease is characterized by gradual developmental delay, stunted growth, microcephaly, seizures, tremors, eczema, vomiting, and musty odor. Untreated patients subsequently develop intellectual disability, behavioral disorders (hyperactivity) and motor disorders. The prevalence is 1:2,600-1:200,000.
PAK3Mental retardation, X-linked, type 30Mental retardation, X-linked, type 30 (MRX30) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations.
PANK2Neurodegeneration with brain iron accumulation type 1Neurodegeneration with brain iron accumulation type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PANK2 gene located on chromosomal region 20p13. The age of onset is infantile. This disease is characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation on the brain and axonal spheroids in the central nervous system. The prevalence is 1-2/1,000,000.
PAPSS2Brachyolmia, type 4, with mild epiphyseal and metaphyseal changesBrachyolmia, type 4, with mild epiphyseal and metaphyseal changes is characterized by short-trunk stature with normal intelligence and facies. The radiographic features include rectangular vertebral bodies with irregular endplates and narrow intervertebral discs, precocious calcification of rib cartilages, short femoral neck, mildly shortened metacarpals, and mild epiphyseal and metaphyseal changes of the tubular bones (Miyake et al., 2012).
PARK7Parkinson disease, type 7, autosomal recessive, early-onsetParkinson disease, type 7 (PARK7) is a neurodegenerative disorder characterized by resting tremor, postural tremor, bradykinesia, muscular rigidity, anxiety and psychotic episodes. PARK7 has onset before 40 years, slow progression and initial good response to treatment with levodopa.
PCPyruvate carboxylase deficiencyPyruvate carboxylase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PC gene located on chromosomal region 11q13.2. The age of onset is infantile. This disease is characterized by metabolic acidosis, failure to thrive, developmental delay, and recurrent seizures. The prevalence is 1:250,000.
PCBD1Hyperphenylalaninemia, BH4-deficient, type DHyperphenylalaninemia, BH4-deficient, type D is an autosomal recessive disorder characterized by mild transient hyperphenylalaninemia often detected by newborn screening. Patients also show increased excretion of 7-biopterin. Affected individuals are asymptomatic and show normal psychomotor development, although transient neurologic deficits in infancy have been reported (Thony et al., 1998). Patients may also develop hypomagnesemia and nonautoimmune diabetes mellitus during puberty (Ferre et al., 2014)
PCCAPropionic acidemiaPropionic acidemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PCCA gene located on chromosomal region 13q32.3. The age of onset is infantile. This disease is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and may be complicated by cardiomyopathy. The prevalence is 1:100,000.
PCCBPropionic acidemiaPropionic acidemia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PCCB gene located on chromosomal region 3q22.3. The age of onset is infantile. This disease is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and may be complicated by cardiomyopathy. The prevalence is 1:100,000.
PCDH15Deafness, autosomal recessive type 23; Usher syndrome, type 1D/F digenicDeafness, autosomal recessive 23 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PCDH15 gene located on chromosomal region 10q21.1. This is a form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. Usher syndrome type 1 is an autosomal recessive condition characterized by profound congenital hearing impairment with unintelligible speech, early retinitis pigmentosa (usually evident within the first decade), and constant vestibular dysfunction.
PCDH19Epileptic encephalopathy, early infantile, type 9Epileptic encephalopathy, early infantile, type 9 (EIEE9) is a condition characterized by seizure with onset in infancy or early childhood, cognitive impairment, and delayed development of variable severity in some patients. Additional features include autistic signs and psychosis. The disorder is sex-limited, with the phenotype being restricted to females.
PCNTMicrocephalic osteodysplastic primordial dwarfism, type 2Microcephalic osteodysplastic primordial dwarfism type 1 is characterized by intrauterine growth retardation, severe proportionate short stature, and microcephaly. It is distinct from Seckel syndrome (210600) by more severe growth retardation, radiologic abnormalities, and absent or mild mental retardation (Willems et al., 2010).
PCSK1Obesity with impaired prohormone processingObesity with impaired prohormone processing is a disease due to proprotein convertase 1/3 deficiency and is characterized by obesity, hypogonadism, hypoadrenalism, reactive hypoglycemia as well as marked small-intestinal absorptive dysfunction.
PDE10ADyskinesia, limb and orofacial, infantile-onsetInfantile-onset limb and orofacial dyskinesia is an autosomal recessive neurologic disorder characterized by delayed motor development and onset of a hyperkinetic movement disorder in the first year of life. The disorder results in impaired walking and orofacial dyskinesia with difficulty talking; the severity is variable (Diggle et al., 2016).
PDE6ARetinitis pigmentosa type 43Retinitis pigmentosa type 43 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDE6A gene located on chromosomal region 5q32. The age of onset is variable. This disease is characterized by night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife. The prevalence is 1:10,000-5:10,000.
PDE6BRetinitis pigmentosa type 40Retinitis pigmentosa 40 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDE6B gene located on chromosomal region 4p16.3. The age of onset is variable. Retinitis pigmentosa 40 is a retinal dystrophy belonging to the group of pigmentary retinopathies.This disease is characterized by night blindness, followed by a progressive loss of peripheral vision in the daylight period and leading to blindness.
PDE6CCone dystrophy type 4Cone dystrophy type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDE6C gene located on chromosomal region 10q23.33. The age of onset is infantile. This disease is characterized by reduced visual acuity, achromatopsia, pendular nystagmus, increased sensitivity to light (photophobia), a small central scotoma, eccentric fixation, and reduced or complete loss of color discrimination.
PDE6GRetinitis pigmentosa type 57Retinitis pigmentosa type 57 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDE6G gene located on chromosomal region 17q25.3. The age of onset is variable. This disease is characterized by night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife.
PDE6HRetinal cone dystrophy 3Retinal cone dystrophy 3 with supernormal rod electroretinogram (RCD3A) is an autosomal recessive disorder that causes lifelong visual loss combined with a supernormal ERG response to a bright flash of light. RCD3 can be caused by mutation in the PDE6 gene. Furthermore, at least one mutation in the PDE6H gene has been found to cause the vision disorder achromatopsia 6. It is a very rare cause of a form of the disorder called incomplete achromatopsia. This condition is characterized by limited color vision and other vision problems that are present from early infancy.
PDHA1Pyruvate dehydrogenase E1-alpha deficiencyPyruvate dehydrogenase E1-alpha deficiency follows an X-linked pattern of inheritance and is caused by pathogenic variants in the PDHA1 gene located on chromosomal region Xp22.12. The age of onset is variable. This disease is characterized by primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.The prevalence is >1:40,000 newborn.
PDHBPyruvate dehydrogenase E1-beta deficiencyPyruvate dehydrogenase E1-beta deficiency is an enzymatic defect causing primary lactic acidosis in children. It is associated with a broad clinical spectrum ranging from fatal lactic acidosis in the newborn to chronic neurologic dysfunction with structural abnormalities in the central nervous system without systemic acidosis.
PDHXLacticacidemia due to PDX1 deficiencyLacticacidemia due to PDX1 deficiency is a metabolic disorder characterized by decreased activity of the pyruvate dehydrogenase complex without observable reduction in the activities of enzymes E1, E2, or E3. Clinical features include hypotonia and psychomotor retardation.
PDP1Pyruvate dehydrogenase phosphatase deficiencyPyruvate dehydrogenase phosphatase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDP1 gene located on chromosomal region 8q22.1. The age of onset is neonatal. This disease is characterized by lactic acidosis and hypotonia.
PDSS1Coenzyme Q10 deficiency, primary, type 2Coenzyme Q10 deficiency, primary, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDSS1 gene located on chromosome 10p12.1. The age of onset is neonatal/infantile. This disease is characterized by multisystem disorder with early-onset deafness, optic atrophy, mild mental retardation, peripheral neuropathy, obesity and cardiac valvulopathy.
PDSS2Coenzyme Q10 deficiency, primary, type 3Coenzyme Q10 deficiency, primary, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDSS2 gene located on chromosomal region 6q21. The age of onset is infantile. This disease is characterized by onset of symptoms typically between age three and 12 months, often following a viral infection. Neurologic features include hypotonia, spasticity, movement disorders, cerebellar ataxia, and peripheral neuropathy.
PDX1Pancreatic agenesis type 1Pancreatic agenesis type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PDX1 gene located on chromosomal region 13q12.1. The age of onset is infantile. This disease is characterized by isolated hypoplasia or agenesis of the pancreas, pancreatic beta-cell failure resulting in neonatal insulin-dependent diabetes mellitus, and exocrine pancreatic insufficiency.
PDZD7Usher syndrome, type 2C, GPR98/PDZD7 digenicUsher syndrome type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the GPR98 and PDZD7 genes located on chromosomal regions 5q14.3 and 10q24.32, respectively. The age of onset is infantile. This disease is characterized by the association of sensorineural prelingual deafness (usually congenital) with retinitis pigmentosa and progressive vision loss. The prevalence is 1/30,000.
PEPDProlidase deficiencyProlidase deficiency is a rare autosomal recessive multisystem disorder associated with massive imidodipeptiduria and lack of or reduced prolidase activity in erythrocytes, leukocytes, or cultured fibroblasts. The disorder is clinically heterogeneous and severity varies widely. Features include chronic, slowly healing ulcerations, mainly on the legs and feet. The ulcers are often preceded by other dermatologic manifestations that may occur anywhere and include erythematous papular eruptions, telangiectasias with pruritus and photosensitivity, impetigo-like eruptions, pruritic eczematous lesions, and necrotic papules. Mild to severe mental retardation is often a feature, and recurrent respiratory tract infections, sometimes fatal, are common. Facial dysmorphism may include low hairline and hirsutism, saddle nose, ocular hypertelorism, micrognathia, a high-arched palate, mandibular protrusion, and exophthalmos. Clinical manifestations are usually detectable after birth or in early childhood, but late-onset cases have been reported (Lupi et al., 2008).
PEX1Heimler syndrome type 1Heimler syndrome 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX1 gene located on chromosomal region 7q21.2. This disease is characterized by sensorineural hearing loss, enamel hyoplasia of the secondary dentition, and nail abnormalities.
PEX10Peroxisome biogenesis disorder, type 6A (Zellweger syndrome); Peroxisome biogenesis disorder, type 6BZellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006). This severe form of Zellweger syndrome (PBD6A) is caused by homozygous or compound heterozygous mutation in the PEX10 gene on chromosome 1p36. Mutations in the PEX10 gene also cause peroxisome biogenesis disorder 6B (PBD6B). PBD6B is a peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid
PEX12Peroxisome biogenesis disorder type 3A (Zellweger)Peroxisome biogenesis disorder 3A (Zellweger) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX12 gene located on chromosomal region 17q12. The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life?
PEX13Peroxisome biogenesis disorder, type 11A (Zellweger syndrome); Peroxisome biogenesis disorder, type 11BZellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006). This form of Zellweger syndrome (PBD11A) is caused by homozygous mutation in the PEX13 gene on chromosome 2p15. Mutations in the PEX13 gene also cause peroxisome biogenesis disorder 11B (PBD11B). PBD11B is a peroxisome biogenesis disorder that includes neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), two milder manifestations of the Zellweger disease spectrum. The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy and vision impairment. Children with the NALD presentation may reach their teens, while patients with the IRD presentation may reach adulthood. The clinical conditions are often slowly progressive in particular with respect to loss of hearing and vision. The biochemical abnormalities include accumulation of phytanic acid, very long chain fatty acids (VLCFA), di- and trihydroxycholestanoic acid and pipecolic acid.
PEX14Peroxisome biogenesis disorder, type 13A (Zellweger syndrome)Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006).
PEX16Peroxisome biogenesis disorder, type 8A (Zellweger syndrome); Peroxisome biogenesis disorder, type 8BZellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006). This form of Zellweger syndrome (PBD8A) is caused by homozygous mutation in the PEX16 gene on chromosome 11p11. Mutations in PEX16 also cause peroxisome biogenesis disorder 8B (PBD8B). PBD8B is a relatively mild peroxisome biogenesis disorder. Affected individuals manifest lower limb spasticity and ataxia resulting in wheelchair dependence. Other features include optic atrophy, cataracts, dysarthria, dysphagia, constipation, and a peripheral demyelinating motor and sensory neuropathy. Cognition is relatively preserved. Biochemical abnormalities are mild and include increased very-long-chain fatty acids (VLCFA), increased bile acid intermediates, and increased branched chain fatty acids. Phytanic acid alpha-oxidation, pristanic acid beta-oxidation, and red cell plasmalogen are normal.
PEX19Peroxisome biogenesis disorder, type 12A (Zellweger syndrome)Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006).
PEX2Peroxisome biogenesis disorder type 5A (Zellweger)Peroxisome biogenesis disorder 5A (Zellweger) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX2 gene located on chromosomal region 8q21.13. The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life?
PEX26Peroxisome biogenesis disorder type 7A (Zellweger)Peroxisome biogenesis disorder 7A (Zellweger) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX26 gene located on chromosomal region 22q11.21. The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life?
PEX3Peroxisome biogenesis disorder, type 10A (Zellweger syndrome)Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006).
PEX5Peroxisome biogenesis disorder type 2A (Zellweger)Peroxisome biogenesis disorder 2A (Zellweger) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX5 gene located on chromosomal region 12p13.31. The peroxisomal biogenesis disorder (PBD) Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome resulting from disordered peroxisome biogenesis. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life?
PEX6Peroxisome biogenesis disorder, type 4A (Zellweger syndrome); Peroxisome biogenesis disorder, type 4B; Heimler syndrome 2Zellweger syndrome (ZS) is an autosomal recessive multiple congenital anomaly syndrome. Affected children present in the newborn period with profound hypotonia, seizures, and inability to feed. Characteristic craniofacial anomalies, eye abnormalities, neuronal migration defects, hepatomegaly, and chondrodysplasia punctata are present. Children with this condition do not show any significant development and usually die in the first year of life (Steinberg et al., 2006), Mutations in the PEX6 gene also cause the milder phenotypes peroxisome biogenesis disorder, type 4B (PBD4B) and Heimler syndrome, type 2 (HMLR2). PBD4B includes the overlapping phenotypes of neonatal adrenoleukodystrophy (NALD) and infantile Refsum disease (IRD), which represent milder manifestations of the Zellweger syndrome spectrum (ZSS) of peroxisome biogenesis disorders (PBDs). The clinical course of patients with the NALD and IRD presentation is variable and may include developmental delay, hypotonia, liver dysfunction, sensorineural hearing loss, retinal dystrophy, and visual impairment. Children with the NALD presentation may reach their teens, and those with the IRD presentation may reach adulthood (Waterham and Ebberink, 2012). Heimler syndrome, which represents the mildest end of the peroxisomal biogenesis disorder spectrum (PBD1A, 214100), is a rare autosomal recessive disorder characterized by sensorineural hearing loss, enamel hypoplasia of the secondary dentition, and nail abnormalities (Ratbi et al., 2015).
PEX7Rhizomelic chondrodysplasia punctata, type 1Rhizomelic chondrodysplasia punctata type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PEX7 gene located on chromosomal region 6q23.3. The age of onset is early. This disease is characterized by proximal shortening of the humerus and to a lesser degree the femur (rhizomelia), punctate calcifications in cartilage with epiphyseal and metaphyseal abnormalities (chondrodysplasia punctata), coronal clefts of the vertebral bodies, cataracts, postnatal growth deficiency is profound, intellectual disability is severe, seizures. The prevalence is <1:100,000.
PFKMGlycogen storage disease, type 7Glycogen storage disease, type 7 is an autosomal recessive metabolic disorder characterized clinically by exercise intolerance, muscle cramping, exertional myopathy, and compensated hemolysis. Myoglobinuria may also occur. The deficiency of the muscle isoform of PFK results in a total and partial loss of muscle and red cell PFK activity, respectively. Raben and Sherman (1995) noted that not all patients with GSD VII seek medical care because in some cases it is a relatively mild disorder.
PGK1Phosphoglycerate kinase 1 deficiencyPhosphoglycerate kinase-1 deficiency is an X-linked recessive condition with a highly variable clinical phenotype that includes hemolytic anemia, myopathy, and neurologic involvement. Patients can express 1, 2, or all 3 of these manifestations (Shirakawa et al., 2006).
PGM1Congenital disorder of glycosylation, type 1tCongenital disorder of glycosylation, type 1T follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PGM1 gene located on chromosomal region 1p31.3. The age of onset is infantile. It is a multisystem disorder caused by a defect in glycoprotein biosynthesis and characterized by under-glycosylated serum glycoproteins. Congenital disorders of glycosylation result in a wide variety of clinical features, such as defects in the nervous system development, psychomotor retardation, dysmorphic features, hypotonia, coagulation disorders, and immunodeficiency. The broad spectrum of features reflects the critical role of N-glycoproteins during embryonic development, differentiation, and maintenance of cell functions. The prevalence is <1:1,000,000.
PHEXHypophosphatemic rickets, X-linked dominantX-linked dominant hypophosphatemic rickets, although variable in its expressivity, is characterized by rickets with bone deformities, short stature, dental anomalies, and at the biologic level, hypophosphatemia with low renal phosphate reabsorption, normal serum calcium level with hypocalciuria, normal or low serum level of vitamin D (1,25(OH)2D3, or calcitriol), normal serum level of PTH, and increased activity of serum alkaline phosphatases (Gaucher et al., 2009).
PHF6Borjeson-Forssman-Lehmann syndromeBoerjeson-Forssman-Lehmann syndrome (BFLS) is an X-linked recessive disorder characterized by moderate to severe mental retardation, epilepsy, hypogonadism, hypometabolism, obesity with marked gynecomastia, swelling of subcutaneous tissue of the face, narrow palpebral fissure and large but not deformed ears.
PHF8Mental retardation syndrome, X-linked, Siderius typeX-linked intellectual disability, Siderius type is a condition characterized by mild to moderate intellectual disability that affects only males. Affected boys often have delayed development of motor skills such as walking, and their speech may be delayed.Individuals with X-linked intellectual disability, Siderius type frequently also have an opening in the lip (cleft lip) with an opening in the roof of the mouth (cleft palate). A cleft can occur on one or both sides of the upper lip. Some boys and men with this condition have distinctive facial features, including a long face, a sloping forehead, a broad nasal bridge, a prominent bone in the lower forehead (supraorbital ridge), and outside corners of the eyes that point upward (upslanting palpebral fissures).
PHGDHNeu-Laxova syndrome, type 1; Phosphoglycerate dehydrogenase deficiencyNeu-Laxova syndrome is an autosomal recessive lethal multiple malformation syndrome characterized by ichthyosis, marked intrauterine growth restriction, microcephaly, short neck, central nervous system anomalies (lissencephaly, cerebellar hypoplasia and/or abnormal/agenesis of the corpus callosum), limb deformities, hypoplastic lungs, edema, and abnormal facial features including severe proptosis with ectropion, hypertelorism, micrognathia, flattened nose, and malformed ears (Manning et al., 2004). Neu-Laxova syndrome, type 1 (NLS1) is caused by homozygous mutation in the PHGDH gene on chromosome 1p12. Mutation in PHGDH also causes phosphoglycerate dehydrogenase deficiency (PHGDH) deficiency, an allelic disorder with a less severe phenotype. PHGDH is an autosomal recessive inborn error of L-serine biosynthesis that is characterized by congenital microcephaly, psychomotor retardation, and seizures (Jaeken et al., 1996).
PHKA1Glycogen storage disease, type 9DGlycogen storage disease, type 9D is an X-linked recessive, relatively mild metabolic disorder characterized by variable exercise-induced muscle weakness or stiffness. Most patients have adult-onset of symptoms, and some can remain asymptomatic even in late adulthood. The phenotype is usually only apparent with intense exercise (Preisler et al., 2012).
PHKA2Glycogen storage disease, type 9A1 and type 9A2Glycogen storage disease type 9 (GSD9) is a metabolic disorder resulting from a deficiency of hepatic phosphorylase kinase, a hexadecameric enzyme comprising 4 copies each of 4 unique subunits encoded by 4 different genes: alpha (PHKA2), beta (PHKB), gamma (PHKG2), and delta (CALM1). Mutations within the PHKA2, PHKB, and PHKG2 genes result in GSD9A, GSD9B, and GSD9C, respectively. GSD IXa is an X-linked recessive disorder, whereas the others are autosomal recessive.GSD9A has been further divided into types: GSD9A1, with no PHK activity in liver or erythrocytes, and GSD9A2, with no PHK in liver, but normal activity in erythrocytes. The clinical presentation of both subtypes is the same, and both are caused by mutations in the PHKA2 gene. However, mutations that result in GSD9A2 are either missense or small in-frame deletions or insertions enabling residual enzyme expression in erythrocytes (Keating et al., 1985; Hendrickx et al., 1994; Beauchamp et al., 2007).
PHKBGlycogen storage disease, type 9BGlycogen storage disease, type 9B is a metabolic disorder characterized by hepatomegaly, only slightly elevated transaminases and plasma lipids, clinical improvement with increasing age, and remarkably no clinical muscle involvement. Biochemical observations suggest that this mild phenotype is caused by an incomplete holoenzyme that lacks the beta subunit, but that may possess residual activity.
PHKG2Glycogen storage disease type 9cGlycogen storage disease type 9C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PHKG2 gene located on chromosomal region 16p12.1-p11.2. The age of onset is infantile. This disease is characterized by hepatomegaly, growth retardation, and mild delay in motor development during childhood. The incidence is <1:100.000 births.
PHYHRefsum diseaseRefsum disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PHYH gene located on chromosomal region 10p13. The age of onset is variable. This disease is characterized by hemeralopia (loss of vision in the dark), followed by episods of chronic distal motor polyneuropathy. Other associated signs include perceptive deafness, anosmia, cerebellous ataxia and sometimes, severe intellectual deficiency. Over the course of time cutaneous signs appear (ichtyosis), along with polyepiphyseal dysplasia, myocardiopathy, elevated protein in cerebrospinal fluid, and pigmentary retinitis that may result in blindness. The prevalence is 1:1.000,000-9:1.000,000.
PIEZO1Lymphedema, hereditary, type 3Hereditary lymphedema, type 3 is a form of generalized lymphatic dysplasia (GLD), which is characterized by a uniform, widespread lymphedema affecting all segments of the body, with systemic involvement such as intestinal and/or pulmonary lymphangiectasia, pleural effusions, chylothoraces and/or pericardial effusions. In LMPH3, there is a high incidence of nonimmune hydrops fetalis (NIHF) with either death or complete resolution of the neonatal edema but childhood onset of lymphedema with or without systemic involvement. Mild facial edema is often present. Patients have normal intelligence and no seizures (Fotiou et al., 2015).
PIEZO2Arthrogryposis, distal, with impaired proprioception and touchDistal arthrogryposis with impaired proprioception and touch is an autosomal recessive neurologic disorder characterized by loss of certain mechanosensation modalities resulting in ataxia, difficulty walking, dysmetria, muscle weakness and atrophy, and progressive skeletal contractures. Patients have onset of symptoms in early childhood (Chesler et al., 2016; Delle Vedove et al., 2016).
PIGAMultiple congenital anomalies-hypotonia-seizures syndrome, type 2Multiple congenital anomalies-hypotonia-seizures syndrome, type 2 is an X-linked recessive neurodevelopmental disorder characterized by dysmorphic features, neonatal hypotonia, myoclonic seizures, and variable congenital anomalies involving the central nervous, cardiac, and urinary systems. Some affected individuals die in infancy (Johnston et al., 2012). The phenotype shows clinical variability with regard to severity and extraneurologic features. However, most patients present in infancy with early-onset epileptic encephalopathy associated with developmental arrest and subsequent severe neurologic disability (Belet et al., 2014; Kato et al., 2014). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
PIGLZunich neuroectodermal syndromeZunich neuroectodermal syndrome is an extremely rare autosomal recessive multisystem disorder clinically characterized by colobomas, congenital heart defects, migratory ichthyosiform dermatosis, mental retardation, and ear anomalies (CHIME). Other clinical features include distinctive facial features, abnormal growth, genitourinary abnormalities, seizures, and feeding difficulties (Ng et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
PIGNMultiple congenital anomalies-hypotonia-seizures syndrome, type 1Multiple congenital anomalies-hypotonia-seizures syndrome, type 1 is an autosomal recessive disorder characterized by neonatal hypotonia, lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. Most affected individuals die before 3 years of age (Maydan et al., 2011). The disorder is caused by a defect in glycosylphosphatidylinositol biosynthesis.
PIGOHyperphosphatasia with mental retardation syndrome 2Hyperphosphatasia with mental retardation syndrome 2 is an autosomal recessive disorder characterized by moderately to severely delayed psychomotor development, facial dysmorphism, brachytelephalangy, and increased serum alkaline phosphatase (hyperphosphatasia). Some patients may have additional features, such as cardiac septal defects or seizures (Krawitz et al., 2012). The disorder is caused by a defect in glycosylphosphatidylinositol (GPI) biosynthesis.
PINK1Parkinson disease, type 6, early onsetParkinson disease, type 6 (PARK6) is an early-onset form of Parkinson disease, a neurodegenerative disorder characterized by parkinsonian signs such as rigidity, resting tremor and bradykinesia. A subset of patients manifest additional symptoms including hyperreflexia, autonomic instability, dementia and psychiatric disturbances. Symptoms show diurnal fluctuation and can improve after sleep. PARK6 pathogenesis involves respiratory complex I deficiency causing mitochondrial depolarization and dysfunction.
PIP5K1CLethal congenital contractural syndrome, type 3Lethal congenital contracture syndrome 3 (LCCS3) is a form of lethal congenital contracture syndrome, an autosomal recessive disorder characterized by degeneration of anterior horn neurons, extreme skeletal muscle atrophy, and congenital non- progressive joint contractures (arthrogryposis). The contractures can involve the upper or lower limbs and/or the vertebral column, leading to various degrees of flexion or extension limitations evident at birth. LCCS3 patients present at birth with severe multiple joint contractures and severe muscle wasting and atrophy, mainly in the legs. Death occurs minutes to hours after birth due to respiratory insufficiency. The phenotype can be distinguished from that of LCCS1 by the absence of hydrops, fractures and multiple pterygia, and from LCCS2 by the absence of neurogenic bladder defect.
PJVKDeafness, autosomal recessive type 59Autosomal recessive nonsyndromic sensorineural deafness type 59 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PJVK gene located on chromosomal region 2q31.2. The age of onset is neonatal/infantile. This disease is characterized by congenital, non-progressive, mild-to-profound sensorineural hearing impairment.
PKHD1Polycystic kidney disease type 4Polycystic kidney disease type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PKHD1 gene located on chromosomal region 6p12.3-p12.2. The age of onset is early. This disease is a severe form of polycystic kidney disease affecting the kidneys and, in some cases, the hepatic biliary tract. Up to 50% of the affected neonates die shortly after birth, as a result of severe pulmonary hypoplasia and secondary respiratory insufficiency. In the subset that survives the perinatal period, morbidity and mortality are mainly related to severe systemic hypertension, renal insufficiency, and portal hypertension due to portal-tract fibrosis.
PKLRPyruvate kinase deficiencyPyruvate kinase deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PKLR gene located on chromosomal region 1q22. The age of onset is early. This disease is characterized by highly variable degree of chronic hemolysis, with severe neonatal jaundice and fatal anemia at birth, severe transfusion-dependent chronic hemolysis, and moderate hemolysis with exacerbation during infection. The prevalence is 1:20,000.
PKP1Ectodermal dysplasia/skin fragility syndromeEctodermal dysplasia-skin fragility syndrome is a form of ectodermal dysplasia, a heterogeneous group of disorders due to abnormal development of two or more ectodermal structures. Characterized by features of both cutaneous fragility and congenital ectodermal dysplasia affecting skin, hair and nails. There is no evidence of significant abnormalities in other epithelia or tissues.
PLA2G6Infantile neuroaxonal dystrophy type 1Infantile neuroaxonal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLA2G6 gene located on chromosomal region 22q13.1. The age of onset is infantile. This disease is a type of neurodegeneration with brain iron accumulation characterized by psychomotor delay and regression, increasing neurological involvement with symmetrical pyramidal tract signs and spastic tetraplegia. INAD may be classic or atypical and patients present with symptoms anywhere along a continuum between the two.
PLCB1Epileptic encephalopathy, early infantile, type 12Epileptic encephalopathy, early infantile, type 12 (EIEE12) is an extremely rare nervous system disorder. Infants with EIEE12 develop very frequent epileptic seizures. Seizures present within the first days to months of life. Seizures may trigger eye rolling, eyelid fluttering, lip smacking, drooling, bluish coloring around the mouth, limpness, or muscle stiffening (particularly those in his or her back, legs, and arms). The seizures associated with this disease are difficult to treat and the syndrome is severely progressive.
PLCB4Auriculocondylar syndrome, type 2Auriculocondylar syndrome (ARCND), also known as 'question-mark ear syndrome' or 'dysgnathia complex,' is an autosomal dominant craniofacial malformation syndrome characterized by highly variable mandibular anomalies, including mild to severe micrognathia, often with temporomandibular joint ankylosis, cleft palate, and a distinctive ear malformation that consists of separation of the lobule from the external ear, giving the appearance of a question mark. Other frequently described features include prominent cheeks, cupped and posteriorly rotated ears, preauricular tags, and microstomia (Rieder et al., 2012).
PLCD1Nail disorder, nonsyndromic congenital, type 3 (leukonychia)A white appearance of the nails can result from whitening of the nail plate (true leukonychia), the nail bed (pseudoleukonychia), or neither (apparent leukonychia), and can be due to a variety of factors including infectious, metabolic, or systemic diseases, trauma, or drugs. One of the rare causes of whitening of the nail plate is hereditary leukonychia (Kiuru et al., 2011). Leukonychia may involve all of the nail (leukonychia totalis) or only part of the nail (leukonychia partialis), or can appear as one or more transverse bands (leukonychia striata) or white spots (leukonychia punctata).
PLCE1Nephrotic syndrome, type 3Nephrotic syndrome type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLCE1 gene located on chromosomal region 10q23.33. The age of onset is variable. This disease is characterized by low blood protein levels, high cholesterol levels, high triglyceride levels, and presence of protein in the urine. The prevalence is 2:100,000-7:100,000 Children; 3:100,000 adults.
PLECEpidermolysis bullosa simplex with muscular dystrophyEpidermolysis bullosa simplex with muscular dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLEC gene located on chromosomal region 8q24. The age of onset is early. This disease is characterized by generalized blistering associated with muscular dystrophy, dystrophic nails, and focal keratoderma of the palms and soles. The prevalence is 1:30,000-1:50,000.
PLEKHG5Charcot-Marie-Tooth disease, recessive intermediate CCharcot-Marie-Tooth disease, intermediate type C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLEKHG5 gene located on chromosomal region 1p36.31. The age of onset is infantile. This disease is a disorder of the peripheral nervous system, characterized by progressive weakness and atrophy, initially of the peroneal muscles and later of the distal muscles of the arms. Recessive intermediate forms of Charcot-Marie-Tooth disease are characterized by clinical and pathologic features intermediate between demyelinating and axonal peripheral neuropathies, and motor median nerve conduction velocities ranging from 25 to 45 m/sec.
PLGPlasminogen deficiency, type IPlasminogen deficiency type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLG gene located on chromosomal region 6q26. The age of onset is infantile.This disease is characterized by markedly impaired extracellular fibrinolysis leading to the formation of ligneous (fibrin-rich) pseudomembranes on mucosae during wound healing. The prevalence is 1:1,000,000-9:1,000,000.
PLOD1Ehlers-Danlos syndrome, kyphoscoliotic type, 1Ehlers-Danlos syndrome kyphoscoliotic type, 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PLOD1 gene located on chromosomal region 1p36. The age of onset is early. This disease is characterized by progressive scoliosis from birth, severe muscle hypotonia, hyperextensible joints and fragile eyeballs. The weakness can lead to ocular retinal hemorrhage, glaucoma, coloring of the sclera or even to rupture of the globe. The prevalence is <1:5,000.
PLOD2Bruck syndrome 2Bruck syndrome 2 is an autosomal recessive disease characterized by generalized osteopenia, congenital joint contractures, fragile bones with onset of fractures in infancy or early childhood, short stature, severe limb deformity, progressive scoliosis, and pterygia. It is distinguished from osteogenesis imperfecta by the absence of hearing loss and dentinogenesis imperfecta, and by the presence of clubfoot and congenital joint limitations.
PLOD3Lysyl hydroxylase 3 deficiencyLysyl hydroxylase 3 deficiency is a connective tissue disorder. The syndrome is characterized by congenital malformations severely affecting many tissues and organs and revealing features of several collagen disorders.
PLP1Pelizaeus-Merzbacher diseasePelizaeus-Merzbacher disease follows an X-linked pattern of inheritance and is caused by pathogenic variants in the PLP1 gene located on chromosomal region Xq22.2. The age of onset is infantile. It is a hypomyelinative leukodystrophy in which myelin is not formed properly in the central nervous system. It is characterized clinically by nystagmus, spastic quadriplegia, ataxia, and developmental delay.
PMM2Congenital disorder of glycosylation, type 1ACongenital disorder of glycosylation type 1a follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PMM2 gene located on chromosomal region 16p13.2. The age of onset is infantile. This disease is characterized by highly variable clinical manifestations that may include feeding problems, vomiting, and diarrhea with failure to thrive in infants, and severe encephalopathy with axial hypotonia, abnormal eye movement, marked psychomotor retardation, peripheral neuropathy, cerebellar hypoplasia, stroke-like episodes, and retinitis pigmentosa in late infancy, childhood or adulthood.
PMP22Dejerine-Sottas diseaseDejerine-Sottas neuropathy is a demyelinating peripheral neuropathy with onset in infancy. It can show autosomal dominant or recessive inheritance. Affected individuals have delayed motor development due to severe distal motor and sensory impairment, resulting in difficulties in gait. Some patients have generalized hypotonia in infancy. Other features may include pes cavus, scoliosis, and sensory ataxia. Nerve conduction velocities are severely decreased (sometimes less than 10 m/s), and sural nerve biopsy shows severe loss of myelinated fibers (Baets et al., 2011).
PNKPAtaxia-oculomotor apraxia, type 4; Microcephaly, seizures, and developmental delayAtaxia-oculomotor apraxia, type 4 (AOA4) is an autosomal recessive neurologic disorder characterized by onset of dystonia and ataxia in the first decade. Additional features include oculomotor apraxia and peripheral neuropathy. Some patients may show cognitive impairment. The disorder is progressive, and most patients become wheelchair-bound in the second or third decade (Bras et al., 2015). AOA4 is caused by homozygous or compound heterozygous mutation in the PNKP gene (605610) on chromosome 19q13. Mutation in PNKP gene also causes microcephaly, seizures, and developmental delay (MCSZ). MCSZ is an autosomal recessive neurodevelopmental disorder with onset in infancy. There is a range of phenotypic severity: some patients have a disease course consistent with early infantile epileptic encephalopathy (EIEE), whereas others have more well-controlled seizures and a protracted course associated with cerebellar atrophy and peripheral neuropathy (Shen et al., 2010 and Poulton et al., 2013).
PNPImmunodeficiency due to purine nucleoside phosphorylase deficiencyPurine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (Aust et al., 1992).
PNPLA1Ichthyosis, congenital, autosomal recessive, type 10Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of disorders of keratinization characterized primarily by abnormal skin scaling over the whole body. These disorders are limited to skin, with approximately two-thirds of patients presenting severe symptoms. The main skin phenotypes are lamellar ichthyosis (LI) and nonbullous congenital ichthyosiform erythroderma (NCIE), although phenotypic overlap within the same patient or among patients from the same family can occur (Fischer, 2009). Neither histopathologic findings nor ultrastructural features clearly distinguish between NCIE and LI. In addition, mutations in several genes have been shown to cause both lamellar and nonbullous ichthyosiform erythrodermal phenotypes (Akiyama et al., 2003). At the First Ichthyosis Consensus Conference in Soreze in 2009, the term 'autosomal recessive congenital ichthyosis' (ARCI) was designated to encompass LI, NCIE, and harlequin ichthyosis (ARCI4B; 242500) (Oji et al., 2010).NCIE is characterized by prominent erythroderma and fine white, superficial, semiadherent scales. Most patients present with collodion membrane at birth and have palmoplantar keratoderma, often with painful fissures, digital contractures, and loss of pulp volume. In half of the cases, a nail dystrophy including ridging, subungual hyperkeratosis, or hypoplasia has been described. Ectropion, eclabium, scalp involvement, and loss of eyebrows and lashes seem to be more frequent in NCIE than in lamellar ichthyosis (Fischer et al., 2000). In LI, the scales are large, adherent, dark, and pigmented with no skin erythema. Overlapping phenotypes may depend on the age of the patient and the region of the body. The terminal differentiation of the epidermis is perturbed in both forms, leading to a reduced barrier function and defects of lipid composition in the stratum corneum (Lefevre et al., 2006).In later life, the skin in ARCI may have scales that cover the entire body surface, including the flexural folds, and the scales are highly variable in size and color. Erythema may be very mild and almost invisible. Some affected persons exhibit scarring alopecia, and many have secondary anhidrosis (Eckl et al., 2005).
PNPLA2Neutral lipid storage disease with myopathyNeutral lipid storage disease with myopathy is an autosomal recessive muscle disorder characterized by adult onset of slowly progressive proximal muscle weakness affecting the upper and lower limbs and associated with increased serum creatine kinase; distal muscle weakness may also occur. About half of patients develop cardiomyopathy later in the disease course. Other variable features include diabetes mellitus, hepatic steatosis, hypertriglyceridemia, and possibly sensorineural hearing loss. Leukocytes and muscle cells show cytoplasmic accumulation of triglycerides (Reilich et al., 2011).Neutral lipid storage disease with myopathy belongs to a group of disorders termed neutral lipid storage disorders (NLSDs). These disorders are characterized by the presence of triglyceride-containing cytoplasmic droplets in leukocytes and in other tissues, including bone marrow, skin, and muscle. Chanarin-Dorfman syndrome (CDS; 275630) is defined as NLSD with ichthyosis (NLSDI). Patients with NLSDM present with myopathy but without ichthyosis (Fischer et al., 2007).
PNPLA6Boucher-Neuhauser syndrome; Oliver-McFarlane syndrome; Spastic paraplegia, type 39, autosomal recessiveBoucher-Neuhauser syndrome is an autosomal recessive disorder characterized classically by the triad of spinocerebellar ataxia, hypogonadotropic hypogonadism, and visual impairment due to chorioretinal dystrophy. The age at onset is variable, but most patients develop one or more symptoms in the first decade of life. Chorioretinal dystrophy may not always be present. BNHS is part of a spectrum of neurodegenerative diseases associated with mutations in the PNPLA6 gene that also includes spastic paraplegia-39 (SPG39) (Synofzik et al., 2014). SPG39 is an autosomal recessive progressive spastic paraplegia associated with distal upper and lower extremity wasting. Oliver-McFarlane syndrome is also caused by compound heterozygous mutation in the PNPLA6. Oliver-McFarlane syndrome is a rare congenital disorder characterized by trichomegaly, severe chorioretinal atrophy and multiple pituitary hormone deficiencies, including growth hormone (GH; 139250), gonadotropins (see 118860), and thyroid-stimulating hormone (TSH; 118850). Thyroid and GH abnormalities may be present at birth and, if untreated, result in intellectual impairment and profound short stature. Congenital hypogonadism occurs in half of patients, and nearly all have documented hypogonadotropic hypogonadism during puberty, with subsequent reproductive dysfunction. Chorioretinal atrophy is typically noted in the first 5 years of life. Half of reported cases have spinocerebellar involvement, including ataxia, spastic paraplegia, and peripheral neuropathy (Hufnagel et al., 2015).
PNPOPyridoxamine 5'-phosphate oxidase deficiencyPyridoxamine 5'-phosphate oxidase (PNPO) deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PNPO gene located on chromosomal region 17q21.32. The age of onset is early. This disease is characterized by onset of severe seizures within hours of birth that are not responsive to anticonvulsants.
POLGPOLG-related disordersPOLG-related disorders follow an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the POLG gene located on chromosomal region 15q26.1. POLG-related disorders have overlapping signs and symptoms affecting mucle-, nerve-, and brain-related functions. Mitochondrial DNA depletion syndrome 4A, Alpers type (203700) is characterized by the clinical triad of psychomotor regression, seizures, and liver disease, and its prevalence is 1:1,600 newborn. Mitochondrial DNA depletion syndrome-4B (613662) is an autosomal recessive progressive multisystem disorder clinically characterized by chronic gastrointestinal dysmotility and pseudoobstruction, cachexia, progressive external ophthalmoplegia (PEO), axonal sensory ataxic neuropathy, and muscle weakness Another condition caused by mutations in the POLG gene is ataxia neuropathy spectrum (607459), that is characterized by problems with coordination and balance (ataxia) and disturbances in nerve function (neuropathy). The conditions previously named mitochondrial recessive ataxia syndrome (MIRAS) and sensory ataxia neuropathy dysarthria and ophthalmoplegia (SANDO) are now included in the ataxia neuropathy spectrum.
POLHXeroderma pigmentosum, variant typeXeroderma pigmentosum is an autosomal recessive disorder characterized by increased sensitivity to sunlight and defects in DNA repair. Some patients with xeroderma pigmentosum have been found to have normal DNA excision repair, but defective postreplication repair (Lehman et al., 1975). This XP 'variant' class is characterized by a defect in conversion of newly synthesized DNA from low to high molecular weight after UV irradiation (Masutani et al., 1999).So-called 'pigmentary xerodermoid' is apparently identical to the XP variant, which is characterized by loss of a gene product that permits normal cells to replicate DNA without interruption at UV-damaged sites (Cleaver et al., 1980).
POLR1CLeukodystrophy, hypomyelinating, type 11; Treacher Collins syndrome 3Hypomyelinating leukodystrophy, type 11 is an autosomal recessive neurologic disorder characterized by delayed psychomotor development and other neurologic features associated with hypomyelination on brain imaging. Some patients may have additional nonneurologic features, particularly dental abnormalities and possibly hypogonadotropic hypogonadism (Thiffault et al., 2015). Mutations in POLR1C gene can also cause Treacher Collins syndrome 3. Treacher Collins syndrome is a disorder of craniofacial development characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss (Dauwerse et al., 2011).
POLR1DTreacher Collins syndrome, type 2Treacher Collins syndrome is a disorder of craniofacial development characterized by a combination of bilateral downward slanting of the palpebral fissures, colobomas of the lower eyelids with a paucity of eyelashes medial to the defect, hypoplasia of the facial bones, cleft palate, malformation of the external ears, atresia of the external auditory canals, and bilateral conductive hearing loss (Dauwerse et al., 2011).
POLR3ALeukodystrophy, hypomyelinating, type 7Hypomyelinating leukodystrophy, type 7 is an autosomal recessive neurodegenerative disorder characterized by childhood onset of progressive motor decline manifest as spasticity, ataxia, tremor, and cerebellar signs, as well as mild cognitive regression. Other features may include hypodontia or oligodontia and hypogonadotropic hypogonadism. There is considerable inter- and intrafamilial variability (Bernard et al., 2011).
POLR3BLeukodystrophy, hypomyelinating, type 8Hypomyelinating leukodystrophy, type 8 is an autosomal recessive neurologic disorder characterized by early childhood onset of cerebellar ataxia and mild intellectual disabilities associated with diffuse hypomyelination apparent on brain MRI. Variable features include oligodontia and/or hypogonadotropic hypogonadism (Tetreault et al., 2011).
POMCObesity, adrenal insufficiency, and red hair due to POMC deficiencyObesity, adrenal insufficiency, and red hair (OBAIRH) due to POMC deficiency is an autosomal recessive endocrine disorder characterized by early-onset obesity due to severe hyperphagia, pigmentary abnormalities, mainly pale skin and red hair, and secondary hypocortisolism. In the neonatal period, affected individuals are prone to hypoglycemia, hyperbilirubinemia, and cholestasis that may result in death if not treated. The disorder results from mutation in the POMC gene, which encodes a preproprotein that is processed into a range of bioactive peptides, including alpha-melanocyte-stimulating hormone (MSH) and ACTH (Kuhnen et al., 2016; Clement et al., 2008).
POMGNT1Muscular dystrophy-dystroglycanopathy, type 3A (Walker-Warburg syndrome); Type 3B; Type 3C (limb-girdle muscular dystrophy, type 15 [LGMDR15])Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies) type A3 which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the POMGNT1 gene located on chromosomal region 1p34.1. The age of onset is infantile. This disease is characterized by generalized severe hypotonia, muscle weakness, absent psychomotor development, eye involvement and seizures. The prevalence is 1-9:100,000.
POMGNT2Muscular dystrophy-dystroglycanopathy, type 8A (Walker-Warburg syndrome); Type 8C (limb-girdle muscular dystrophy, type 24 [LGMD R24])Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies, type A8 is an autosomal recessive disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and death usually in the first years of life. The phenotype includes the alternative clinical designation Walker-Warburg syndrome (WWS). The disorder represents the most severe end of a phenotypic spectrum of similar disorders resulting from defective glycosylation of alpha-dystroglycan (DAG1; 128239), collectively known as 'dystroglycanopathies' (Manzini et al., 2012).
POMPKeratosis linearis with ichthyosis congenita and sclerosing keratodermaKeratosis linearis with ichthyosis congenita and sclerosing keratoderma is a keratinizing disorder characterized by ichthyosis, palmoplantar keratoderma with constricting bands around fingers, flexural deformities of fingers and keratotic papules in a linear distribution on the flexural side of large joints. Histological examination of the skin of affected individuals shows hypertrophy and hyperplasia of the spinous, granular and horny epidermal layer.
POMT1Muscular dystrophy-dystroglycanopathy, type 1A (Walker-Warburg syndrome); Type 1B; Type 1C (limb-girdle muscular dystrophy, type 11 [LGMD R11])Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type 1A follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the POMT1 gene located on chromosomal region 9q34.13. Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. Congenital muscular dystrophy-dystroglycanopathies with or without mental retardation (type 1B) represent the intermediate range of the spectrum of dystroglycanopathies. The muscular dystrophy-dystroglycanopathy type 1C (limb-girdle phenotype) is characterized by onset of muscular weakness apparent after ambulation is achieved; mental retardation and mild brain anomalies are variable (Balci et al., 2005; review by Godfrey et al., 2007).
POMT2Muscular dystrophy-dystroglycanopathy, type 2A (Walker-Warburg syndrome); Type 2B; Type 2C (limb-girdle muscular dystrophy, type 14 [LGMD R14])Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the POMT2 gene located on chromosomal region 14q24.3. Congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies (type A), which includes both the more severe Walker-Warburg syndrome (WWS) and the slightly less severe muscle-eye-brain disease (MEB), is a genetically heterogeneous disorder with characteristic brain and eye malformations, profound mental retardation, congenital muscular dystrophy, and early death. The phenotype commonly includes cobblestone (type II) lissencephaly, cerebellar malformations, and retinal malformations. MD Type 2B is associated with mental retardation and mild structural brain abnormalities. Type 2C has an onset after ambulation is achieved. Cognition is normal.
POP1Anauxetic dysplasia, type 2Anauxetic dysplasia, type 2 is a spondyloepimetaphyseal dysplasia characterized by severe short stature of prenatal onset, very short adult height (less than 1 meter), hypodontia, midface hypoplasia, and mild intellectual disability. Vertebrae are ovoid with concave dorsal surfaces in the lumbar region and show delayed bone maturation. Femoral heads and necks are hypoplastic, as are the iliac bodies. Long bones show irregular mineralization of the metaphyses. The first and fifth metacarpals are short and wide with small, late-ossifying epiphyses and bullet-shaped middle phalanges (Barraza-Garcia et al., 2017).
PORAntley-Bixler syndrome with genital anomalies and disordered steroidogenesisThe Antley-Bixler syndrome (ABS) is an exceptionally rare craniosynostosis syndrome characterized by radiohumeral synostosis present from the perinatal period. There is a wide spectrum of anomalies seen in ABS; other features include midface hypoplasia, choanal stenosis or atresia, multiple joint contractures, visceral anomalies (particularly of the genitourinary system), and impaired steroidogenesis (present only in patients with POR mutations). Mortality has been reported to be as high as 80% in the neonatal period, primarily due to airway compromise, and prognosis improves with increasing age (McGlaughlin et al., 2010).
PORCNFocal dermal hypoplasiaFocal dermal hypoplasia is inherited as an X-linked dominant with in utero lethality in males. The features include atrophy and linear pigmentation of the skin, herniation of fat through the dermal defects, and multiple papillomas of the mucous membranes or skin. In addition, digital anomalies consist of syndactyly, polydactyly, camptodactyly, and absence deformities. Oral anomalies, in addition to lip papillomas, include hypoplastic teeth. Ocular anomalies (coloboma of iris and choroid, strabismus, microphthalmia) have also been present in some cases. Mental retardation occurs in some patients. Striated bones are probably a nearly constant feature (Larregue and Duterque, 1975; Happle and Lenz, 1977; Fete and Fete, 2016).
POU1F1Pituitary hormone deficiency, combined, type 1Pituitary hormone deficiency, combined, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the POU1F1 gene located on chromosomal region 3p11.2. The age of onset is early. This disease is characterized by short stature, cognitive alterations or delayed puberty. The prevalence is 1:8,000.
POU3F4Deafness, X-linked type 2 (DFNX2)X-linked deafness type 2 (DFNX2, also known as DFN3) follows an X-linked pattern of inheritance and is caused by pathogenic variants in the POU3F4 gene located on chromosomal region Xq21.1. The age of onset is infantile. This disease is characterized by progressive conductive and sensorineural hearing loss and a pathognomonic temporal bone deformity that includes dilatation of the inner auditory canal and a fistulous connection between the internal auditory canal and the cochlear basal turn, resulting in a perilymphatic fluid 'gusher' during stapes surgery (summary by de Kok et al., 1995 and Song et al., 2010). Note: Choroideremia, deafness, and mental retardation (OMIM 303110), is caused by a contiguous gene deletion syndrome involving the POU3F4 and CHM genes on Xq21. This deletion is not detected by this CGT test.
PPIBOsteogenesis imperfecta, type 9Osteogenesis imperfecta (OI) is a connective tissue disorder characterized clinically by bone fragility and increased susceptibility to fractures. OI type 9 is a severe autosomal recessive form of the disorder (van Dijk et al., 2009).
PPT1Ceroid lipofuscinosis, neuronal, type 1Neuronal ceroid lipofuscinoses, type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PPT1 gene located on chromosomal region 1p32. The age of onset is adult. This disease is characterized by dementia, seizures and loss of motor capacities, and sometimes associated with visual loss caused by retinal degeneration. The prevalence is 1.5:1,000,000-9:1,000,000.
PQBP1Renpenning syndromeRenpenning syndrome is an X-linked mental retardation syndrome with clinically recognizable features. Affected individuals have microcephaly, short stature, small testes, and dysmorphic facies, including tall narrow face, upslanting palpebral fissures, abnormal nasal configuration, cupped ears, and short philtrum. The nose may appear long or bulbous, with overhanging columella. Less consistent manifestations include ocular colobomas, cardiac malformations, cleft palate, and anal anomalies. Stevenson et al. (2005) proposed that the various X-linked mental retardation syndromes due to PQBP1 mutations be combined under the name of Renpenning syndrome.
PRCDRetinitis pigmentosa, type 36Retinitis pigmentosa, type 36 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PRCD gene located on chromosomal region 17q25.1. The age of onset is variable. This disease is characterized by night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife.
PRDM5Brittle cornea syndrome, type 2Brittle cornea syndrome (BCS) is characterized by blue sclerae, corneal rupture after minor trauma, keratoconus or keratoglobus, hyperelasticity of the skin, and hypermobility of the joints (Al-Hussain et al., 2004). It is classified as a form of Ehlers-Danlos syndrome (Malfait et al., 2017).
PREPLMyasthenic syndrome, congenital, type 22Myasthenic syndrome, congenital, type 22 (CMS22) is a form of congenital myasthenic syndrome, a group of disorders characterized by failure of neuromuscular transmission, including pre- synaptic, synaptic, and post-synaptic disorders that are not of autoimmune origin. Clinical features include easy fatigability and muscle weakness. CMS22 is an autosomal recessive form characterized by neonatal hypotonia.
PRF1Hemophagocytic lymphohistiocytosis, familial, type 2Familial hemophagocytic lymphohistiocytosis, type 2 (FHL2) is an autosomal recessive disorder of immune dysregulation with onset in infancy or early childhood. It is characterized clinically by fever, edema, hepatosplenomegaly, and liver dysfunction. Neurologic impairment, seizures, and ataxia are frequent. Laboratory studies show pancytopenia, coagulation abnormalities, hypofibrinogenemia, and hypertriglyceridemia. There is increased production of cytokines, such as gamma-interferon (IFNG; 147570) and TNF-alpha (191160), by hyperactivation and proliferation of T cells and macrophages. Activity of cytotoxic T cells and NK cells is reduced, consistent with a defect in cellular cytotoxicity. Bone marrow, lymph nodes, spleen, and liver show features of hemophagocytosis. Chemotherapy and/or immunosuppressant therapy may result in symptomatic remission, but the disorder is fatal without bone marrow transplantation (Dufourcq-Lagelouse et al., 1999; Stepp et al., 1999; Molleran Lee et al., 2004).
PRG4Camptodactyly-arthropathy-coxa vara-pericarditis syndromeThe camptodactyly-arthropathy-coxa vara-pericarditis syndrome is an autosomal recessive condition characterized by the association of congenital or early-onset camptodactyly and noninflammatory arthropathy with synovial hyperplasia. Progressive coxa vara deformity and/or noninflammatory pericardial or pleural effusions are found in some patients (Faivre et al., 2000).
PRICKLE1Epilepsy, progressive myoclonic, type 1BEpilepsy, progressive myoclonic, type 1B is an autosomal recessive disorder characterized by myoclonus that progressed in severity over time, tonic-clonic seizures and ataxia.
PRKNParkinson disease, type 2, juvenileParkinson disease, type 2, juvenile (PARK2) is a neurodegenerative disorder characterized by bradykinesia, rigidity, postural instability, tremor, and onset usually before 40. It differs from classic Parkinson disease by early DOPA-induced dyskinesia, diurnal fluctuation of the symptoms, sleep benefit, dystonia and hyper-reflexia. Dementia is absent. Pathologically, patients show loss of dopaminergic neurons in the substantia nigra, similar to that seen in Parkinson disease; however, Lewy bodies (intraneuronal accumulations of aggregated proteins) are absent.
PRKRADystonia, type 16Dystonia, type 16 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PRKRA gene located on chromosomal region 2q31.2. The age of onset is early. This disease is characterized by progressive limb dystonia, laryngeal and oromandibular dystonia and parkinsonism.
PRMT7Short stature, brachydactyly, intellectual developmental disability, and seizuresShort stature, brachydactyly, intellectual developmental disability, and seizures is an autosomal recessive disease characterized by developmental delay, learning disabilities, mild mental retardation, delayed speech, and skeletal abnormalities. Skeletal features include short stature, brachydactyly, and short metacarpals and metatarsals.
PROCThrombophilia due to protein C deficiency, autosomal recessiveAutosomal recessive protein C deficiency resulting from homozygous or compound heterozygous PROC mutations is a thrombotic condition that can manifest as a severe neonatal disorder or as a milder disorder with late-onset thrombophilia (Millar et al., 2000).
PRODHHyperprolinemia, type 1Hyperprolinemia is an excess of a particular amino acid, called proline, in the blood. This condition generally occurs when proline is not broken down properly by the body. There are two inherited forms of hyperprolinemia, called type I and type II. People with hyperprolinemia type I often do not show any symptoms, although they have proline levels in their blood between 3 and 10 times the normal level. Some individuals with hyperprolinemia type I exhibit seizures, intellectual disability, or other neurological or psychiatric problems.
PROM1Retinitis pigmentosa, type 41Retinitis pigmentosa, type 41 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PROM1 gene located on chromosomal region 4p15.32. The age of onset is early. This disease is characterized by night blindness often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife. The prevalence is 19:100,000-27:100,000.
PROP1Pituitary hormone deficiency, combined, type 2Pituitary hormone deficiency, combined, type 2, genetic forms follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PROP1 gene located on chromosomal region 5q35.3. The age of onset is early. This disease is characterized by short stature, cognitive alterations or delayed puberty.
PROS1Thrombophilia due to protein S deficiency, autosomal recessiveAutosomal recessive thrombophilia due to protein S deficiency is a very rare and severe hematologic disorder resulting in thrombosis and secondary hemorrhage usually beginning in early infancy. Some affected individuals develop neonatal purpura fulminans, multifocal thrombosis, or intracranial hemorrhage (Pung-amritt et al., 1999; Fischer et al., 2010), whereas others have recurrent thromboses later in childhood (Comp et al., 1984).
PRPH2Leber congenital amaurosis 18; Retinitis punctata albescensHomozygous mutation in the PRPH2 gene causes retinal dystrophy of earlier onset, diagnosed clinically as Leber congenital amaurosis (LCA18). Leber congenital amaurosis comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (summary by Chung and Traboulsi, 2009). Heterozygous mutation in the PRPH2 gene has also been reported to cause various retinal disorders with overlapping or related phenotypes, e.g., retinitis pigmentosa, type 7 (RP7), retinitis punctata albescens. Retinitis punctata albescens is characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (Krill and Folk, 1962; Krill, 1977).
PRPS1Deafness, X-linked 1 (DFNX1); Arts syndrome; PRPS1-related disordersThe DFNX1 locus (PRPS1 gene) is associated with phenotypically heterogeneous non-syndromic hearing loss. In general, hearing impairment in male patients with PRPS1 mutations is bilateral, moderate to profound, and can be pre- or post-lingual, progressive or non-progressive. Female carriers may also be affected by unilateral or bilateral hearing impairment. Mutations in PRPS1 might also result in a spectrum of syndromic conditions, including PRS-I superactivity (OMIM #300661), Charcot-Marie Tooth neuropathy type X-5 (CMTX5 or Rosenberg-Chutorian syndrome, OMIM #311070) and Arts syndrome. Arts syndrome is an X-linked disorder characterized by mental retardation, early-onset hypotonia, ataxia, delayed motor development, hearing impairment, and optic atrophy (de Brouwer et al., 2007). In the Arts syndrome, susceptibility to infections, especially of the upper respiratory tract, can result in early death.
PRRX1Agnathia-otocephaly complexAgnathia-otocephaly is a rare condition characterized by mandibular hypoplasia or agnathia, ventromedial auricular malposition (melotia) and/or auricular fusion (synotia), and microstomia with oroglossal hypoplasia or aglossia. Holoprosencephaly is the most commonly identified association, but skeletal, genitourinary, and cardiovascular anomalies, and situs inversus have been reported. The disorder is almost always lethal (Faye-Petersen et al., 2006).
PRSS1Trypsinogen deficiencyTrypsinogen deficiency is a disease characterized by failure to thrive, nutritional edema, hypoproteinemia with normal sweat electrolytes and anal atresia.
PRSS12Mental retardation, autosomal recessive, type 1Mental retardation, autosomal recessive, type 1 is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Non-syndromic mental retardation patients do not manifest other clinical signs.
PRSS56Microphthalmia, isolated, type 6Microphthalmia, isolated, type 6 is a rare distinct phenotype restricted to the posterior segment of the eye. In adults, it is clinically characterized by extreme hyperopia (from +7.5 to +21 diopters) due to short axial length (14 mm to 20 mm; normal is greater than 21 mm). Other features include an essentially normal anterior segment, steep corneal curvatures, shallow anterior chamber, thick lenses, and thickened scleral wall. The palpebral fissures appear narrow because of relatively deep-set eyes, visual acuity is mildly to moderately reduced, and anisometropic or strabismic amblyopia is common. The fundus of the eye shows crowded optical discs, tortuous vessels, and an abnormal foveal avascular zone; in addition, papillomacular folds are often reported. Morphometric features of the small eyes predispose to complications such as narrow-angle glaucoma and uveal effusion (Gal et al., 2011).
PRXCharcot-Marie-Tooth disease, type 4FCharcot-Marie-Tooth disease, type 4F follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PRX gene located on chromosomal region 19q13.2. The age of onset is infantile. This disease is characterized by delayed motor milestones, and proximal and distal muscle weakness. The prevalence is <1:1,000,000.
PSAPCombined SAP deficiencyCombined saposin (SAP) deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PSAP gene located on chromosomal region 10q22.1. The age of onset is neonatal/infancy. This disease is characterized by hypotonia, massive myoclonic bursts, abnormal ocular movements and dystonia. Grand mal seizures and seizures triggered by tactile stimuli have been described. Patients also develop hepatosplenomegaly. Death between 1 and 4 months usually occurs from respiratory failure following repeated pulmonary infections. The prevalence is below 1/1,000,000.
PSAT1Neu-Laxova syndrome, type 2Neu-Laxova syndrome, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PSAT1 gene located on chromosomal region 9q21.2. The age of onset is prenatal. This disease is characterized by severe congenital malformations leading to prenatal or early postnatal lethality. Affected patients have abnormal craniofacial features, microcephaly, intrauterine growth retardation, ichthyosis, flexion deformities, limb malformations, and edema of the hands and feet. Some patients have malformations of the central nervous system. The prevalence is below 1/1,000,000.
PSMB8Autoinflammation, lipodystrophy, and dermatosis syndromeThis autosomal recessive systemic autoinflammatory disorder is characterized by early childhood onset of annular erythematous plaques on the face and extremities with subsequent development of partial lipodystrophy and laboratory evidence of immune dysregulation. More variable features include recurrent fever, severe joint contractures, muscle weakness and atrophy, hepatosplenomegaly, basal ganglia calcifications, and microcytic anemia (Agarwal et al., 2010; Kitamura et al., 2011; Arima et al., 2011).This disorder encompasses Nakajo-Nishimura syndrome (NKJO); joint contractures, muscular atrophy, microcytic anemia, and panniculitis-induced lipodystrophy (JMP syndrome); and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome (CANDLE). Among Japanese patients, this disorder is best described as Nakajo-Nishimura syndrome, since both Nakajo (1939) and Nishimura et al. (1950) contributed to the original phenotypic descriptions.
PSPHPhosphoserine phosphatase deficiencyPhosphoserine phosphatase deficiency is an autosomal recessive disorder that results in pre- and postnatal growth retardation, moderate psychomotor retardation and facial features suggestive of Williams syndrome.
PTHHypoparathyroidism, autosomal recessiveHypoparathyroidism is a clinical disorder characterized by hypocalcemia and hyperphosphatemia. It manifests when parathyroid hormone (PTH; 168450) secreted from the parathyroid glands is insufficient to maintain normal extracellular fluid calcium concentrations or, less commonly, when PTH is unable to function optimally in target tissues, despite adequate circulating levels.Congenital absence of the parathyroid and thymus glands (III and IV pharyngeal pouch syndrome, or DiGeorge syndrome, 188400) is usually a sporadic condition (Taitz et al., 1966).
PTH1RChondrodysplasia, Blomstrand type; Eiken syndromeBlomstrand chondrodysplasia is an autosomal recessive disorder characterized by short limbs, polyhydramnios, hydrops fetalis, facial anomalies, increased bone density, and advanced skeletal maturation (Loshkajian et al., 1997). Eiken syndrome (EISD) is also caused by homozygous mutation in the PTHR1 gene. EISD is a rare skeletal dysplasia characterized by severely retarded ossification, principally of the epiphyses, pelvis, hands and feet, as well as by abnormal modeling of the bones in hands and feet, abnormal persistence of cartilage in the pelvis and mild growth retardation.
PTPRCSevere combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positiveSevere combined immunodeficiency, T cell-negative, B-cell/natural killer-cell positive is a form of severe combined immunodeficiency (SCID), a genetically and clinically heterogeneous group of rare congenital disorders characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development.
PTPRQDeafness, autosomal recessive, type 84ANonsyndromic hearing loss is a partial or total loss of hearing that is not associated with other signs and symptoms. Nonsyndromic hearing loss can be classified by the condition's pattern of inheritance: autosomal dominant (DFNA), autosomal recessive (DFNB), X-linked (DFNX), or mitochondrial (which does not have a special designation). DFNA, DFNB, and DFNX subtypes are numbered in the order in which they were first described. The characteristics vary among the different types. Hearing loss can affect one ear (unilateral) or both ears (bilateral). Degrees of hearing loss range from mild (difficulty understanding soft speech) to profound (inability to hear even very loud noises). The term "deafness" is often used to describe severe-to-profound hearing loss. Hearing loss can be stable, or it may be progressive, becoming more severe as a person gets older. Particular types of nonsyndromic hearing loss show distinctive patterns of hearing loss. Most forms of nonsyndromic hearing loss are described as sensorineural, which means they are associated with a permanent loss of hearing caused by damage to structures in the inner ear.
PTSHyperphenylalaninemia, BH4-deficient, type ATetrahydrobiopterin (BH4)-deficient hyperphenylalaninemia (HPA) comprises a genetically heterogeneous group of progressive neurologic disorders caused by autosomal recessive mutations in the genes encoding enzymes involved in the synthesis or regeneration of BH4. BH4 is a cofactor for phenylalanine hydroxylase (PAH; 612349), tyrosine hydroxylase (TH; 191290) and tryptophan hydroxylase (TPH1; 191060), the latter 2 of which are involved in neurotransmitter synthesis. The BH4-deficient HPAs are characterized phenotypically by hyperphenylalaninemia, depletion of the neurotransmitters dopamine and serotonin, and progressive cognitive and motor deficits (Dudesek et al., 2001). HPABH4A, caused by mutations in the PTS gene, represents the most common cause of BH4-deficient hyperphenylalaninemia (Dudesek et al., 2001). Other forms of BH4-deficient HPA include HPABH4B (233910), caused by mutation in the GCH1 gene (600225), HPABH4C (261630), caused by mutation in the QDPR gene (612676), and HPABH4D (264070), caused by mutation in the PCBD1 gene (126090). Niederwieser et al. (1982) noted that about 1 to 3% of patients with hyperphenylalaninemia have one of these BH4-deficient forms. These disorders are clinically and genetically distinct from classic phenylketonuria (PKU; 261600), caused by mutation in the PAH gene.Two additional disorders associated with BH4 deficiency and neurologic symptoms do not have overt hyperphenylalaninemia as a feature: dopa-responsive dystonia (612716), caused by mutation in the SPR gene (182125), and autosomal dominant dopa-responsive dystonia (DYT5; 128230), caused by mutation in the GCH1 gene. Patients with these disorders may develop hyperphenylalaninemia when stressed.
PUS1Myopathy, lactic acidosis, and sideroblastic anemia, type 1Myopathy, lactic acidosis, and sideroblastic anemia, type 1 is a rare autosomal recessive oxidative phosphorylation disorder specific to skeletal muscle and bone marrow (Bykhovskaya et al., 2004).
PXDNAnterior segment dysgenesis, type 7, with sclerocorneaAnterior segment dysgeneses (ASGD or ASMD) are a heterogeneous group of developmental disorders affecting the anterior segment of the eye, including the cornea, iris, lens, trabecular meshwork, and Schlemm canal. The clinical features of ASGD include iris hypoplasia, an enlarged or reduced corneal diameter, corneal vascularization and opacity, posterior embryotoxon, corectopia, polycoria, an abnormal iridocorneal angle, ectopia lentis, and anterior synechiae between the iris and posterior corneal surface (Cheong et al., 2016).In sclerocornea there is congenital, nonprogressive corneal opacification that may be peripheral, sectoral, or central in location. Visual prognosis is related to the central corneal involvement. The cornea has a flat curvature. The majority of cases are bilateral (Smith and Traboulsi, 2012).Isolated sclerocornea is caused by displacement of the limbal arcades and may be associated with cornea plana; in this condition, the anterior chamber is visible and the eye is not microphthalmic. In complex sclerocornea, however, corneal opacification is associated with microphthalmia, cataract, and/or infantile glaucoma. The central cornea is usually relatively clear, but the thickness is normal or increased, never reduced (Nischal, 2007).
PYCR1Cutis laxa, autosomal recessive, type 2BThe phenotype of autosomal recessive cutis laxa type 2 (ARCL2) includes cutis laxa of variable severity, abnormal growth, developmental delay, and associated skeletal abnormalities (Morava et al., 2009). No specific clinical features distinguish ARCL2A (219200), which includes a glycosylation defect, and ARCL2B, in which abnormal glycosylation has not been reported (Morava et al., 2009; Guernsey et al., 2009).
PYGLGlycogen storage disease, type 6Glycogen storage disease, type 6 is a metabolic disorder which symptoms usually begin in infancy or childhood and include low blood sugar (hypoglycemia), an enlarged liver (hepatomegaly), and an increase in the amount of lactic acid in the blood (lactic acidosis).
PYGMMcArdle diseaseMcArdle disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the PYGM gene located on chromosomal region 11q13.1. The age of onset is infantile. This disease is characterized by muscular exercise intolerance with myalgia, cramps, fatigue, and muscle weakness.
QDPRHyperphenylalaninemia, BH4-deficient, type CHyperphenylalaninemia, BH4-deficient, type C (HPABH4C) is a are autosomal recessive disorder characterized by hyperphenylalaninemia and severe neurologic symptoms (malignant hyperphenylalaninemia) including axial hypotonia and truncal hypertonia, abnormal thermogenesis, and microcephaly. These signs are attributable to depletion of the neurotransmitters dopamine and serotonin, whose syntheses are controlled by tryptophan and tyrosine hydroxylases that use BH-4 as cofactor. Patients do not respond to phenylalanine-restricted diet. HPABH4C is lethal if untreated.
RAB18Warburg micro syndrome, type 3Warburg Micro syndrome is a rare autosomal recessive syndrome characterized by microcephaly, microphthalmia, microcornea, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism (Morris-Rosendahl et al., 2010).
RAB23Carpenter syndromeCarpenter syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAB23 gene located on chromosomal region 6p11.2. The age of onset is early. This disease is characterized by acrocephaly, peculiar facies, brachydactyly and syndactyly in the hands, and preaxial polydactyly and syndactyly of the toes. The prevalence is <1:1,000,000.
RAB27AGriscelli syndrome, type 2Griscelli disease type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAB27A gene located on chromosome 15q15-q21.1. The age of onset is infantile. This disease is characterized by immune system abnormalities in addition to having hypopigmented skin and hair. Affected individuals are prone to recurrent infections. They also develop an immune condition called hemophagocytic lymphohistiocytosis, in which the immune system produces too many activated immune cells called T-lymphocytes and macrophages (histiocytes).
RAB28Cone-rod dystrophy 18Cone-rod dystrophy 18 (CORD18) is form of cone-rod dystrophy, an inherited retinal dystrophy characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors.
RAB39BMental retardation, X-linked, type 72; Waisman syndromeMental retardation, X-linked, type 72 (MRX72) is a disorder characterized by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period. Intellectual deficiency is the only primary symptom of non-syndromic X-linked mental retardation, while syndromic mental retardation presents with associated physical, neurological and/or psychiatric manifestations. MRX72 patients can manifest autism spectrum disorder, seizures and macrocephaly as additional features. Mutations in the RAB39B gene can also caused Waisman syndrome, an X-linked neurologic disorder characterized by delayed psychomotor development, impaired intellectual development, and early-onset Parkinson disease (Wilson et al., 2014).
RAB3GAP1Warburg micro syndrome, type 1Warburg micro syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAB3GAP1 gene located on chromosomal region 2q21.3. The age of onset is infantile. This disease is characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. The prevalence is <1:1,000,000.
RAB3GAP2Martsolf syndromeWarburg micro syndrome type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAB3GAP2 gene located on chromosomal region 1q41. The age of onset is early. This disease is characterized by microcephaly, microphthalmia, microcornia, congenital cataracts, optic atrophy, cortical dysplasia, in particular corpus callosum hypoplasia, severe mental retardation, spastic diplegia, and hypogonadism. The prevalence is <1:1,000,000.
RAG1Omenn syndrome; Severe combined immunodeficiency, B cell-negativeOmenn syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAG1 and RAG2 genes located on chromosomal region 11p12. The age of onset is early. This disease is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency.
Severe combined immunodeficiency, autosomal recessive, T cell-negative (T-), B cell negative (B-), NK cell positive (NK+) is also caused by mutation in the RAG1 and RAG2 genes. This disease is characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Without treatment, patients usually die within the first year of life.
RAG2Omenn syndrome; Severe combined immunodeficiency, B cell-negativeOmenn syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAG1 and RAG2 genes located on chromosomal region 11p12. The age of onset is early. This disease is characterized by erythroderma, desquamation, alopecia, chronic diarrhea, failure to thrive, lymphadenopathy, and hepatosplenomegaly, associated with severe combined immunodeficiency.
Severe combined immunodeficiency, autosomal recessive, T cell-negative (T-), B cell negative (B-), NK cell positive (NK+) is also caused by mutation in the RAG1 and RAG2 genes. This disease is characterized by impairment of both humoral and cell-mediated immunity, leukopenia, and low or absent antibody levels. Patients present in infancy recurrent, persistent infections by opportunistic organisms. The common characteristic of all types of SCID is absence of T-cell-mediated cellular immunity due to a defect in T-cell development. Without treatment, patients usually die within the first year of life.
RAPSNFetal akinesia deformation sequence; Myasthenic syndrome, congenital, 11, associated with AChR deficiencyFetal akinesia deformation sequence follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAPSN gene located on chromosomal region 11p11.2. The age of onset is early. This disease is characterized by multiple joint contractures, facial anomalies and pulmonary hypoplasia. The prevalence is 1:3,000. Congenital myasthenic syndrome associated with AChR deficiency is a disorder of the postsynaptic neuromuscular junction (NMJ) clinically characterized by early-onset muscle weakness with variable severity.
RARS2Pontocerebellar hypoplasia, type 6Pontocerebellar hypoplasia (PCH) is a heterogeneous group of disorders characterized by an abnormally small cerebellum and brainstem and associated with severe developmental delay (Edvardson et al., 2007).
RAXIsolated microphthalmia, type 3Isolated microphthalmia type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RAX gene located on chromosomal region 18q21.32. Microphthalmia designates a heterogeneous group of ocular malformations with a more or less evident reduction in the size of the eyeball. Additional features include high hypermetropia and a short axial length.
RBBP8Jawad syndrome; Seckel syndrome, type 2Jawad syndrome (JWDS) is characterized by congenital microcephaly, moderately severe mental retardation, and symmetrical digital anomalies. Digital malformations of variable degree include hallux valgus, syndactyly of toes 4 and 5, short fifth fingers, single flexion crease of fifth fingers, polydactyly and synpolydactyly. Seckel syndrome, type 2, a microcephaly syndrome involving growth retardation and a characteristic facial appearance, is also caused by mutation in the RBBP8 gene.
RBM10TARP syndromeTARP syndrome is a rare condition affecting males that causes several birth defects. TARP stands for Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava. Those with TARP syndrome have clubfoot deformity (talipes equinovarus) and congenital heart defects involving failure of the upper heart chambers to close (atrial septal defect). The Robin sequence is characterized by a small lower jaw at birth that prevents proper feeding of the infant, followed by a retracted or displaced tongue. A high-arched, cleft soft palate is also commonly seen. Affected individuals also have persistent left superior vena cava. TARP syndrome has been reported to cause death before birth or soon after birth.
RBM8AThrombocytopenia-absent radius syndromeThe thrombocytopenia-absent radius syndrome (TAR) is characterized by reduction in the number of platelets and absence of the radius; preservation of the thumb distinguishes TAR from other syndromes that combine blood abnormalities with absence of the radius, such as Fanconi anemia (227650). Individuals with TAR have low numbers of megakaryocytes, platelet precursor cells that reside in bone marrow, and frequently present with bleeding episodes in the first year of life that diminish in frequency and severity with age. The severity of skeletal anomalies varies from absence of radii to virtual absence of upper limbs, with or without lower limb defects such as malformations of the hip and knee (Albers et al., 2012).
RBP4Retinal dystrophy, iris coloboma, and comedogenic acne syndromeRetinal dystrophy, iris coloboma, and comedogenic acne syndrome is a disease characterized by retinal degeneration, ocular colobomas involving both the anterior and posterior segment, impaired night vision and loss of visual acuity. Additional characteristic features include developmental abnormalities and severe acne.
RD3Leber congenital amaurosis 12Leber congenital amaurosis 12 is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.
RDH12Leber congenital amaurosis, type 13Leber congenital amaurosis type 13 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RDH12 gene located on chromosomal region 14q24.1. The age of onset is early. This disease is characterized by blindness, nystagmus, roving eye movement and lack of detectable signals on an electroretinogram, leading to severe visual impairment within the first year of life.
RDH5Fundus albipunctatusThis form of fleck retina disease is characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (Krill and Folk, 1962; Krill, 1977).
RDXDeafness, autosomal recessive, type 24Autosomal recessive nonsyndromic sensorineural deafness type DFNB24 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RDX gene located on chromosomal region 11q22.3. The age of onset is early. This disease is characterized by hearing loss and deafness, no associated visible abnormalities of the external ear or any related medical problems.
RECQL4Baller-Gerold syndrome; RAPADILINO syndrome; Rothmund-Thomson syndromeMutations in RECQL4 gene cause different type of diseases such as Baller-Gerold syndrome; RAPADILINO syndrome and Rothmund-Thomson syndrome. The cardinal features of the Baller-Gerold syndrome are craniosynostosis and radial aplasia (Galea and Tolmie, 1990). Cases reported as Baller-Gerold syndrome have phenotypic overlap with several other disorders, including Saethre-Chotzen syndrome (SCS; 101400). RAPADILINO syndrome is a rare condition that involves many parts of the body. Bone development is especially affected, causing many of the characteristic features of the condition. Rothmund-Thomson syndrome is rare autosomal recessive disorder characterized by skin atrophy, telangiectasia, hyper- and hypopigmentation, congenital skeletal abnormalities, short stature, premature aging, and increased risk of malignant disease (Simon et al., 2010).
RELNLissencephaly 2 (Norman-Roberts type)Lissencephaly syndrome 2, Norman-Roberts type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RELN gene located on chromosomal region 7q22. The age of onset is early. This disease is characterized by craniofacial anomalies (severe microcephaly, a low sloping forehead, a broad and prominent nasal bridge and widely set eyes) and postnatal growth retardation, severe intellectual deficit, spasticity and epilepsy. The prevalence is 1:1,000,000-9:1,000,000.
RENRenal tubular dysgenesisRenal tubular dysgenesis deficiency follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in REN gene located on chromosomal region 1q32.1. The age of onset is fetal. This disease is characterized by absent or poorly developed proximal tubules of the kidneys, persistent oligohydramnios, leading to Potter sequence, and skull ossification defects.
RETREG1Neuropathy, hereditary sensory and autonomic, type 2BNeuropathy, hereditary sensory and autonomic, type 2B is an autosomal recessive neurologic disorder characterized by early childhood onset of distal sensory impairment usually resulting in ulceration and associated with variable autonomic features, such as hyperhidrosis and urinary incontinence. Some patients may show impaired gait (Ilgaz Aydinlar et al., 2014).HSAN2A is caused by mutation in the HSN2 isoform of the WNK1 gene.
RFX6Mitchell-Riley syndromeMitchell-Riley syndrome is characterized by neonatal diabetes, pancreatic hypoplasia, intestinal atresia, and gallbladder aplasia or hypoplasia. There is considerable phenotypic overlap between Mitchell-Riley syndrome and Martinez-Frias syndrome (601346), the latter being characterized by the features of the Mitchell-Riley syndrome except for neonatal diabetes, and including tracheoesophageal fistula in some patients (Smith et al., 2010).
RFXANKBare lymphocyte syndrome, type 2, complementation group BBare lymphocyte syndrome type 2 is a severe combined immunodeficiency disease with early onset. It is characterized by a profound defect in constitutive and interferon- gamma induced MHC II expression, absence of cellular and humoral T- cell response to antigen challenge, hypogammaglobulinemia and impaired antibody production. The consequence include extreme susceptibility to viral, bacterial and fungal infections.
RGRRetinitis pigmentosa, type 44Retinitis pigmentosa type 44 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RGR gene located on chromosomal region 10q23.1. The age of onset is variable. This disease is characterized by night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife. The prevalence is 1:10,000-5:10,000.
RHORetinitis pigmentosa, type 4, autosomal recessive; Fundus albipunctatusRetinitis pigmentosa type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RHO gene located on chromosomal region 3q22.1. The age of onset is variable. This disease is characterized by night blindness (nyctalopia) due to loss of rod function, often in adolescence or earlier. They then develop peripheral visual field impairment, and overtime loss of central vision, usually at late stages, often around midlife. The prevalence is 1:10,000-5:10,000. Mutation in the RHO gene can also cause fundus albipunctatus, a form of fleck retina disease characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (Krill and Folk, 1962; Krill, 1977).
RIN2Macs syndromeMacs syndrome is characterized by macrocephaly, alopecia, cutis laxa (a connective tissue disorder characterized by skin that is sagging and not stretchy), scoliosis (an abnormal curvature of the spine, usually in an elongated "s" or "C" shape), and occasionally by life-threatening visceral complications.
RIPK4Popliteal pterygium syndrome, Bartsocas-Papas typeBartsocas-Papas syndrome (lethal popliteal pterygium syndrome) is an autosomal recessive disorder characterized by multiple popliteal pterygia, ankyloblepharon, filiform bands between the jaws, cleft lip and palate, and syndactyly. Early lethality is common, although survival into childhood and beyond has been reported (Mitchell et al., 2012).A less severe form of popliteal pterygium syndrome (119500) is caused by mutation in the IRF6 gene (607199).
RLBP1Bothnia retinal dystrophy; Fundus albipunctatusBothnia retinal dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RLBP1 gene located on chromosomal region 15q26.1. This disease is characterized by night blindness from early childhood with features consistent with retinitis punctata albescens and macular degeneration. The prevalence is unknown. Mutation in the RLBP1 gene can also cause fundus albipunctatus, a form of fleck retina disease characterized by discrete uniform white dots over the entire fundus with greatest density in the midperiphery and no macular involvement. Night blindness occurs. Both autosomal dominant and autosomal recessive inheritance had been suggested (Krill and Folk, 1962; Krill, 1977).
RMRPAnauxetic dysplasia, type 1Anauxetic dysplasia, type 1 is a form of spondylometaepiphyseal dysplasia characterized by the prenatal onset of extreme short stature, an adult height of less than 85 cm, hypodontia, and mild mental retardation. Major radiographic characteristics are late-maturing ovoid vertebral bodies with concave dorsal surfaces in the lumbar region; small capital femoral epiphyses; hypoplastic femoral necks; hypoplastic iliac bodies and shallow acetabulae; irregular metaphyseal mineralization and demarcation of the long tubular bones; short first and fifth metacarpals with widened shafts; very short and broad phalanges with small, late-ossifying epiphyses and bullet-shaped middle phalanges; and midface hypoplasia. The number of chondrocytes is severely reduced in the resting and proliferating cartilage, with diminished columnization of the hypertrophic zone (Thiel et al., 2005).Mutations in RMRP also cause 2 milder types of short stature with susceptibility to cancer, cartilage-hair hypoplasia (CHH; 250250) and metaphyseal dysplasia without hypotrichosis (250460).
RNASEH2AAicardi-Goutieres syndrome 4Aicardi-Goutieres syndrome 4 is an autosomal recessive disorder characterized by onset of encephalopathy in the first year of life following normal early development. Affected infants typically show extreme irritability, intermittent unexplained fever, chilblains, progressive microcephaly, spasticity, dystonia, and profound psychomotor retardation. Laboratory studies show lymphocytosis and raised titers of alpha-interferon in the cerebrospinal fluid. Brain imaging may show white matter abnormalities, intracerebral calcifications, and cerebral atrophy. Many patients die in childhood (Vogt et al., 2013).
RNASEH2BAicardi-Goutieres syndrome 2Aicardi-Goutieres syndrome 2 is an autosomal recessive disorder characterized by onset of encephalopathy in the first year of life following normal early development. Affected infants typically show extreme irritability, intermittent unexplained fever, chilblains, progressive microcephaly, spasticity, dystonia, and profound psychomotor retardation. Laboratory studies show lymphocytosis and raised titers of alpha-interferon in the cerebrospinal fluid. Brain imaging may show white matter abnormalities, intracerebral calcifications, and cerebral atrophy. Many patients die in childhood (Vogt et al., 2013).
RNASEH2CAicardi-Goutieres syndrome 3Aicardi-Goutieres syndrome 3 is an autosomal recessive disorder characterized by onset of encephalopathy in the first year of life following normal early development. Affected infants typically show extreme irritability, intermittent unexplained fever, chilblains, progressive microcephaly, spasticity, dystonia, and profound psychomotor retardation. Laboratory studies show lymphocytosis and raised titers of alpha-interferon in the cerebrospinal fluid. Brain imaging may show white matter abnormalities, intracerebral calcifications, and cerebral atrophy. Many patients die in childhood (Vogt et al., 2013).
RNF168RIDDLE syndromeRiddle syndrome is an autosomal recessive disease characterized by increased radiosensitivity, immunodeficiency, mild motor control and learning difficulties, facial dysmorphism, and short stature.
ROBO3Gaze palsy, familial horizontal, with progressive scoliosis, type 1Gaze palsy, familial horizontal, with progressive scoliosis, type 1 (HGPPS) is an autosomal recessive neurologic disorder characterized by eye movement abnormalities apparent from birth and childhood-onset progressive scoliosis. These features are associated with a developmental malformation of the brainstem including hypoplasia of the pons and cerebellar peduncles and defective decussation of certain neuronal systems. Cognitive function is normal (Bosley et al., 2005).
ROGDIKohlschutter-Tonz syndromeKohlschutter-Tonz syndrome is an autosomal recessive disorder characterized by severe global developmental delay, early-onset intractable seizures, spasticity, and amelogenesis imperfecta affecting both primary and secondary teeth and causing yellow or brown discoloration of the teeth. Although the phenotype is consistent, there is variability. Intellectual disability is related to the severity of seizures, and the disorder can thus be considered an epileptic encephalopathy. Some infants show normal development until seizure onset, whereas others are delayed from birth. The most severely affected individuals have profound mental retardation, never acquire speech, and become bedridden early in life (Schossig et al., 2012; Mory et al., 2012).
ROM1Retinitis pigmentosa, type 7, digenicRetinitis pigmentosa, type 7 (RP7) is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.
ROR2Robinow syndrome, autosomal recessiveRobinow syndrome, autosomal recessive is a severe skeletal dysplasia characterized by dysmorphic facial features, including frontal bossing, hypertelorism, and broad nose, short-limbed dwarfism, vertebral segmentation, and genital hypoplasia (van Bokhoven et al., 2000).
RP1Retinitis pigmentosa, type 1Retinitis pigmentosa, type 1 is a retinal dystrophy belonging to the group of pigmentary retinopathies. Retinitis pigmentosa is characterized by retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.
RP2Retinitis pigmentosa, type 2, X-linkedRetinitis pigmentosa type 2 (RP2) follows an X-linked (XLRP) pattern of inheritance and is caused by pathogenic variants in the RP2 gene located on chromosomal region Xp11.23. The age of onset is variable. This condition primarily affects males, causing night blindness in early childhood followed by progressive daytime vision loss. RP2 gene mutations account for 10 to 15 percent of all cases of X-linked retinitis pigmentosa. A gradual loss of photoreceptors underlies the progressive vision loss characteristic of retinitis pigmentosa (RP). The prevalence of RP2 is 1:3,500.
RPE65Leber congenital amaurosis, type 2Leber congenital amaurosis 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RPE65 gene located on chromosomal region 1p31.3-p31.2. The age of onset is variable. This disease is characterized by a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.
RPGRRetinitis pigmentosa, type 3, X-linkedRetinitis pigmentosa type 3 (RP3) follows an X-linked (XLRP) pattern of inheritance and is caused by pathogenic variants in the RPGR gene located on chromosomal region Xp11.4. XLRP are severe forms of inherited retinal degeneration that primarily affects the rod photoreceptors (Demirci et al., 2002). It typically causes an early-onset night blindness and loss of peripheral vision, often causing patients to become legally blind by the age of 30 to 40 years. Mutation in the RPGR gene is believed to account for approximately 70% of XLRP (RP3)(Vervoort et al., 2000). In RP3, affected males have a severe phenotype, and carrier females show a wide spectrum of clinical features ranging from completely asymptomatic to severe RP (Jin et al., 2007). Mutations in the RPGR gene can also cause X-linked cone-rod dystrophy (CORDX1; 304020) and a syndromic form of retinitis pigmentosa (RP) with deafness and sinorespiratory infections (300455). Cone-rod dystrophy is a group of related [to RP] eye disorders that causes vision loss, which becomes more severe over time. These disorders affect the retina, which is the layer of light-sensitive tissue at the back of the eye. In people with cone-rod dystrophy, vision loss occurs as the light-sensing cells of the retina gradually deteriorate. X-linked cone-rod dystrophy is a rare, progressive visual disorder primarily affecting cone photoreceptors (Demirci et al., 2002). Affected individuals, essentially all of whom are males, present with decreased visual acuity, myopia, photophobia, abnormal color vision, full peripheral visual fields, decreased photopic electroretinographic responses, and granularity of the macular retinal pigment epithelium. The degree of rod photoreceptor involvement is variable, with increasing degeneration. Although penetrance appears to be nearly 100%, there is variable expressivity with respect to age at onset, severity of symptoms, and findings (Hong et al., 1994).
RPGRIP1Leber congenital amaurosis 6Leber congenital amaurosis 6 comprises a group of early-onset childhood retinal dystrophies characterized by vision loss, nystagmus, and severe retinal dysfunction. Patients usually present at birth with profound vision loss and pendular nystagmus. Electroretinogram (ERG) responses are usually nonrecordable. Other clinical findings may include high hypermetropia, photodysphoria, oculodigital sign, keratoconus, cataracts, and a variable appearance to the fundus (Chung and Traboulsi, 2009).
RPGRIP1LJoubert syndrome, type 7; Meckel syndrome, type 5; COACH syndromeJoubert syndrome (JBTS) type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the RPGRIP1L gene located on chromosomal region 16q12.2. The age of onset is early. JBTS is characterized by congenital malformation of the brainstem and agenesis of the cerebellar vermis (molar tooth sign) leading to an abnormal respiratory pattern, nystagmus, hypotonia, mental retardation, ataxia, and delay in achieving motor milestones. Other variable features include retinal dystrophy (less common in JBTS7) and nephronophthisis (usually juvenile). The prevalence is 1:100,000. RPGRIP1L gene is also associated with Meckel syndrome type 5, a rare, autosomal recessive lethal condition characterized by central nervous system malformations, postaxial, polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. Other phenotype associated is COACH syndrome, an autosomal recessive disorder characterized by mental retardation, ataxia due to cerebellar hypoplasia, and hepatic fibrosis. Other features, such as coloboma and renal cysts, may be variable. COACH syndrome is considered by some to be a subtype of Joubert syndrome with congenital hepatic fibrosis.
RPL10Mental retardation, X-linked, syndromic, type 35Mental retardation, X-linked, syndromic, type 35 (MRXS35) is a mental retardation syndrome characterized by intellectual deficit, delayed psychomotor development, poor speech, and dysmorphic features. Mental retardation is defined by significantly below average general intellectual functioning associated with impairments in adaptive behavior and manifested during the developmental period.
RPS6KA3Mental retardation, X-linked, type 19X-linked mental retardation, type 19 (MRX19) is a nonsyndromic form of mild to moderate mental retardation. Carrier females may be mildly affected. Mutation in the RPS6KA3 gene also causes Coffin-Lowry syndrome (CLS; 303600), a mental retardation syndrome with dysmorphic facial features and skeletal anomalies. Some patients with RPS6KA3 mutations have an intermediate phenotype with mental retardation and only mild anomalies reminiscent of CLS. These individuals have mutations resulting in some residual protein function, which likely explains the milder phenotype (Field et al., 2006).
RRM2BMitochondrial DNA depletion syndrome, type 8A (encephalomyopathic type with renal tubulopathy) and type 8B (MNGIE type)Mitochondrial DNA depletion syndrome, type 8A is a severe autosomal recessive disorder characterized by neonatal hypotonia, lactic acidosis, and neurologic deterioration. Renal tubular involvement may also occur (Bourdon et al., 2007). Mitochondrial DNA depletion syndrome, type 8B is characterized by ophthalmoplegia, ptosis, gastrointestinal dysmotility, cachexia, peripheral neuropathy, and brain MRI changes, known as the MNGIE phenotype (Shaibani et al., 2009).
RS1RetinoschisisX-linked retinoschisis (XLRS) is a retinal dystrophy that leads to schisis (splitting) of the neural retina leading to reduced visual acuity in affected men. The condition accounts for almost all congenital retinoschisis, with occasional reports of autosomal dominant retinoschisis (180270) making up the remainder. The split in the retina occurs predominantly within the inner retinal layers and is very different from retinal detachment, which is a split between the neural retina and the retinal pigment epithelium. In general, carrier females remain asymptomatic (Sikkink et al., 2007).
RSPH4ACiliary dyskinesia, primary, type 11Ciliary dyskinesia, primary, type 11 (CILD11) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit situs inversus, due to dysfunction of monocilia at the embryonic node and randomization of left-right body asymmetry. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome.
RSPH9Ciliary dyskinesia, primary, type 12Ciliary dyskinesia, primary, type 12 (CILD12) is a disorder characterized by abnormalities of motile cilia. Respiratory infections leading to chronic inflammation and bronchiectasis are recurrent, due to defects in the respiratory cilia; reduced fertility is often observed in male patients due to abnormalities of sperm tails. Half of the patients exhibit situs inversus, due to dysfunction of monocilia at the embryonic node and randomization of left-right body asymmetry. Primary ciliary dyskinesia associated with situs inversus is referred to as Kartagener syndrome.
RSPO4Anonychia congenitaCongenital anonychia is defined as the absence of fingernails and toenails. Anonychia and its milder phenotypic variant, hyponychia, usually occur as a feature of genetic syndromes, in association with significant skeletal and limb anomalies. Isolated nonsyndromic congenital anonychia/hyponychia is a rare entity that usually follows autosomal recessive inheritance with variable expression, even within a given family. The nail phenotypes observed range from no nail field to a nail field of reduced size with an absent or rudimentary nail (Bruchle et al., 2008). This form of nail disorder is referred to here as nonsyndromic congenital nail disorder-4 (NDNC4).
RTEL1Dyskeratosis congenita, autosomal recessive 5Dyskeratosis congenita (DKC) is a bone marrow failure syndrome characterized by severely shortened telomeres and diverse clinical symptoms. The classic presentation of DKC includes nail dystrophy, abnormal skin pigmentation, and oral leukoplakia. Hoyeraal-Hreidarsson syndrome (HHS) is a severe clinical variant of DKC that is characterized by intrauterine growth failure, microcephaly, developmental delay, immunodeficiency, bone marrow failure, and cerebellar hypoplasia. Patients with mutations in the RTEL1 gene tend to present with HHS (summary by Walne et al., 2013).
RYR1Minicore myopathy with external ophthalmoplegiaMultiminicore disease (MMD) is an inherited neuromuscular disorder defined pathologically by the presence of multiple areas of reduced mitochondrial oxidative activity running along a limited extent of the longitudinal axis of the muscle fiber, so-called 'minicores.' These regions show sarcomere disorganization and mitochondria depletion. Typically, no dystrophic signs, such as muscle fiber necrosis or regeneration or significant endomysial fibrosis, are present. MMD is a pathologic diagnosis and shows clinical and genetic heterogeneity. Affected individuals have clinical features of a congenital myopathy, including neonatal hypotonia, delayed motor development, and generalized muscle weakness and amyotrophy, which may progress slowly or remain stable (Ferreiro and Fardeau, 2002).Patients with recessive mutations in the RYR1 gene typically show severe congenital muscular dystrophy with ophthalmoplegia, although there is phenotypic variability. Some patients may present in utero with fetal akinesia, arthrogryposis, and lung hypoplasia resulting in fetal or perinatal death (McKie et al., 2014). Skeletal muscle biopsy of patients with recessive RYR1 mutations show variable features, including central cores (Jungbluth et al., 2007), congenital fiber-type disproportion (CFTD) (Monnier et al., 2009), and centronuclear myopathy (Wilmshurst et al., 2010).
SACSSpastic ataxia, Charlevoix-Saguenay, typeSpastic ataxia, Charlevoix-Saguenay type follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SACS gene located on chromosomal region 13q11. The age of onset is early. This disease is characterized by early-onset cerebellar ataxia with spasticity, a pyramidal syndrome and peripheral neuropathy. The prevalence is 1:1,500-1:2,000.
SAGOguchi disease, type 1Oguchi disease type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SAG gene located on chromosomal region 2q37. The age of onset is infantile. This disease is characterized by congenital stationary night blindness and the Mizuo-Nakamura phenomenon which is a unique morphological and functional abnormality of the retina that presents with a typical golden-yellow or silver-gray discoloration of the fundus in the presence of light that disappears after dark-adaptation and appears again after the onset of light.
SAMHD1Aicardi-Goutieres syndrome 5Aicardi-Goutieres syndrome 5 is a form of Aicardi-Goutieres syndrome, a genetically heterogeneous disease characterized by cerebral atrophy, leukoencephalopathy, intracranial calcifications, chronic cerebrospinal fluid (CSF) lymphocytosis, increased CSF alpha-interferon, and negative serologic investigations for common prenatal infection. Clinical features as thrombocytopenia, hepatosplenomegaly and elevated hepatic transaminases along with intermittent fever may erroneously suggest an infective process. Severe neurological dysfunctions manifest in infancy as progressive microcephaly, spasticity, dystonic posturing and profound psychomotor retardation. Death often occurs in early childhood.
SAR1BChylomicron retention diseaseChylomicron retention disease is an autosomal recessive disorder of severe fat malabsorption associated with failure to thrive in infancy (Dannoura et al., 1999).
SARS2Hyperuricemia, pulmonary hypertension, renal failure, and alkalosisHUPRA syndrome is a severe autosomal recessive multisystem disorder characterized by onset in infancy of progressive renal failure leading to electrolyte imbalances, metabolic alkalosis, pulmonary hypertension, hypotonia, and delayed development. Affected individuals are born prematurely (Belostotsky et al., 2011).
SBDSShwachman-Diamond syndromeShwachman-Diamond syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SBDS gene located on chromosomal region 7q11.21. The age of onset is infantile. This disease is characterized by chronic and usually mild neutropenia, pancreatic exocrine insufficiency associated with steatorrhea and growth failure, skeletal dysplasia with short stature, and an increased risk of bone marrow aplasia or leukemic transformation, cutaneous (eczema or ichthyosis) and dental anomalies, and psychomotor retardation. The prevalence is 1:76,000 newborn.
SBF2Charcot-Marie-Tooth disease, type 4B2Charcot-Marie-Tooth disease, type 4B2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SBF2 gene located on chromosomal region 11p15.4. The age of onset is infantile. This disease is characterized by muscle weakness, sensory loss, reduced nerve conduction velocities, characteristic myelin outfoldings and a severe disease course.
SC5DLathosterolosisLathosterolosis follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SC5D gene located on chromosomal region 11q23.3. The age of onset is early. This disease is characterized by malformations, intellectual deficit and liver disease. The prevalence is <1:1,000,000.
SCARB2Epilepsy, progressive myoclonic, type 4, with or without renal failureThe action myoclonus-renal failure syndrome is an autosomal recessive progressive myoclonic epilepsy associated with renal failure. Cognitive function is preserved (Badhwar et al., 2004). Some patients do not develop renal failure (Dibbens et al., 2009).
SCARF2Van den Ende-Gupta syndromeVan den Ende-Gupta syndrome is an autosomal recessive disorder characterized by severe contractual arachnodactyly from birth and distinctive facial dysmorphism, including triangular face, malar hypoplasia, narrow nose, everted lips, and blepharophimosis. Skeletal anomalies include slender ribs, hooked clavicles, and dislocated radial head. There is no neurologic involvement (Patel et al., 2014).
SCN1BEpileptic encephalopathy, early infantile, type 52Epileptic encephalopathy, early infantile, type 52 (EIEE52) is an autosomal recessive seizure disorder characterized by infantile onset of refractory seizures with resultant delayed global neurologic development that causes intellectual disability and other persistent neurologic abnormalities (Patino et al., 2009).
SCN4AMyasthenic syndrome, congenital, type 16Congenital myasthenic syndrome, type 16 is a disorder characterized by variable degrees of muscle fatigability caused by impaired transmission of electrical signals at the neuromuscular junction (NMJ) (Arnold et al., 2015).
SCN9AIndifference to pain and autosomal recessive hereditary sensory neuropathy type 2DCongenital indifference to pain is a rare autosomal recessive disorder characterized by the complete absence of pain perception typically associated with noxious stimuli. Affected individuals are aware of a stimulus, but have lost the ability to perceive pain. Most patients are hyposmic or anosmic. Other sensory modalities are unaffected, and there is an absence of overt autonomic symptoms. Sural nerve biopsy and nerve conduction velocity studies are normal (Cox et al., 2006; Goldberg et al., 2012). Hereditary sensory and autonomic neuropathy type 2D (HSAN2D) is an autosomal recessive disorder characterized by congenital or childhood-onset distal loss of pain and temperature sensation as well as autonomic dysfunction accompanied by hyposmia, hearing loss, hypogeusia, and sometimes bone dysplasia. The phenotype is highly variable, even within families. Two Japanese families have been reported (Yuan et al., 2013).
SCNN1APseudohypoaldosteronism, type 1Pseudohypoaldosteronism type 1, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SCNN1A (12p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12) genes. The age of onset is early. This disease is characterized by severe dehydration, vomiting and failure to thrive occurring in the first weeks of life, the clinical picture may be complicated by cardiac dysrhythmias, collapse, shock or cardiac arrest.
SCNN1BPseudohypoaldosteronism, type 1Pseudohypoaldosteronism type 1, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SCNN1A (12p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12) genes. The age of onset is early. This disease is characterized by severe dehydration, vomiting and failure to thrive occurring in the first weeks of life, the clinical picture may be complicated by cardiac dysrhythmias, collapse, shock or cardiac arrest.
SCNN1GPseudohypoaldosteronism, type 1Pseudohypoaldosteronism type 1, follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SCNN1A (12p13), SCNN1B (16p12.2-p12.1) and SCNN1G (16p12) genes. The age of onset is early. This disease is characterized by severe dehydration, vomiting and failure to thrive occurring in the first weeks of life, the clinical picture may be complicated by cardiac dysrhythmias, collapse, shock or cardiac arrest.
SCO1Mitochondrial complex IV deficiencyComplex IV (cytochrome c oxidase) is the terminal enzyme of the respiratory chain and consists of 13 polypeptide subunits, 3 of which are encoded by mitochondrial DNA. The 3 mitochondrially encoded proteins in the cytochrome oxidase complex are the actual catalytic subunits that carry out the electron transport function (Saraste, 1983). Shoubridge (2001) provided a comprehensive review of cytochrome c oxidase deficiency and noted that most isolated COX deficiencies are inherited as autosomal recessive disorders caused by mutations in nuclear-encoded genes; mutations in the mtDNA-encoded COX subunit genes are relatively rare.
SCO2Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency, type 1Cardioencephalomyopathy due to cytochrome c oxidase deficiency is an autosomal recessive mitochondrial disorder characterized by onset of cardiomyopathy either in utero or in the first days of life. Most patients also show neurologic abnormalities, such as abnormal breathing pattern, nystagmus, and gyral abnormalities, consistent with encephalopathy. The disorder is usually fatal in early infancy (Papadopoulou et al., 1999).
SDCCAG8Bardet-Biedl syndrome, type 16Bardet-Biedl syndrome 16 (BBS16) is an autosomal recessive ciliopathy characterized by retinal degeneration, obesity, renal disease, and cognitive impairment. Although polydactyly is considered a primary feature of BBS overall, it has not been reported in any BBS16 patient (Billingsley et al., 2012).
SDHAMitochondrial respiratory chain complex II deficiency; Leigh syndromeMitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (Jain-Ghai et al., 2013). Mutation in SDHA gene also causes Leigh syndrome. Leigh syndrome is a clinically and genetically heterogeneous disorder resulting from defective mitochondrial energy generation. It most commonly presents as a progressive and severe neurodegenerative disorder with onset within the first months or years of life, and may result in early death. Affected individuals usually show global developmental delay or developmental regression, hypotonia, ataxia, dystonia, and ophthalmologic abnormalities, such as nystagmus or optic atrophy. The neurologic features are associated with the classic findings of T2-weighted hyperintensities in the basal ganglia and/or brainstem on brain imaging. Leigh syndrome can also have detrimental multisystemic affects on the cardiac, hepatic, gastrointestinal, and renal organs. Biochemical studies in patients with Leigh syndrome tend to show increased lactate and abnormalities of mitochondrial oxidative phosphorylation. Thus, Leigh syndrome may be a clinical feature of a primary deficiency of any of the mitochondrial respiratory chain complexes: complex I deficiency (OMIM 252010), complex II deficiency (OMIM 252011), complex III deficiency (OMIM 124000), complex IV deficiency (cytochrome c oxidase; OMIM 220110), or complex V deficiency (OMIM 604273) (summary by Lake et al., 2015).
SDHAF1Mitochondrial complex II deficiencyMitochondrial complex II deficiency is an autosomal recessive disorder with a highly variable phenotype. Some patients have multisystem involvement of the brain, heart, muscle, liver, and kidneys resulting in death in infancy, whereas others have only isolated cardiac or muscle involvement with onset in adulthood and normal cognition. Measurement of complex II activity in muscle is the most reliable means of diagnosis; however, there is no clear correlation between residual complex II activity and severity or clinical outcome. In some cases, treatment with riboflavin may have clinical benefit (Jain-Ghai et al., 2013).
SEC23ACraniolenticulosutural dysplasiaCraniolenticulosutural dysplasia is an autosomal recessive disorder characterized by facial dysmorphism, late-closing fontanels, cataract, and skeletal defects (Boyadjiev et al., 2011).
SEC23BDyserythropoietic anemia, congenital, type 2Dyserythropoietic anemia, congenital, type 2 is an autosomal recessive blood disorder characterized by hepatosplenomegaly, gallbladder stones, and a milder form of anemia. After 20 years of age, some affected people develop iron overload.
SECISBP2Thyroid hormone metabolism, abnormalThyroid hormone metabolism, abnormal is a rare, genetic congenital hypothyroidism disorder characterized by mild global developmental delay in childhood, short stature, delayed bone age, and abnormal thyroid and selenium levels in serum (high total and free T4 concentrations, low T3, high reverse T3, normal to high TSH, decreased selenium). Intellectual disability, primary infertility, hypotonia, muscle weakness, and impaired hearing have also been reported.
SELENONMuscular dystrophy, rigid spine, type 1Rigid spine syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SELENON gene located on chromosomal region 1p36.11. The age of onset is infantile. This disease is characterized by contractures of the spinal extensor muscles associated with abnormal posture (limitation of neck and trunk flexure), progressive scoliosis of the spine, early marked cervico-axial muscle weakness with relatively preserved strength and function of the extremities and progressive respiratory insufficiency. The prevalence is 3.5:100,000–5:100,000.
SEMA4ACone-rod dystrophy, type 10; Retinitis pigmentosa, type 35Cone-rod dystrophy, type 10 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SEMA4A gene located on chromosomal region 1q22. The age of onset is childhood/adolescent. This disease is characterized by retinal pigment deposits visible on fundus examination, predominantly in the macular region, and initial loss of cone photoreceptors followed by rod degeneration. This leads to decreased visual acuity and sensitivity in the central visual field, followed by loss of peripheral vision. Severe loss of vision occurs earlier than in retinitis pigmentosa, due to cone photoreceptors degenerating at a higher rate than rod photoreceptors. The prevalence is 1-9/100,000. Retinitis pigmentosa-35 (RP35) can be caused by compound heterozygous mutation in the SEMA4A gene. RP35 is characterized by retinal pigment deposits and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Patients typically have night vision blindness and loss of midperipheral visual field. As their condition progresses, they lose their far peripheral visual field and eventually central vision as well.
SEPSECSPontocerebellar hypoplasia, type 2DPontocerebellar hypoplasia, type 2D (PCH2D) is an autosomal recessive disorder characterized by progressive microcephaly, postnatal onset of progressive atrophy of the cerebrum and cerebellum, profound mental retardation, spasticity, and variable seizures (Ben-Zeev et al., 2003).
SERPINC1Thrombophilia due to antithrombin III deficiencyDeficiency of antithrombin III is a major risk factor for venous thromboembolic disease. Two categories of AT-III deficiency have been defined on the basis of AT-III antigen levels in the plasma of affected individuals. The majority of AT-III deficiency families belong in the type I (classic) deficiency group and have a quantitatively abnormal phenotype in which antigen and heparin cofactor levels are both reduced to about 50% of normal. The second category of AT-III deficiency has been termed type II (functional) deficiency. Affected individuals from these kindreds produce dysfunctional AT-III molecules; they have reduced heparin cofactor activity levels (about 50% of normal) but levels of AT-III antigen are often normal or nearly normal (Bock and Prochownik, 1987).The 2 categories of antithrombmin III deficiency have been classified further. Type I (low functional and immunologic antithrombin) has been subdivided into subtype Ia (reduced levels of normal antithrombin), and type Ib (reduced levels of antithrombin and the presence of low levels of a variant). Type II (low functional but normal immunologic antithrombin) has been subdivided into subtype IIa (functional abnormalities affecting both the reactive site and the heparin-binding site of AT3); subtype IIb (functional abnormalities limited to the reactive site); and subtype IIc (functional abnormalities limited to the heparin-binding site) (Lane et al., 1992).
SERPINE1Plasminogen activator inhibitor-1 deficiencyPlasminogen inhibitor-1 deficiency is a rare autosomal recessive hematologic disorder characterized by increased bleeding after trauma, injury, or surgery. Affected females have menorrhagia. The bleeding defect is due to increased fibrinolysis of fibrin blood clots due to deficiency of PAI1, which inhibits tissue (PLAT; 173370) and urinary (PLAU; 191840) activators of plasminogen (PLG; 173350) (Mehta and Shapiro, 2008).
SERPINF1Osteogenesis imperfecta, type 6Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type 6 is a severe autosomal recessive form of the disorder (Glorieux et al., 2002; Becker et al., 2011).
SERPING1Angioedema, hereditary, types 1 and 2Hereditary angioedema (HAE) is an autosomal dominant disorder characterized by episodic local subcutaneous edema and submucosal edema involving the upper respiratory and gastrointestinal tracts. There are 2 classic types of the disorder. In type 1, representing 85% of patients, serum levels of C1NH are less than 35% of normal (Cicardi and Agostoni, 1996; Bowen et al., 2001). In type 2, the levels are normal or elevated, but the protein is nonfunctional. The 2 types are clinically indistinguishable.
SERPINH1Osteogenesis imperfecta, type 10Osteogenesis imperfecta (OI) comprises a group of connective tissue disorders characterized by bone fragility and low bone mass. The disorder is clinically and genetically heterogeneous. OI type 10 is an autosomal recessive form characterized by multiple bone deformities and fractures, generalized osteopenia, dentinogenesis imperfecta, and blue sclera (Christiansen et al., 2010).
SETXSpinocerebellar ataxia, autosomal recessive, type 1Spinocerebellar ataxia with axonal neuropathy type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SETX gene located on chromosomal region 9q34.13. The age of onset is infantile. This disease is characterized by progressive cerebellar ataxia, axonal sensorimotor neuropathy with oculomotor apraxia, fixation instability, extrapyramidal features and an elevated serum alpha-fetoprotein level. The prevalence is 4:100,000-8:100,000.
SFTPBSurfactant metabolism dysfunction, pulmonary, type 1Inborn errors of pulmonary surfactant metabolism are genetically heterogeneous disorders resulting in severe respiratory insufficiency or failure in full-term neonates or infants. These disorders are associated with various pathologic entities, including pulmonary alveolar proteinosis (PAP), desquamative interstitial pneumonitis (DIP), or cellular nonspecific interstitial pneumonitis (NSIP) (Clark and Clark, 2005).A clinically similar disorder characterized by respiratory distress (267450) can affect preterm infants, who show developmental deficiency of surfactant.Acquired PAP (610910) is an autoimmune disorder characterized by the presence of autoantobodies to CSF2 (138960).
SGCALimb-girdle muscular dystrophy, type 3 (LGMD R3)Autosomal recessive limb-girdle muscular dystrophy type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SGCA gene located on chromosomal region 4q12. The age of onset is variable. This disease is characterized by limb-girdle weakness and calf pseudohypertrophy. The prevalence is 1:1,000,000-9:1,000,000.
SGCBLimb-girdle muscular dystrophy, type 4 (LGMD R4)Autosomal recessive limb-girdle muscular dystrophy type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SGCB gene located on chromosomal region 4q12. The age of onset is variable. This disease is characterized by limb-girdle weakness, particularly of the pelvic girdle muscles.
SGCDLimb-girdle muscular dystrophy, type 6 (LGMD R6)Muscular dystrophy, limb-girdle, type 2F (LGMD2F) is an autosomal recessive form of limb-girdle muscular dystrophy characterized by a variable age of onset of progressive weakness and wasting of the proximal skeletal muscles of the shoulder and pelvic girdles, frequently associated with progressive respiratory muscle impairment and cardiomyopathy. Calf hypertrophy, muscle cramps and elevated serum creatine kinase levels are also observed. Neuropsychomotor development is usually normal.
SGCGLimb-girdle muscular dystrophy, type 5 (LGMD R5)Autosomal recessive limb-girdle muscular dystrophy type 5 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SGCG gene located on chromosomal region 13q12.12. The age of onset is variable. This disease is characterized by limb-girdle weakness, calf hypertrophy, diaphragmatic weakness, and variable cardiac abnormalities.
SGSHMucopolysaccharidosis, type 3A (Sanfilippo A)Mucopolysaccharidosis type 3A (Sanfilippo syndrome type A) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SGSH gene located on chromosomal region 17q25.3. The age of onset is infantile. This disease is characterized by behavioural disorders (hyperkinesia, aggressiveness) and intellectual deterioration, sleep disorders and very mild dysmorphism. The prevalence is >1:70,000 newborn.
SH2D1ALymphoproliferative syndrome, X-linked, type 1X-linked lymphoproliferative disease type 1 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the SH2D1A gene located on chromosomal region Xq25. The age of onset is infantile. This disease is characterized by an inadequate immune response to infection with the Epstein-Barr virus: fulminant infectious mononucleosis, macrophage-activation syndrome or hemophagocytic lymphohistiocytosis (HLH) (see these terms), and/or progressive hypogammaglobulinemia and/or lymphomas. The prevalence is 1:1, 000,000 men.
SH3PXD2BFrank-ter Haar syndromeThe primary characteristics of the Frank-ter Haar syndrome are brachycephaly, wide fontanels, prominent forehead, hypertelorism, prominent eyes, macrocornea with or without glaucoma, full cheeks, small chin, bowing of the long bones, and flexion deformity of the fingers. Protruding, simple ears and prominent coccyx are also regarded as important diagnostic signs (Maas et al., 2004). Borrone syndrome was described as a severe progressive multisystem disorder with features overlapping those of FTHS, including thick skin, acne conglobata, osteolysis, gingival hypertrophy, brachydactyly, camptodactyly, and mitral valve prolapse. Although it was initially thought to be a distinct phenotype, mutations in the FTHS-associated gene SH3PXD2B have been identified in patients diagnosed with Borrone syndrome. The earlier differential description was attributed to phenotypic variability as well as to differences in the ages at which patients were examined (Wilson et al., 2014).
SH3TC2Charcot-Marie-Tooth disease, type 4CCharcot-Marie-Tooth disease, type 4C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SH3TC2 gene located on chromosomal region 5q32. The age of onset is infantile. This disease is characterized by scoliosis or kyphoscoliosis, neuropathy, foot deformities, respiratory insufficiency, hypoacousis and deafness.
SHOXLanger mesomelic dysplasiaLanger mesomelic dysplasia (LMD) is characterized by severe limb aplasia or severe hypoplasia of the ulna and fibula, and a thickened and curved radius and tibia. These changes can result in displacement deformities of the hands and feet. Hypoplasia of the mandible is also observed (Langer, 1967).
SHROOM4Stocco dos Santos X-linked mental retardation syndromeStocco dos Santos X-linked mental retardation syndrome is characterized by severe mental retardation with hyperactivity, aggressive behavior, delayed or no speech, and seizures. Additional features include congenital bilateral hip luxation, short stature, and kyphosis.
SISucrase-isomaltase deficiency, congenitalCongenital sucrase-isomaltase deficiency (CSID) is a carbohydrate intolerance disorder characterised by malabsorption of oligosaccharides and disaccharides. The symptoms include fermentative diarrhea, abdominal pain, and cramps upon ingestion of sugar.
SIL1Marinesco-Sjogren syndromeMarinesco-Sj?gren syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SIL1 gene located on chromosomal region 5q31.2. The age of onset is infantile. This disease is characterized by dysarthria, nystagmus, muscle weakness and hypotonia. The prevalence is <1:1,000,000.
SIX6Optic disc anomalies with retinal and/or macular dystrophyOptic disc anomalies with retinal and/or macular dystrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SIX6 gene located on chromosomal region 14q23.1. The age of onset is neonatal. This disease is characterized by optic nerve dysplasia, optic disk anomalies, chorioretinal dystrophy and macular atrophy. Some patients have microphthalmia. The prevalence is <1/1,000,000.
SKIV2LTrichohepatoenteric syndrome, type 2 (diarrhea, syndromic)Trichohepatoenteric syndrome (THES) is a rare and severe disease characterized by intrauterine growth retardation, facial dysmorphism, hair abnormalities, intractable diarrhea, and immunodeficiency (Fabre et al., 2012).
SLC10A2Bile acid malabsorption, primaryPrimary bile acid malabsorption is an intestinal disorder associated with chronic watery diarrhea, excess fecal bile acids, and steatorrhea. Bile acid malabsorption has been classified into 3 main types depending on the etiology. Types 1 and 3 are secondary disorders: type 1 is due to ileal dysfunction resulting from Crohn disease or ileal resection, and type 3 is secondary to other conditions, including cholecystectomy, post-vagotomy, celiac disease, and pancreatic insufficiency. Type 2 bile acid malabsorption is a primary congenital disorder, including the rare type due to mutations in the SLC10A2 gene (Pattni and Walters, 2009).
SLC12A1Bartter syndrome, type 1Bartter syndrome type 1 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC12A1 gene located on chromosomal region 15q15-21. The age of onset is infantile. This disease is characterized by polyhydramnios, premature delivery, polyuria, dehydration, hypercalciuria and nephrocalcinosis. The prevalence is 1:1,000,000.
SLC12A3Gitelman syndromeGitelman syndrome is an autosomal recessive renal tubular salt-wasting disorder characterized by hypokalemic metabolic alkalosis with hypomagnesemia and hypocalciuria. It is the most common renal tubular disorder among Caucasians (prevalence of 1 in 40,000). Most patients have onset of symptoms as adults, but some can present in childhood. Clinical features include transient periods of muscle weakness and tetany, abdominal pains, and chondrocalcinosis (Glaudemans et al., 2012). Gitelman syndrome is sometimes referred to as a mild variant of classic Bartter syndrome (607364).
SLC12A6Agenesis of the corpus callosum with peripheral neuropathyCorpus callosum agenesis with neuronopathy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC12A6 gene located on chromosomal region 15q13-q14. The age of onset is early. This disease is characterized by a delay in developmental milestones, a severe sensory-motor polyneuropathy with areflexia, a variable degree of agenesis of the corpus callosum, amyotrophy, hypotonia, and cognitive impairment. The prevalence is 1:2,117.
SLC16A1Monocarboxylate transporter 1 deficiencyMonocarboxylate transporter 1 deficiency is a metabolic disorder characterized by recurrent ketoacidosis, a pathologic state due to ketone formation exceeding ketone utilization. The clinical consequences of ketoacidosis are vomiting, osmotic diuresis, dehydration, and Kussmaul breathing. The condition may progress to decreased consciousness and, ultimately, death.
SLC16A2Allan-Herndon-Dudley syndromeAllan-Herndon-Dudley syndrome is a rare disorder of brain development that causes moderate to severe intellectual disability and problems with movement. This condition, which occurs exclusively in males, disrupts development from before birth. Although affected males have impaired speech and a limited ability to communicate, they seem to enjoy interaction with other people. Most children with Allan-Herndon-Dudley syndrome have weak muscle tone (hypotonia) and underdevelopment of many muscles (muscle hypoplasia). As they get older, they usually develop joint deformities called contractures, which restrict the movement of certain joints. Abnormal muscle stiffness (spasticity), muscle weakness, and involuntary movements of the arms and legs also limit mobility.
SLC17A5Salla diseaseSalla disease follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC17A5 gene located on chromosomal region 6q13. The age of onset is from infantile to adult forms. The main symptoms are hypotonia, cerebellar ataxia, and mental retardation; visceromegaly and coarse features are also present in the infantile cases.
SLC19A2Thiamine-responsive megaloblastic anemia syndromeThiamine-responsive megaloblastic anemia syndrome comprises megaloblastic anemia, diabetes mellitus, and sensorineural deafness. Onset is typically between infancy and adolescence, but all of the cardinal findings are often not present initially. The anemia, and sometimes the diabetes, improves with high doses of thiamine. Other more variable features include optic atrophy, congenital heart defects, short stature, and stroke (Bergmann et al., 2009).
SLC19A3Thiamine metabolism dysfunction syndrome, type 2 (biotin- or thiamine-responsive encephalopathy type)Thiamine metabolism dysfunction syndrome-2 is an autosomal recessive metabolic disorder characterized by episodic encephalopathy, often triggered by febrile illness, presenting as confusion, seizures, external ophthalmoplegia, dysphagia, and sometimes coma and death. Administration of high doses of biotin, and sometimes thiamine, during these crises results in partial or complete improvement within days. If untreated, encephalopathies can result in permanent dystonia. Brain imaging may show characteristic bilateral lesions of the basal ganglia. It is not known why biotin administration results in clinical improvement, as the molecular basis of the disorder is mutation in a gene encoding a thiamine transporter. However, biotin may increase the gene expression of SLC19A3 (Debs et al., 2010).
SLC22A12Hypouricemia, renalRenal hypouricemia is characterized by impaired uric acid reabsorption at the apical membrane of proximal renal tubule cells. The syndrome is not lethal and may be asymptomatic. However, it is accompanied by nephrolithiasis and exercise-induced acute renal failure in about 10% of patients (Ichida et al., 2008).
SLC22A5Carnitine deficiency, systemic primaryPrimary systemic carnitine deficiency is due to a defect in the high-affinity carnitine transporter expressed in muscle, heart, kidney, lymphoblasts, and fibroblasts. This results in impaired fatty acid oxidation in skeletal and heart muscle. In addition, renal wasting of carnitine results in low serum levels and diminished hepatic uptake of carnitine by passive diffusion, which impairs ketogenesis (Lamhonwah et al., 2002). If diagnosed early, all clinical manifestations of the disorder can be completely reversed by supplementation of carnitine. However, if left untreated, patients will develop lethal heart failure (Shibbani et al., 2014).
SLC24A1Night blindness, congenital stationary (complete), type 1D, autosomal recessiveNight blindness, congenital stationary (complete), type 1D (CSNB1D) is an autosomal recessive form of congenital stationary night blindness that is characterized by a Riggs type of electroretinogram (proportionally reduced a- and b-waves). Patients with Riggs-type CSNB have visual acuity within the normal range and no symptoms of myopia and/or nystagmus (Riazuddin et al., 2010).
SLC24A5Albinism, oculocutaneous, type 6Albinism, oculocutaneous, type 6 is a heterogeneous autosomal recessive disorder, with a worldwide prevalence of approximately 1:17,000. It manifests as a reduction or complete loss of melanin in the skin, hair, and eyes, often accompanied by eye symptoms such as photophobia, strabismus, moderate to severe visual impairment, and nystagmus (Wei et al., 2013).
SLC25A12Epileptic encephalopathy, early infantile, type 39Epileptic encephalopathy, early infantile, type 39 (EIEE39) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. Development is normal prior to seizure onset, after which cognitive and motor delays become apparent. EIEE39 is characterized by global hypomyelination of the central nervous system, with the gray matter appearing relatively unaffected.
SLC25A13Citrullinemia, adult-onset, type 2Citrullinemia, adult-onset, type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC25A13 gene located on chromosomal region 7q21.3. This disease is characterized by hyperammonemia and associated neuropsychiatric symptoms such as nocturnal delirium, confusion, restlessness, disorientation, drowsiness, memory loss, abnormal behavior (aggression, irritability, and hyperactivity), seizures, and coma. The prevalence is 1:17,000-1:230,000.
SLC25A15Hyperornithinemia-hyperammonemia-homocitrullinemia syndromeHyperornithinemia-hyperammonemia-homocitrullinuria follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC25A15 gene located on chromosomal region 13q14.11. The age of onset is early. This disease is characterized by coma due to hyperammonemia, convulsions, and hypotonia. The prevalence is 1:5,500.
SLC25A19Microcephaly, Amish type; Thiamine metabolism dysfunction syndrome 4 (progressive polyneuropathy type)Amish type microcephaly, also known as thiamine metabolism dysfunction syndrome-3 (THMD3). is a severe autosomal recessive metabolic disorder characterized by severe microcephaly apparent at birth, profoundly delayed psychomotor development, brain malformations, and episodic encephalopathy associated with lactic acidosis and alpha-ketoglutaric aciduria (Kelley et al., 2002). Amish lethal microcephaly is caused by homozygous mutation in the SLC25A19 gene on chromosome 17q25. Mutation in SLC25A19 gene also causes thiamine metabolism dysfunction syndrome-4 (THMD4), an allelic disorder with a milder phenotype. THMD4 is an autosomal recessive metabolic disorder characterized by childhood onset of episodic encephalopathy, often associated with a febrile illness, and causing transient neurologic dysfunction. Most patients recover fully, but some may have mild residual weakness. Affected individuals also develop a slowly progressive axonal polyneuropathy beginning in childhood. Brain imaging during the acute episodes shows lesions consistent with bilateral striatal degeneration or necrosis (Spiegel et al., 2009).
SLC25A20Carnitine-acylcarnitine translocase deficiencyCarnitine-acylcarnitine translocase deficiency is a rare autosomal recessive metabolic disorder of long-chain fatty acid oxidation. Metabolic consequences include hypoketotic hypoglycemia under fasting conditions, hyperammonemia, elevated creatine kinase and transaminases, dicarboxylic aciduria, very low free carnitine and abnormal acylcarnitine profile with marked elevation of the long-chain acylcarnitines. Clinical features include neurologic abnormalities, cardiomyopathy and arrhythmias, skeletal muscle damage, and liver dysfunction. Most patients become symptomatic in the neonatal period with a rapidly progressive deterioration and a high mortality rate. However, presentations at a later age with a milder phenotype have been reported (Rubio-Gozalbo et al., 2004).
SLC25A22Epileptic encephalopathy, early infantile, type 3Early infantile epileptic encephalopathy, type 3 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC25A22 gene located on chromosomal region 11p15.5. The age of onset is early. This disease is characterized by the onset of tonic spasms within the first 3 months of life leading to psychomotor impairment and death. The prevalence is <1:1,000,000.
SLC25A3Mitochondrial phosphate carrier deficiencyMitochondrial phosphate carrier deficiency is a fatal disorder of oxidative phosphorylation. Patients have lactic acidosis, hypertrophic cardiomyopathy and muscular hypotonia and die within the first year of life.
SLC25A38Anemia, sideroblastic, type 2, pyridoxine-refractoryCongenital autosomal recessive sideroblastic anemia is a non-syndromic, microcytic/hypochromic sideroblastic anemia, present from early infancy and characterized by severe microcytic anemia, which is not pyridoxine responsive, and increased serum ferritin.
SLC25A4Mitochondrial DNA depletion syndrome, type 12B (cardiomyopathic type) ARMitochondrial DNA depletion syndrome, type 12B is an autosomal recessive mitochondrial disorder characterized by childhood onset of slowly progressive hypertrophic cardiomyopathy and generalized skeletal myopathy resulting in exercise intolerance and, in some patients, muscle weakness and atrophy. Skeletal muscle biopsy shows ragged red fibers, mtDNA depletion, and accumulation of abnormal mitochondria (Echaniz-Laguna et al., 2012).
SLC26A2Achondrogenesis, type 1B (diastrophic dysplasia)Achondrogenesis type 1B (diastrophic dysplasia) follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC26A2 gene located on chromosomal region 5q32. The age of onset is early. This disease is characterized by severe micromelia with very short fingers and toes, a flat face, a short neck, thickened soft tissue around the neck, hypoplasia of the thorax, protuberant abdomen, a hydropic fetal appearance and distinctive histological features of the cartilage. The prevalence is 1:20,000.
SLC26A3Diarrhea 1, secretory chloride, congenitalCongenital secretory chloride diarrhea is an autosomal recessive form of severe chronic diarrhea characterized by excretion of large amounts of watery stool containing high levels of chloride, resulting in dehydration, hypokalemia, and metabolic alkalosis. The electrolyte disorder resembles the renal disorder Bartter syndrome (607364), except that chloride diarrhea is not associated with calcium level abnormalities (Choi et al., 2009).
SLC26A4Deafness, autosomal recessive, type 4; Pendred syndromeAutosomal recessive nonsyndromic sensorineural deafness type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC26A4 gene located on chromosomal region 7q22.3. The age of onset is early. This disease is characterized by hearing loss and deafness, no associated visible abnormalities of the external ear or any related medical problems. Pendred syndrome, the most common syndromal form of deafness, is an autosomal recessive disorder associated with developmental abnormalities of the cochlea, sensorineural hearing loss, and diffuse thyroid enlargement (goiter).
SLC27A4Ichthyosis prematurity syndromeIchthyosis prematurity syndrome (IPS) is a keratinization disorder characterized by complications in the second trimester of pregnancy resulting from polyhydramnion, with premature birth of a child with thick caseous desquamating epidermis, respiratory complications and transient eosinophilia. After recovery during the first months of life, the symptoms are relatively benign and the patients suffer from a lifelong non-scaly ichthyosis with atopic manifestations.
SLC29A3Histiocytosis-lymphadenopathy plus syndromeThe histiocytosis-lymphadenopathy plus syndrome comprises features of 4 histiocytic disorders previously thought to be distinct: Faisalabad histiocytosis (FHC), sinus histiocytosis with massive lymphadenopathy (SHML), H syndrome, and pigmented hypertrichosis with insulin-dependent diabetes mellitus syndrome (PHID). FHC described an autosomal recessive disease involving joint deformities, sensorineural hearing loss, and subsequent development of generalized lymphadenopathy and swellings in the eyelids that contain histiocytes (Morgan et al., 2010). SHML, or familial Rosai-Dorfman disease, was described as a rare cause of lymph node enlargement in children, consisting of chronic massive enlargement of cervical lymph nodes frequently accompanied by fever, leukocytosis, elevated erythrocyte sedimentation rate, and polyclonal hypergammaglobulinemia. Extranodal sites were involved in approximately 25% of patients, including salivary glands, orbit, eyelid, spleen, and testes. The involvement of retropharyngeal lymphoid tissue sometimes caused snoring and sleep apnea (Kismet et al., 2005). H syndrome was characterized by cutaneous hyperpigmentation and hypertrichosis, hepatosplenomegaly, heart anomalies, and hypogonadism; hearing loss was also found in about half of patients, and many had short stature. PHID was characterized by predominantly antibody-negative insulin-dependent diabetes mellitus associated with pigmented hypertrichosis and variable occurrence of other features of H syndrome, with hepatosplenomegaly occurring in about half of patients (Cliffe et al., 2009). Bolze et al. (2012) noted that mutations in the SLC29A3 gene (612373) had been implicated in H syndrome, PHID, FHC, and SHML, and that some patients presented a combination of features from 2 or more of these syndromes, leading to the suggestion that these phenotypes should be grouped together as 'SLC29A3 disorder.' Bolze et al. (2012) suggested that the histologic features of the lesions seemed to be the most uniform phenotype in these patients. In addition, the immunophenotype of infiltrating cells in H syndrome patients was shown to be the same as that seen in patients with the familial form of Rosai-Dorfman disease, further supporting the relationship between these disorders (Avitan-Hersh et al., 2011; Colmenero et al., 2012).
SLC2A1GLUT1 deficiency syndrome 1, infantile onset, severeGLUT1 deficiency syndrome-1 is a neurologic disorder showing wide phenotypic variability. The most severe 'classic' phenotype comprises infantile-onset epileptic encephalopathy associated with delayed development, acquired microcephaly, motor incoordination, and spasticity. Onset of seizures, usually characterized by apneic episodes, staring spells, and episodic eye movements, occurs within the first 4 months of life. Other paroxysmal findings include intermittent ataxia, confusion, lethargy, sleep disturbance, and headache. Varying degrees of cognitive impairment can occur, ranging from learning disabilities to severe mental retardation. Hypoglycorrhachia (low CSF glucose, less than 40 mg/dl) and low CSF lactate are essentially diagnostic for the disorder. As more cases with GLUT1 deficiency syndrome were described, the phenotype was broadened to include individuals with ataxia and mental retardation but without seizures, individuals with dystonia and choreoathetosis, and rare individuals with absence seizures and no movement disorder. The disorder, which results from a defect in the GLUT1 glucose transporter causing decreased glucose concentration in the central nervous system, is part of a spectrum of neurologic phenotypes resulting from GLUT1 deficiency. GLUT deficiency syndrome-2 (612126) represents the less severe end of the phenotypic spectrum and is associated with paroxysmal exercise-induced dystonia with or without seizures. Correct diagnosis of GLUT1 deficiency is important because a ketogenic diet often results in marked clinical improvement of the motor and seizure symptoms (Pascual et al., 2004; Brockmann, 2009).
SLC2A10Arterial tortuosity syndromeArterial tortuosity syndrome (ATS) is a rare connective tissue disorder characterized by tortuosity and elongation of the large and medium-sized arteries and a propensity towards aneurysm formation, vascular dissection, and stenosis of the pulmonary arteries.
SLC2A2Fanconi-Bickel syndromeFanconi-Bickel syndrome is a rare but well-defined clinical entity, inherited in an autosomal recessive mode and characterized by hepatorenal glycogen accumulation, proximal renal tubular dysfunction, and impaired utilization of glucose and galactose (Manz et al., 1987). Because no underlying enzymatic defect in carbohydrate metabolism had been identified and because metabolism of both glucose and galactose is impaired, a primary defect of monosaccharide transport across the membranes had been suggested (Berry et al., 1995; Fellers et al., 1967; Manz et al., 1987; Odievre, 1966).Use of the term glycogenosis type XI introduced by Hug (1987) is to be discouraged because glycogen accumulation is not due to the proposed functional defect of phosphoglucomutase, an essential enzyme in the common degradative pathways of both glycogen and galactose, but is secondary to nonfunctional glucose transport.
SLC2A9Hypouricemia, renal, type 2Renal hypouricemia is a common inherited disorder characterized by impaired renal urate reabsorption and subsequent low serum urate levels. It may be associated with severe complications such as exercise-induced acute renal failure (EIARF) and nephrolithiasis (Matsuo et al., 2008).
SLC30A10Hypermanganesemia with dystonia, type 1Hypermanganesemia with dystonia, type 1 is an autosomal recessive metabolic disorder characterized by increased serum manganese, motor neurodegeneration with extrapyramidal features, polycythemia, and hepatic dysfunction, which leads to cirrhosis in some cases. Intellectual function is preserved (Tuschl et al., 2012; Quadri et al., 2012).
SLC33A1Congenital cataracts, hearing loss, and neurodegenerationCongenital cataracts, hearing loss, and neurodegeneration (CCHLND) is an autosomal recessive disorder characterized by congenital cataracts, severe psychomotor retardation, and hearing loss associated with decreased serum ceruloplasmin and copper. Brain MRI shows cerebral and cerebellar atrophy and hypomyelination (Huppke et al., 2012).
SLC34A1Hypercalcemia, infantile, type 2Infantile hypercalcemia is a condition characterized by high levels of calcium in the blood (hypercalcemia). Two types of idiopathic infantile hypercalcemia have been identified and are distinguished by their genetic causes: infantile hypercalcemia 1 and infantile hypercalcemia 2. In infants with either type, hypercalcemia can cause vomiting, increased urine production (polyuria), dehydration, constipation, poor feeding, weight loss, and an inability to grow and gain weight as expected (failure to thrive). As they age, affected babies usually have delayed development of mental and movement abilities (psychomotor delay). Individuals with infantile hypercalcemia 1 or 2 may also have high levels of calcium in their urine (hypercalciuria) and deposits of calcium in their kidneys (nephrocalcinosis). Individuals with infantile hypercalcemia 2 also have low levels of a mineral called phosphate in the blood (hypophosphatemia).
SLC34A2Pulmonary alveolar microlithiasisPulmonary alveolar microlithiasis is a rare disease characterized by the deposition of calcium phosphate microliths throughout the lungs. Most patients are asymptomatic for several years or even for decades, and, generally, the diagnosis is incidental to clinical investigations unrelated to the specific disorder. Cases with early onset or rapid progression are rare. A 'sandstorm-appearing' chest roentgenogram is a typical diagnostic finding. The onset of this potentially lethal disease varies from the neonatal period to old age, and the disease follows a long-term progressive course, resulting in a slow deterioration of lung functions. About one-third of the reported cases are said to be familial (Corut et al., 2006).
SLC34A3Hypophosphatemic rickets with hypercalciuriaHereditary hypophosphatemic rickets with hypercalciuria is a rare autosomal recessive disorder characterized by the presence of hypophosphatemia secondary to renal phosphate wasting, radiographic and/or histologic evidence of rickets, limb deformities, muscle weakness, and bone pain. HHRH is distinct from other forms of hypophosphatemic rickets in that affected individuals present with hypercalciuria due to increased serum 1,25-dihydroxyvitamin D levels and increased intestinal calcium absorption (Bergwitz et al., 2006).
SLC35A1Congenital disorder of glycosylation, type 2FCongenital disorder of glycosylation type 2F follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC35A1 gene located on chromosomal region 6q15. The age of onset is early. This disease is characterized by repeated hemorrhagic incidents, including severe pulmonary hemorrhage.
SLC35A3?Arthrogryposis, mental retardation, and seizuresArthrogryposis, mental retardation, and seizures is a disease characterized by arthrogryposis, mental retardation, autism spectrum disorder, and epilepsy. Additional features include limb malformations, distal joint involvement, microcephaly, retromicrognathia, and general muscle hypotonia.
SLC35C1Congenital disorder of glycosylation, type 2CCongenital disorder of glycosylation type 2C follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC35C1 gene located on chromosomal region 11p11.2. The age of onset is infantile. This disease is characterized by recurrent bacterial infections, severe growth delay and severe intellectual deficit.
SLC35D1Schneckenbecken dysplasiaSchneckenbecken dysplasia follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC35D1 gene located on chromosomal region 1p31.3. The age of onset is fetal. This disease is characterized by nail-like configuration of the hypoplastic iliac bone, flattened hypoplastic vertebral bodies, short ribs, short and wide fibulae, short and broad long bones with a dumbbell-like appearance, and precocious ossification of the tarsus.
SLC37A4Glycogen storage disease, type 1bGlycogen storage disease due to glucose-6-phosphatase deficiency type 1b follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC37A4 gene located on chromosomal region 11q23. The age of onset is early. This disease is characterized by impairment of terminal steps of glycogenolysis and gluconeogenesis. Patients manifest a wide range of clinical symptoms and biochemical abnormalities, including hypoglycemia, severe hepatomegaly due to excessive accumulation of glycogen, kidney enlargement, growth retardation, lactic acidemia, hyperlipidemia, and hyperuricemia. Glycogen storage disease type 1B patients also present a tendency towards infections associated with neutropenia, relapsing aphthous gingivostomatitis, and inflammatory bowel disease. The incidence is 1:100,000.
SLC39A4Acrodermatitis enteropathicaAcrodermatitis enteropathica (AE) is a disorder of zinc metabolism that lead to the inability to absorb zinc from the intestine. The clinical features are growth retardation, immune- system dysfunction, alopecia, severe dermatitis, diarrhea and occasionally mental disorders.
SLC3A1CystinuriaCystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low solubility causes the formation of calculi in the urinary tract, resulting in obstructive uropathy, pyelonephritis, and, rarely, renal failure (Barbosa et al., 2012).
SLC45A2Albinism, oculocutaneous, type 4Oculocutaneous albinism type 4 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC45A2 gene located on chromosomal region 5p13.2. The age of onset is early. This disease is characterized by skin and hair hypopigmentation, numerous ocular changes and misrouting of the optic nerves at the chiasm. The prevalence is 1:100.000.
SLC46A1Folate malabsorption, hereditaryHereditary folate malabsorption is an autosomal recessive disorder characterized by signs and symptoms of folate deficiency that appear within a few months after birth. Infants exhibit low blood and cerebrospinal fluid folate levels with megaloblastic anemia, diarrhea, immune deficiency, infections, and neurologic deficits. Treatment with folate supplementation results in resolution of the signs and symptoms. The disorder is caused by impaired intestinal folate absorption and impaired transport of folate into the central nervous system (Qiu et al., 2006).
SLC4A1Distal renal tubular acidosis (dRTA) with hemolytic anemiaDistal renal tubular acidosis (dRTA), autosomal recessive is a disease characterized by reduced ability to acidify urine, variable hyperchloremic hypokalemic metabolic acidosis, nephrocalcinosis, and nephrolithiasis. It is due to functional failure of alpha-intercalated cells of the cortical collecting duct of the distal nephron.
SLC4A11Corneal endothelial dystrophy, autosomal recessiveCongenital hereditary endothelial dystrophy type 2 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SLC4A11 gene located on chromosomal region 20p13. The age of onset is early. This disease is characterized by a diffuse ground-glass appearance of the corneas and marked corneal thickening from birth with nystagmus, and blurred vision.
SLC4A4Renal tubular acidosis, proximal, with ocular abnormalitiesRenal tubular acidosis, proximal (pRTA), with ocular abnormalities and mental retardation is an extremely rare autosomal recessive syndrome characterized by short stature, profound proximal renal tubular acidosis, mental retardation, bilateral glaucoma, cataracts and bandkeratopathy. pRTA is due to a failure of the proximal tubular cells to reabsorb filtered bicarbonate from the urine, leading to urinary bicarbonate wasting and subsequent acidemia.
SLC52A2Brown-Vialetto-Van Laere syndrome, type 2Brown-Vialetto-Van Laere syndrome, type 2 is an autosomal recessive progressive neurologic disorder characterized by early childhood onset of sensorineural deafness, bulbar dysfunction, and severe diffuse muscle weakness and wasting of the upper and lower limbs and axial muscles, resulting in respiratory insufficiency. Some patients may lose independent ambulation. Because it results from a defect in riboflavin metabolism, some patients may benefit from high-dose riboflavin supplementation (Johnson et al., 2012; Foley et al., 2014).
SLC52A3Brown-Vialetto-Van Laere syndrome, type 1Brown-Vialetto-Van Laere syndrome is a rare autosomal recessive neurologic disorder characterized by sensorineural hearing loss and a variety of cranial nerve palsies, usually involving the motor components of the seventh and ninth to twelfth (more rarely the third, fifth, and sixth) cranial nerves. Spinal motor nerves and, less commonly, upper motor neurons are sometimes affected, giving a picture resembling amyotrophic lateral sclerosis (ALS; 105400). The onset of the disease is usually in the second decade, but earlier and later onset have been reported. Hearing loss tends to precede the onset of neurologic signs, mostly progressive muscle weakness causing respiratory compromise. However, patients with very early onset may present with bulbar palsy and may not develop hearing loss until later. The symptoms, severity, and disease duration are variable (Green et al., 2010).
SLC5A2Renal glucosuriaRenal glucosuria is characterised by decreased renal tubular resorption of glucose form the urine in the absence of hyperglycemia and any other signs of tubular dysfunction. Glucosuria in these patients can range from less than 1 to over 150 g/1.73 m(2) per day (Santer and Calado, 2010).
SLC5A5Thyroid dyshormonogenesis, type 1Approximately 10% of patients with congenital hypothyroidism harbor inborn errors of metabolism in one of the steps for thyroid hormone synthesis in thyrocytes (Vono-Toniolo et al., 2005). Dyshormonogenesis can be caused by recessive defects at any of the steps required for normal thyroid hormone synthesis. In untreated patients thyroid dyshormonogenesis is typically associated with goitrous enlargement of the thyroid secondary to long-term thyrotropin (TSH; 188540) stimulation. Park and Chatterjee (2005) reviewed the genetics of primary congenital hypothyroidism, summarizing the different phenotypes associated with known genetic defects and proposing an algorithm for investigating the genetic basis of the disorder.
SLC5A7Myasthenic syndrome, congenital, type 20, presynapticCongenital myasthenic syndromes (CMS) are a group of inherited disorders affecting the neuromuscular junction (NMJ). Patients present clinically with onset of variable muscle weakness between infancy and adulthood. These disorders have been classified according to the location of the defect: presynaptic, synaptic, and postsynapti. Congenital myasthenic syndrome, type 20 is an autosomal recessive neuromuscular disorder characterized by severe hypotonia associated with episodic apnea soon after birth. Patients have muscle weakness resulting in delayed walking, ptosis, poor sucking and swallowing, and generalized limb fatigability and weakness. EMG studies usually show a decremental response to repetitive nerve stimulation, and some patients may show a good response to AChE inhibitors (Bauche et al., 2016).
SLC6A19Hartnup disorderHartnup disease is characterized by increased levels of various amino acids in their urine (aminoaciduria). For most affected individuals, this is the only sign of the condition. However, some people with Hartnup disease have episodes during which they exhibit other signs, which can include skin rashes; difficulty coordinating movements (cerebellar ataxia); and psychiatric symptoms, such as depression or psychosis. These episodes are typically temporary and are often triggered by illness, stress, nutrient-poor diet, or fever. These features tend to go away once the trigger is remedied, although the aminoaciduria remains. In affected individuals, signs and symptoms most commonly occur in childhood.
SLC6A3Parkinsonism-dystonia, infantileInfantile parkinsonism-dystonia, also known as dopamine transporter deficiency syndrome (DTDS), is an autosomal recessive complex motor neurologic disorder with onset in infancy. Affected individuals show hyperkinesia with orolingual and limb dyskinesia, dystonia, and chorea, or hypokinesia with parkinsonian features, such as bradykinesia, rigidity, and tremor. Other features may include axial hypotonia, pyramidal tract signs, and eye movement abnormalities. Many patients are misdiagnosed as having cerebral palsy. Cognitive function appears to be less severely affected, but most patients die in the teenage years. There is no effective treatment. Laboratory studies show an increased ratio of homovanillic acid (HVA) to 5-hydroxyindoleacetic acid (5-HIAA) in cerebrospinal fluid (CSF), which represents an increase in dopamine metabolites (Kurian et al., 2011).
SLC6A5Hyperekplexia, type 3Hyperekplexia, type 3 is a neurologic disorder characterized by neonatal hypertonia, an exaggerated startle response to tactile or acoustic stimuli, and life- threatening neonatal apnea episodes. Notably, in some cases, symptoms resolved in the first year of life.
SLC6A8Cerebral creatine deficiency syndrome, type 1Cerebral creatine deficiency syndrome type 1 follows an X-linked pattern of inheritance and is caused by pathogenic variants in the SLC6A8 gene located on chromosomal region Xq28. The age of onset is infantile. People with this disorder have intellectual disability, which can range from mild to severe, and delayed speech development. Some affected individuals develop behavioral disorders such as attention deficit hyperactivity disorder or autistic behaviors that affect communication and social interaction. They may also experience seizures. The disorder has been estimated to account for between 1 and 2 percent of males with intellectual disability. Carrier females may show mild neuropsychologic impairment (summary by van de Kamp et al., 2011). The prevalence is 11:1,000.
SLC7A7Lysinuric protein intoleranceLysinuric protein intolerance is caused by defective cationic amino acid (CAA) transport at the basolateral membrane of epithelial cells in kidney and intestine. Metabolic derangement is characterized by increased renal excretion of CAA, reduced CAA absorption from intestine, and orotic aciduria (Borsani et al., 1999).
SLC7A9CystinuriaCystinuria is an autosomal disorder characterized by impaired epithelial cell transport of cystine and dibasic amino acids (lysine, ornithine, and arginine) in the proximal renal tubule and gastrointestinal tract. The impaired renal reabsorption of cystine and its low solubility causes the formation of calculi in the urinary tract, resulting in obstructive uropathy, pyelonephritis, and, rarely, renal failure (Barbosa et al., 2012).
SLC9A6Mental retardation, X-linked syndromic, Christianson typeChristianson syndrome is an X-linked neurodevelopmental and progressive mental retardation syndrome characterized by microcephaly, impaired ocular movements, severe global developmental delay, developmental regression, hypotonia, abnormal movements, and early-onset seizures of variable types. Female carriers may be mildly affected (Schroer et al., 2010 and Pescosolido et al., 2014).
SLCO2A1Hypertrophic osteoarthropathy, primary, autosomal recessive, type 2Primary hypertrophic osteoarthropathy (PHO), which is also known as pachydermoperiostosis, is a rare genetic disease that affects the skin and bones. PHO is characterized by digital clubbing, periostosis, acroosteolysis, painful joint enlargement, and skin manifestations that include thickened facial skin, a thickened scalp, and coarse facial features (Zhang et al., 2012).
SLURP1Meleda diseaseMeleda disease is a rare autosomal recessive skin disorder, characterized by diffuse transgressive palmoplantar keratoderma with keratotic lesions extending onto the dorsa of the hands and the feet (transgrediens). Patients may have hyperhidrosis. Other features include perioral erythema, lichenoid plaques on the knees and the elbows, and nail abnormalities.
SMARCAL1Schimke immunoosseous dysplasiaSchimke immunoosseous dysplasia (SIOD) is a condition that results in short stature, kidney disease (nephropathy), and a weakened immune system. Some people develop a severe form in early childhood, and others develop a milder form in childhood or later. Short stature is due to spondyloepiphyseal dysplasia, which involves abnormal development of the spine and the ends of the long bones. Nearly all people with SIOD have kidney disease, which progresses to end-stage renal disease. Most people with SIOD also have T-cell deficiency causing an increased risk for infections, which can be life-threatening.
SMC1ACornelia de Lange syndrome 2Cornelia de Lange syndrome is a clinically heterogeneous developmental disorder characterized by malformations affecting multiple systems. Affected individuals have dysmorphic facial features, cleft palate, distal limb defects, growth retardation, and developmental delay. About 4 to 6% of patients have mutations in the X-linked SMC1A gene, whereas about 60% have mutations in the NIPBL gene (608667) on chromosome 5p13 (CDLS1; 122470) (Musio et al., 2006; Hoppman-Chaney et al., 2012).
SMN1Spinal muscular atrophySpinal muscular atrophy follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SMN1 gene located on chromosomal region 5q13.2. The age of onset is variable. This disease comprise a group of neuromuscular disorders characterized by degeneration of the anterior horn cells of the spinal cord, leading to symmetrical muscle weakness and atrophy. Autosomal recessive forms are classified according to the age of onset, the maximum muscular activity achieved, and survivorship. The severity of the disease is mainly determined by the copy number of SMN2, a copy gene which predominantly produces exon 7-skipped transcripts and only low amount of full-length transcripts that encode for a protein identical to SMN1. Only about 4% of patients bear one SMN1 copy with an intragenic mutation. Type 1 is a severe form, with onset before 6 months of age. Patients never achieve the ability to sit. Type 2 has intermediate severity, with onset between 6 and 18 months. Patients do not reach the motor milestone of standing, and survive into adulthood. Type 3 onset is after 18 months. Patients develop ability to stand and walk and survive into adulthood. Type 4 onset is in adulthood, disease progression is slow, and patients can stand and walk. The incidence is 1:10,000 and the prevalence is 1:80,000.
SMOC1Microphthalmia. with limb anomaliesMicrophthalmia with limb anomalies is a rare disorder presenting with ocular anomalies, ranging from mild microphthalmia to true anophthalmia, and limb anomalies. Limb malformations include fused 4th and 5th metacarpals and short 5th finger in hands, and oligodactyly in foot (four toes). Most patients have bilateral anophthalmia/ microphthalmia, but unilateral abnormality is also noted.
SMOC2Dentin dysplasia, type 1, with microdontia and misshapen teethIn dentin dysplasia type 1 ,both primary and secondary dentitions are affected. The color and general morphology of the teeth are usually normal, although they may be slightly opalescent and blue or brown. Teeth may be very mobile and exfoliate spontaneously because of inadequate root formation. On radiographs, the roots are short and may be more pointed than normal. Pulp chambers are usually absent except for a chevron-shaped remnant in the crown (Witkop, 1975). Root canals are usually absent. Periapical radiolucencies may be present at the apices of affected teeth, for reasons unknown. On light microscopic examination of the permanent teeth, the coronal dentin is normal, but further apically becomes irregular, fills the pulp chamber, and has a 'sand-dune' morphology. Scanning electron microscopic studies of the deciduous and permanent teeth have been reported (Sauk et al., 1972; Melnick et al., 1980)
SMPD1Niemann-Pick disease, type A; Niemann-Pick disease, type BNiemann-Pick disease, type A and type B follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SMPD1 gene located on chromosomal region 11p15.4. The clinical phenotype ranges from a severe infantile form with neurologic degeneration resulting in death usually by 3 years of age (type A) to a later-onset nonneurologic form (type B) that is compatible with survival into adulthood. Since intermediate cases also have been reported, the disease is best regarded a single entity with a clinical spectrum.
SMPXDeafness, X-linked, type 4Deafness, X-linked, type 4 is a nonsyndromic form of progressive hearing loss with postlingual onset. Affected males show earlier onset of hearing loss than affected females (del Castillo et al., 1996).
SMSMental retardation, X-linked, Snyder-Robinson typeSnyder-Robinson mental retardation syndrome is an X-linked intellectual disability syndrome with characteristic features including facial asymmetry, marfanoid habitus, unsteady gait, thickened lower lip, nasal dysarthic speech, narrow or cleft palate, diminished muscle mass, osteoporosis, kyphoscoliosis, long great toes, short stature, pectus carinatum, and myopia (Zhang et al., 2013).
SNAP29Cerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndromeCerebral dysgenesis, neuropathy, ichthyosis, and palmoplantar keratoderma syndrome follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SNAP29 gene located on chromosomal region 22q11.2. The age of onset is early. This disease is characterized by severe developmental abnormalities of the nervous system and aberrant differentiation of the epidermis. The prevalence is <1:1,000,000.
SNX10Osteopetrosis, autosomal recessive, type 8Osteopetrosis, autosomal recessive, type 8 (OTPB8) is a rare genetic disease characterized by abnormally dense bone, due to defective resorption of immature bone. Osteopetrosis occurs in two forms: a severe autosomal recessive form occurring in utero, infancy, or childhood, and a benign autosomal dominant form occurring in adolescence or adulthood. Recessive osteopetrosis commonly manifests in early infancy with macrocephaly, feeding difficulties, evolving blindness and deafness, bone marrow failure, severe anemia, and hepatosplenomegaly. Deafness and blindness are generally thought to represent effects of pressure on nerves. OPTB8 is clinically characterized by dense bones with no distinction between outer and inner plates, due to extensive encroachment of cortical bone into the medullary space, increased head circumference, broad open fontanelle, frontal bossing, and hepatosplenomegaly. Osteoclasts number is low and their bone resorptive capacity is impaired.
SOD1Spastic tetraplegia and axial hypotonia, progressive; Amyotrophic lateral sclerosis, type 1Progressive spastic tetraplegia and axial hypotonia (STAHP) is an autosomal recessive neurologic disorder characterized by onset of severe and progressive motor dysfunction in the first year of life. Affected individuals have severe axial hypotonia combined with spastic tetraplegia, hyperekplexia, hypertonia, and myokymia, reflecting upper motor neuron involvement. Cognitive development may be affected, but only 2 unrelated patients have been reported (Andersen et al., 2019; Park et al., 2019). Mutation in the SOD1 gene can also cause amyotrophic lateral sclerosis, type 1 (ALS1). ALS1 is a neurodegenerative disorder characterized by the death of motor neurons in the brain, brainstem, and spinal cord, resulting in fatal paralysis. ALS usually begins with asymmetric involvement of the muscles in middle adult life. Approximately 10% of ALS cases are familial (Siddique and Deng, 1996). ALS is sometimes referred to as 'Lou Gehrig disease' after the famous American baseball player who was diagnosed with the disorder. Rowland and Shneider (2001) and Kunst (2004) provided extensive reviews of ALS. Some forms of ALS occur with frontotemporal dementia (FTD).Familial ALS is distinct from a form of ALS with dementia reported in cases on Guam (105500) (Espinosa et al., 1962; Husquinet and Franck, 1980), in which the histology is different and dementia and parkinsonism complicate the clinical picture.
SOHLH1Ovarian dysgenesis 5Ovarian dysgenesis 5 is a disorder characterized by lack of spontaneous pubertal development, primary amenorrhea, uterine hypoplasia, and hypergonadotropic hypogonadism as a result of streak gonads.
SOSTSclerosteosis, type 1; Van Buchem diseaseSclerosteosis is a severe sclerosing bone dysplasia characterized by progressive skeletal overgrowth. Syndactyly is a variable manifestation. The disorder is rare and the majority of affected individuals have been reported in the Afrikaner population of South Africa (Brunkow et al., 2001). Mutation in SOSTS gene also causes Van Buchem disease. Van Buchem disease is an autosomal recessive bone dysplasia characterized by a symmetrically increased thickness of bones, most frequently found as an enlarged jawbone, but also an enlargement of the skull, ribs, diaphysis of long bones, as well as tubular bones of hands and feet, resulting in increased cortical bone density. The clinical consequences of increased thickness of the skull include facial nerve palsy causing hearing loss, visual problems, neurologic pain, and very rarely, blindness resulting from optic atrophy. Bone anomalies appear in the first decade of life and progress with age (Wergedal et al., 2003).
SOX18Hypotrichosis-lymphedema-telangiectasia syndromeHypotrichosis-lymphedema-telangiectasia syndrome is an autosomal recessive disorder characterized by these 3 features, which begin at birth or in early childhood and are progressive (Irrthum et al., 2003).
SP110Hepatic venoocclusive disease with immunodeficiencyHepatic venoocclusive disease with immunodeficiency syndrome (VODI) is an autosomal recessive primary immunodeficiency associated with hepatic vascular occlusion and fibrosis. The immunodeficiency is characterized by severe hypogammaglobulinemia, combined T and B cell immunodeficiency, absent lymph node germinal centers, and absent tissue plasma cells (Roscioli et al., 2006).
SPARTSpactic paraplegia, type 20, autosomal recessiveSpactic paraplegia, type 20 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SPART gene located on chromosomal region 13q13.3. The age of onset is infancy. This disease is characterized by a slow, gradual, progressive weakness and spasticity of the lower limbs. Rate of progression and the severity of symptoms are quite variable. Initial symptoms may include difficulty with balance, weakness and stiffness in the legs, muscle spasms, and dragging the toes when walking. In some forms of the disorder, bladder symptoms (such as incontinence) may appear, or the weakness and stiffness may spread to other parts of the body. SPG20 is characterized by dysarthria, distal amyotrophy, mild developmental delay and short stature. The prevalence is <1/1,000,000.
SPATA7Leber congenital amaurosis 3Leber congenital amaurosis 3 is a severe dystrophy of the retina, typically becoming evident in the first years of life. Visual function is usually poor and often accompanied by nystagmus, sluggish or near-absent pupillary responses, photophobia, high hyperopia and keratoconus.
SPG11Amyotrophic lateral sclerosis, type 5, juvenileAmyotrophic lateral sclerosis, type 5, juvenile follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SPG11 gene located on chromosomal region 15q21.1. The age of onset is infancy/childhood. This disease is characterized by progressive upper and lower motor neuron degeneration causing facial spasticity, dysarthria, and gait disorders with onset before 25 years of age. The prevalence is <1/1,000,000.
SPG21Mast syndromeMast syndrome is an autosomal recessive complicated form of hereditary spastic paraplegia in which progressive spastic paraparesis is associated in more advanced cases with cognitive decline, dementia, and other neurologic abnormalities. Symptom onset usually occurs in adulthood, and the disorder is progressive with variable severity. Brain imaging shows thinning of the corpus callosum. The disorder occurs with high frequency in the Old Order Amish (Simpson et al., 2003).
SPG7Spastic paraplegia, type 7, autosomal recessiveSpastic paraplegia type 7 follows an autosomal recessive pattern of inheritance and is caused by pathogenic variants in the SPG7 gene located on chromosomal region 16q24.3. The age of onset is adult. This disease is characterized by by progressive muscle stiffness (spasticity) and the development of paralysis of the lower limbs (paraplegia) due to degeneration of corticospinal axons. The prevalence is 1:100,000-9:100,000.
SPINK1Tropical calcific pancreatitisTropical calcific pancreatitis (TCP) is a Idiopathic, juvenile, nonalcoholic form of chronic pancreatitis widely prevalent in several tropical countries. It can be associated with fibrocalculous pancreatic diabetes (FCPD) depending on both environmental and genetic factors. TCP differs from alcoholic pancreatitis by a much younger age of onset, pancreatic calcification, a high incidence of insulin dependent but ketosis resistant diabetes mellitus, and an exceptionally high incidence of pancreatic cancer.
SPINK5Netherton syndromeNetherton syndrome is a rare and severe autosomal recessive skin disorder characterized by congenital erythroderma, a specific hair-shaft abnormality, and atopic manifestations with high IgE levels. Generalized scaly erythroderma is apparent at or soon after birth and usually persists. Scalp hair is sparse and brittle with a characteristic 'bamboo' shape under light microscopic examination due to invagination of the distal part of the hair shaft to its proximal part. Atopic manifestations include eczema-like rashes, atopic dermatitis, pruritus, hay fever, angioedema, urticaria, high levels of IgE in the serum, and hypereosinophilia. Life-threatening complications are frequent during the neonatal period, including hypernatremic dehydration, hypothermia, extreme weight loss, bronchopneumonia, and sepsis. During childhood, failure to thrive is common as a result of malnutrition, metabolic disorders, chronic erythroderma, persistent cutaneous infections, or enteropathy (Bitoun et al., 2002).
SPINT2Diarrhea, type 3, secretory sodium, congenital, syndromicDiarrhea, type 3, secretory sodium, congenital, syndromic is a disease characterized by life-threatening secretory diarrhea, severe metabolic acidosis and hyponatremia. Hyponatremia is secondary to extraordinarily high fecal sodium loss, with low or normal excretion of urinary sodium, in the absence of infectious, autoimmune and endocrine causes.
SPRDystonia, dopa-responsive, due to sepiapterin reductase deficiencyDystonia, dopa-responsive, due to sepiapterin reductase deficiency results in neurologic deterioration due to severe dopamine and serotonin deficiencies in the central nervous system caused by a defect in BH4 synthesis. Clinically, affected individuals show an L-DOPA-responsive, diurnally fluctuating movement disorder usually associated with cognitive delay and severe neurologic dysfunction. BH4 is a required cofactor for the synthesis of the neurotransmitters dopamine and serotonin. BH4 is also a required cofactor for phenylalanine hydroxylase (PAH; 612349), but patients with SPR deficiency do not exhibit overt hyperphenylalaninemia. The lack of hyperphenylalaninemia distinguishes SPR deficiency from other disorders of BH4 synthesis (see, e.g., HPABH4A, 261640). However, the neurologic phenotype of SPR deficiency resembles the other BH4-deficient disorders (Bonafe et al., 2001; Friedman et al., 2012).Another form of dopa-responsive dystonia (DTY5; 128230) is caused by mutation in the gene encoding GTP cyclohydrolase I (GCH1; 600225), which is also a component of the biopterin synthetic pathway.
SPTA1Pyropoikilocytosis; Apherocytosis, type 3Pyropoikilocytosis was originally described by Zarkowsky et al. (1975) as a distinct hemolytic anemia characterized by microspherocytosis, poikilocytosis, and an unusual thermal sensitivity of red cells. Pyropoikilocytosis is a subset of hereditary elliptocytosis (611804) due to homozygous or compound heterozygous mutations in spectrin leading to severe disruption of spectrin self-association (An and Mohandas, 2008). Biallelic mutation in the SPTA1 gene can also cause spherocytosis, type 3 , a hematologic disorder leading to chronic hemolytic anemia and characterized by numerous abnormally shaped erythrocytes which are generally spheroidal.