97
(68.1%)

autosomal recessive osteopetrosis 3

Anemia Elevated serum acid phosphatase Hepatosplenomegaly

Autosomal recessive inheritance

Osteopetrosis with renal tubular acidosis is a rare disorder characterized by osteopetrosis, renal tubular acidosis (RTA), and neurological disorders related to cerebral calcifications.

97
(68.1%)

classic galactosemia

Cirrhosis Hemolytic anemia Hepatomegaly Metabolic acidosis

Autosomal recessive inheritance

Classic galactosemia is a life-threatening metabolic disease with onset in the neonatal period. Infants usually develop feeding difficulties, lethargy, and severe liver disease.

97
(68.1%)

myopathy, lactic acidosis, and sideroblastic anemia 2

Hepatomegaly Increased serum lactate Sideroblastic anemia

Autosomal recessive inheritance

Any mitochondrial myopathy and sideroblastic anemia in which the cause of the disease is a mutation in the YARS2 gene.

97
(68.1%)

severe early-onset pulmonary alveolar proteinosis due to MARS deficiency

Acidosis Anemia Cirrhosis Hepatomegaly

Autosomal recessive inheritance

97
(68.1%)

infantile liver failure syndrome 1

Anemia Hepatic steatosis Hepatomegaly Lactic acidosis

Autosomal recessive inheritance

Any infantile liver failure in which the cause of the disease is a mutation in the LARS gene.

97
(68.1%)

protein-losing enteropathy (disease)

Hepatomegaly Hypoalbuminemia Iron deficiency anemia

Autosomal recessive inheritance

Pathological conditions in the intestines that are characterized by the gastrointestinal loss of serum proteins, including serum albumin; immunoglobulins; and at times lymphocytes. Severe condition can result in hypogammaglobulinemia or lymphopenia. Protein-losing enteropathies are associated with a number of diseases including intestinal lymphangiectasis; whipple'S disease; and neoplasms of the small intestine.

97
(68.1%)

3-hydroxy-3-methylglutaric aciduria

Anemia Hepatomegaly Metabolic acidosis

Autosomal recessive inheritance

3-hydroxy-3-methylglutaric aciduria (3HMG) 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.

97
(68.1%)

mitochondrial myopathy, episodic, with optic atrophy and reversible leukoencephalopathy

Hepatomegaly Increased serum lactate Microcytic anemia

Autosomal recessive inheritance

97
(68.1%)

Wilson disease

Cirrhosis Hemolytic anemia Hepatomegaly Proteinuria

Autosomal recessive inheritance

Wilson disease is a very rare inherited multisystemic disease presenting non-specific neurological, hepatic, psychiatric or osseo-muscular manifestations due to excessive copper deposition in the body.

97
(68.1%)

propionic acidemia

Anemia Hepatomegaly Metabolic acidosis

Autosomal recessive inheritance

Propionic acidemia (PA) is an organic aciduria caused by the deficient activity of the propionyl Coenzyme A carboxylase and is characterized by life threatening episodes of metabolic decompensation, neurological dysfunction and that may be complicated by cardiomyopathy.

97
(68.1%)

cytochrome-c oxidase deficiency disease

Anemia Hepatomegaly Proteinuria

Autosomal recessive inheritance Heterogeneous Mitochondrial inheritance

A very rare inherited metabolic disorder characterized by deficiency of the enzyme cytochrome-C oxidase. It may be manifested as an isolated myopathy or a systemic disorder. Signs and symptoms include myotonia, dysfunction of the heart, kidney, and brain, and lactic acidosis.

97
(68.1%)

autosomal dominant Aarskog syndrome

Cirrhosis Hepatomegaly Lymphedema Macrocytic anemia

X-linked inheritance Sex-limited autosomal dominant

97
(68.1%)

thrombocytopenia-absent radius syndrome

Anemia Decreased circulating antibody level Hepatosplenomegaly

Autosomal recessive inheritance

Thrombocytopenia-absent radius (TAR) syndrome is a very rare congenital malformation syndrome characterized by bilateral radial aplasia and thrombocytopenia.

114
(67.5%)

combined immunodeficiency due to OX40 deficiency

Coombs-positive hemolytic anemia Splenomegaly

Autosomal recessive inheritance

Combined immunodeficiency due to OX40 deficiency is a rare combined T and B cell immunodeficiency characterized by susceptibility to develop an aggressive, childhood-onset, disseminated, cutaneous and systemic Kaposi sarcoma.

115
(67.3%)

vitamin B12-responsive methylmalonic acidemia type cblB

Anemia Hepatomegaly Methylmalonic acidemia

Autosomal recessive inheritance

An autosomal recessive form of methylmalonic aciduria, caused by mutation(s) in the MMAB gene, encoding cob(I)yrinic acid a,c-diamide adenosyltransferase, mitochondrial.

115
(67.3%)

vitamin B12-responsive methylmalonic acidemia type cblA

Anemia Hepatomegaly Methylmalonic acidemia

Autosomal recessive inheritance

An autosomal recessive form of methylmalonic aciduria, caused by mutation(s) in the MMAA gene, encoding MMAA protein.

117
(67.3%)

autoimmune polyendocrinopathy type 2

Asplenia Cirrhosis Iron deficiency anemia Type II diabetes mellitus

Autosomal dominant inheritance Autosomal recessive inheritance Multifactorial inheritance

Autoimmune polyglandular syndrome of likely polygenic etiology characterized by the presence of primary adrenal insufficiency in association with autoimmune thyroiditis and/or type 1 diabetes mellitus; this condition is not associated with mucocutaneous candidiasis.

118
(67.2%)

cirrhosis - dystonia - polycythemia - hypermanganesemia syndrome

Cirrhosis Hepatomegaly Hyperbilirubinemia Polycythemia

Autosomal recessive inheritance

119
(67.2%)

Stormorken syndrome

Anemia Asplenia Elevated serum creatine kinase Ichthyosis

Autosomal dominant inheritance

Stormorken-Sjaastad-Langslet syndrome is characterized by thrombocytopathy, asplenia, miosis, muscle fatigue, migraine, dyslexia, and ichthyosis. It has been described in six members of one family. It is transmitted as an autosomal dominant trait.

120
(67.2%)

thrombocytopenia, X-linked, with or without dyserythropoietic anemia

Acanthocytosis Anemia of inadequate production Epistaxis Petechiae

X-linked recessive inheritance

An X-linked condition caused by mutation(s) in the GATA1 gene, encoding erythroid transcription factor. It is characterized by thrombocytopenia, as well as abnormal platelet function and morphology. Dyserythropoietic anemia of variable severity may also be present.

121
(66.9%)

congenital dyserythropoietic anemia type 3

Hemosiderinuria Jaundice Macrocytic anemia

Autosomal dominant inheritance

Congenital dyserythropoietic anemia type III (CDA III) is a rare form of CDA characterized by dyserythropoiesis, with big multinucleated erythroblasts in the bone marrow, and manifesting with mild to moderate anemia.

121
(66.9%)

glycogen storage disease VII

Hemolytic anemia Hyperuricemia Jaundice

Autosomal recessive inheritance

Muscle phosphofructokinase (PFK) deficiency (Tarui's disease), or glycogen storage disease type 7 (GSD7), is a rare form of glycogen storage disease characterized by exertional fatigue and muscular exercise intolerance. It occurs in childhood.

123
(66.6%)

acquired polycythemia vera

Cerebral hemorrhage Increased red blood cell mass Splenomegaly

Autosomal dominant inheritance Somatic mutation Sporadic

Polycythemia vera (PV) is an acquired myeloproliferative disorder characterized by an elevated absolute red blood cell mass caused by uncontrolled red blood cell production, frequently associated with uncontrolled white blood cell and platelet production.

124
(66.2%)

STING-associated vasculopathy with onset in infancy

Anemia Cutis marmorata Fever Follicular hyperplasia

Autosomal dominant inheritance

STING-associated vasculopathy with onset in infancy (SAVI) is a rare, genetic autoinflammatory disorder, type I interferonopathy due to constitutive STING (STimulator of INterferon Genes) activation, characterized by neonatal or infantile onset systemic inflammation and small vessel vasculopathy resulting in severe skin, pulmonary and joint lesions. Patients present with intermittent low-grade fever, recurrent cough and failure to thrive, in association with progressive interstitial lung disease, polyarthritis and violaceous scaling lesions on fingers, toes, nose, cheeks, and ears (which are exacerbated by cold exposure) that often progress to chronic acral ulceration, necrosis and autoamputation.

125
(66.0%)

pyridoxine-responsive sideroblastic anemia

Hepatosplenomegaly Pyridoxine-responsive sideroblastic anemia

Autosomal recessive inheritance X-linked inheritance

125
(66.0%)

atypical Gaucher disease due to saposin C deficiency

Anemia Hepatosplenomegaly Osteopenia

Autosomal recessive inheritance

Any Gaucher disease in which the cause of the disease is a mutation in the PSAP gene.

125
(66.0%)

lethal hemolytic anemia-genital anomalies syndrome

Hemolytic anemia Hepatosplenomegaly Hypospadias

Autosomal dominant inheritance

Waters-West syndrome is characterized by the association of lethal non-spherocytic, non-immune hemolytic anemia with abnormalities of the external genitalia (micropenis and hypospadias), flat occiput, dimpled earlobes, deep plantar creases, and increased space between the first and second toes. It has been described only once in two brothers who died a few hours after birth. The second-born infant had massive ascites and hepatosplenomegaly. The mother had two spontaneous abortions (at 6 and 12 weeks gestation) but gave birth to a normal girl, suggesting an autosomal or X-linked recessive mode of inheritance. Although the parents were not known to be consanguineous, they shared a French-Canadian and American Indian ethnic origin.

125
(66.0%)

autosomal recessive osteopetrosis 2

Anemia Hepatosplenomegaly Mandibular prognathia

Autosomal recessive inheritance

Any autosomal recessive malignant osteopetrosis in which the cause of the disease is a mutation in the TNFSF11 gene.

125
(66.0%)

Shwachman-Diamond syndrome 2

Hepatomegaly High palate Normocytic anemia

Autosomal recessive inheritance

Shwachman-Diamond syndrome-2 (SDS2) is characterized by exocrine pancreatic dysfunction, hematopoietic abnormalities, short stature, and metaphyseal dysplasia ({1:Stepensky et al., 2017}).nnFor a discussion of genetic heterogeneity of Shwachman-Diamond syndrome, see SDS1 (OMIM:260400).

125
(66.0%)

Shwachman-Diamond syndrome 1

Anemia Hepatomegaly Nephrocalcinosis

Autosomal recessive inheritance

131
(64.8%)

fumaric aciduria

Cholestasis Metabolic acidosis Polycythemia

Autosomal recessive inheritance

Fumaric aciduria (FA), an autosomal recessive metabolic disorder, is most often characterized by early onset but non-specific clinical signs: hypotonia, severe psychomotor impairment, convulsions, respiratory distress, feeding difficulties and frequent cerebral malformations, along with a distinctive facies. Some patients present with only moderate intellectual impairment.

132
(64.8%)

X-linked congenital hemolytic anemia

Hemolytic anemia Jaundice

X-linked recessive inheritance

133
(64.7%)

neuroblastoma, susceptibility to

Abdominal mass Anemia Fever Skin nodule

Autosomal dominant inheritance Heterogeneous Somatic mutation Sporadic

134
(63.8%)

telangiectasia, hereditary hemorrhagic, type 2

Anemia Cirrhosis Cyanosis Lip telangiectasia Polycythemia

Autosomal dominant inheritance Heterogeneous

Any hereditary hemorrhagic telangiectasia in which the cause of the disease is a mutation in the ACVRL1 gene.

134
(63.8%)

telangiectasia, hereditary hemorrhagic, type 1

Anemia Cirrhosis Cyanosis Lip telangiectasia Polycythemia

Autosomal dominant inheritance

136
(63.4%)

congenital bile acid synthesis defect 2

Abnormality of the coagulation cascade Hyperbilirubinemia Jaundice Splenomegaly

Autosomal recessive inheritance

Congenital 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.

136
(63.4%)

immunodeficiency 47

Decreased circulating antibody level Leukopenia Prolonged neonatal jaundice Splenomegaly

X-linked recessive inheritance

Any primary immunodeficiency disease in which the cause of the disease is a mutation in the ATP6AP1 gene.

136
(63.4%)

Reynolds syndrome

Gastrointestinal hemorrhage Hyperbilirubinemia Jaundice Splenomegaly

Autosomal dominant inheritance

Reynolds syndrome (RS) is an autoimmune disorder characterized by the association of primary biliary cirrhosis (PBC) with limited cutaneous systemic sclerosis (lcSSc).

136
(63.4%)

congenital bile acid synthesis defect 3

Abnormality of the coagulation cascade Elevated alkaline phosphatase Jaundice Splenomegaly

Autosomal recessive inheritance

Congenital bile acid synthesis defect type 3 (BAS defect type 3) is a severe anomaly of bile acid synthesis characterized by severe neonatal cholestatic liver disease.

136
(63.4%)

congenital bile acid synthesis defect 1

Abnormality of the coagulation cascade Hyperbilirubinemia Jaundice Splenomegaly

Autosomal recessive inheritance

Congenital bile acid synthesis defect type 1 (BAS defect type 1) is the most common anomaly of bile acid synthesis characterized by variable manifestations of progressive cholestatic liver disease, and fat malabsorption.

136
(63.4%)

Niemann-Pick disease, type C1

Abnormal circulating cholesterol concentration Prolonged neonatal jaundice Sea-blue histiocytosis Splenomegaly

Autosomal recessive inheritance Heterogeneous

Type C Niemann-Pick disease associated with a mutation in the gene NPC1, encoding Niemann-Pick C1 protein.

136
(63.4%)

Niemann-Pick disease, type C2

Abnormal circulating cholesterol concentration Prolonged neonatal jaundice Sea-blue histiocytosis Splenomegaly

Autosomal recessive inheritance Heterogeneous

Niemann-Pick disease type C2 is a rare metabolic condition that affects many different parts of the body. Although signs and symptoms can develop at any age (infancy through adulthood), most affected people develop features of the condition during childhood. Neimann-Pick disease type C2 may be characterized by ataxia (difficulty coordinating movements), vertical supranuclear gaze palsy (inability to move the eyes vertically), poor muscle tone, hepatosplenomegaly (enlarged liver and spleen), interstitial lung disease, intellectual decline, seizures, speech problems, and difficulty swallowing. Niemann-Pick disease type C2 is caused by changes (mutations) in the NPC2 gene and is inherited in an autosomal recessive manner. There is, unfortunately, no cure for Niemann-Pick disease type C2. Treatment is based on the signs and symptoms present in each person.

136
(63.4%)

mitochondrial DNA depletion syndrome 3

Hypoglycemia Jaundice Splenomegaly Thrombocytopenia

Autosomal recessive inheritance

Any mitochondrial DNA depletion syndrome in which the cause of the disease is a mutation in the DGUOK gene.

136
(63.4%)

Aicardi-Goutieres syndrome 1

Fever Petechiae Prolonged neonatal jaundice Splenomegaly

Autosomal dominant inheritance Autosomal recessive inheritance

Any Aicardi-Goutieres syndrome in which the cause of the disease is a mutation in the TREX1 gene.

145
(63.1%)

X-linked erythropoietic protoporphyria

Cholelithiasis Increased erythrocyte protoporphyrin concentration Iron deficiency anemia

X-linked inheritance X-linked dominant inheritance

X-linked form of erythropoietic protoporphyria.

145
(63.1%)

protoporphyria, erythropoietic, 1

Cholelithiasis Edema Hemolytic anemia

Autosomal recessive inheritance

Erythropoietic protoporphyria caused by a compound heterozygous or homozygous mutation in the gene encoding ferrochelatase (FECH) on chromosome 18q21.

147
(62.9%)

pantothenate kinase-associated neurodegeneration

Acanthocytosis Dysphagia Hyperpigmentation of the skin Urinary incontinence

Autosomal recessive inheritance

Pantothenate kinase-associated neurodegeneration (PKAN) is the most common type of neurodegeneration with brain iron accumulation (NBIA), a rare neurodegenerative disorder characterized by progressive extrapyramidal dysfunction (dystonia, rigidity, choreoathetosis), iron accumulation on the brain and axonal spheroids in the central nervous system.

148
(62.6%)

multiple intestinal atresia

Abnormal abdomen morphology Autoimmune hemolytic anemia Hypertelorism Interface hepatitis

Autosomal recessive inheritance

Multiple intestinal atresia is a rare form of intestinal atresia characterized by the presence of numerous atresic segments in the small bowel (duodenum) or large bowel and leading to symptoms of intestinal obstruction: vomiting, abdominal bloating and inability to pass meconium in newborns.

149
(62.4%)

short stature with microcephaly and distinctive facies

Anemia Anisopoikilocytosis Microcephaly Recurrent infections Spotty hyperpigmentation

Autosomal recessive inheritance

150
(62.2%)

immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome

Autoimmune hemolytic anemia Diabetes mellitus Eczema Lymphadenopathy

X-linked recessive inheritance

Immunodysregulation - polyendocrinopathy - enteropathy - X-linked (IPEX) syndrome is a severe congenital systemic autoimmune disease characterized by refractory diarrhea, endocrinopathies, cutaneous involvement, and infections.

151
(62.0%)

combined immunodeficiency due to STIM1 deficiency

Autoimmune hemolytic anemia Hypohidrosis Lymphadenopathy Recurrent fever

Autosomal recessive inheritance

Aform of combined immunodeficiency due to Calcium release activated Ca2+(CRAC) channel dysfunction characterized by recurrent infections, autoimmunity, congenital myopathy and ectodermal dysplasia.

152
(61.8%)

hemochromatosis type 3

Anemia Cirrhosis Increased circulating ferritin concentration Purpura

Autosomal recessive inheritance

Type 3 hemochromatosis is a form of rare hereditary hemochromatosis (HH), a group of diseases characterized by excessive tissue iron deposition of genetic origin.

153
(61.6%)

autosomal recessive congenital ichthyosis 5

Acanthocytosis Erythroderma Palmoplantar keratoderma

Autosomal recessive inheritance

An autosomal recessive congenital ichthyosis characterized by fine white or greyish-white scales, hyperkeratosis, moderate acanthosis, and moderate parakeratosis that has material basis in homozygous mutation in the CYP4F22 gene on chromosome 19p13.

154
(61.4%)

hereditary fructose intolerance

Fructose intolerance Gastrointestinal hemorrhage Hepatomegaly Jaundice

Autosomal recessive inheritance

Hereditary fructose intolerance (HFI) is an autosomal recessive disorder of fructose metabolism, resulting from a deficiency of hepatic fructose-1-phosphate aldolase activity and leading to gastrointestinal disorders and postprandial hypoglycemia following fructose ingestion. HFI is a benign condition when treated, but it is life-threatening and potentially fatal if left untreated.

155
(61.3%)

pseudo-TORCH syndrome 1

Jaundice Petechiae Renal insufficiency Splenomegaly

Autosomal recessive inheritance

156
(61.1%)

Chuvash polycythemia

Hemangioma Increased red blood cell mass Plethora

Autosomal recessive inheritance

Chuvash erythrocytosis is a rare, genetic, congenital secondary polycythemia disorder characterized by increased hemoglobin, hematocrit and erythropoietin serum levels and normal oxygen affinity, which usually manifests with headache, dizziness, dyspnea and/or plethora. Patients present an increased risk of hemorrhage, thrombosis and early death.

157
(61.0%)

Wolman disease with hypolipoproteinemia and acanthocytosis

Acanthocytosis Hypolipoproteinemia Vomiting

Autosomal recessive inheritance

157
(61.0%)

abetalipoproteinemia

Abetalipoproteinemia Acanthocytosis Fat malabsorption

Autosomal recessive inheritance

Abetalipoproteinemia/ homozygous familial hypobetalipoproteinemia (ABL/HoFHBL) is a severe form of familial hypobetalipoproteinemia characterized by permanently low levels (below the 5th percentile) of apolipoprotein B and LDL cholesterol, and by growth delay, malabsorption, hepatomegaly, and neurological and neuromuscular manifestations.

157
(61.0%)

hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration

Acanthocytosis Decreased LDL cholesterol concentration Dysphagia

Autosomal recessive inheritance

157
(61.0%)

chorea-acanthocytosis

Acanthocytosis Dysphagia Elevated serum creatine kinase

Autosomal recessive inheritance

Chorea-acanthocytosis (ChAc) is a form of neuroacanthocytosis and is characterized clinically by a Huntington disease-like phenotype with progressive neurological symptoms including movement disorders, psychiatric manifestations and cognitive disturbances.

161
(60.9%)

Peutz-Jeghers syndrome

Abnormality of the ureter Biliary tract abnormality Iron deficiency anemia

Autosomal dominant inheritance

Peutz-Jeghers syndrome (PJS) is an inherited gastrointestinal disorder characterized by development of characteristic hamartomatous polyps throughout the gastrointestinal (GI) tract, and by mucocutaneous pigmentation. PJS carries a considerably increased risk of GI and extra-GI malignancies.

162
(60.7%)

CCDC115-CDG

Abnormal glycosylation Long face Prolonged neonatal jaundice Splenomegaly

Autosomal recessive inheritance

163
(60.7%)

congenital bile acid synthesis defect 4

Abnormality of the coagulation cascade Hepatomegaly Hyperbilirubinemia Prolonged neonatal jaundice

Autosomal recessive inheritance

Congenital bile acid synthesis defect type 4 (BAS defect type 4) is an anomaly of bile acid synthesis characterized by mild cholestatic liver disease, fat malabsorption and/or neurological disease.

163
(60.7%)

acute infantile liver failure due to synthesis defect of mtDNA-encoded proteins

Abnormality of the coagulation cascade Hepatomegaly Increased serum lactate Jaundice

Autosomal recessive inheritance

Acute infantile liver failure due to mtDNA-encoded proteins synthesis defect is a very rare mitochondrial respiratory chain deficiency described in fewer than 10 infants, primarily of middle Eastern descent, and characterized clinically by transient but life-threatening liver failure with elevated liver enzymes, jaundice, vomiting, coagulopathy, hyperbilirubinemia, and lactic acidemia.

163
(60.7%)

trichohepatoenteric syndrome 1

Hepatomegaly Hypoalbuminemia Jaundice Thrombocytosis

Autosomal recessive inheritance

Any tricho-hepato-enteric syndrome in which the cause of the disease is a mutation in the TTC37 gene.

166
(60.5%)

SRD5A3-CDG

Elevated hepatic transaminase Microcytic anemia Type I transferrin isoform profile

Autosomal recessive inheritance

SRD5A3-CDG is a rare, non X-linked congenital disorder of gyclosylation due to steroid 5 alpha reductase type 3 deficiency characterized by a highly variable phenotype typically presenting with severe visual impairment, variable ocular anomalies (such as optic nerve hypoplasia/atrophy, iris and optic nerve coloboma, congenital cataract, glaucoma), intellectual disability, cerebellar abnormalities, nystagmus, hypotonia, ataxia, and/or ichthyosiform skin lesions. Other reported manifestations include retinitis pigmentosa, kyphosis, congenital heart defects, hypertrichosis and abnormal coagulation.

167
(60.4%)

thrombocythemia 1

Acrocyanosis Hypertension Splenomegaly Thrombocytosis

Autosomal dominant inheritance

168
(59.9%)

paroxysmal nocturnal hemoglobinuria 2

Hemolytic anemia Paroxysmal nocturnal hemoglobinuria Urticaria

Autosomal dominant inheritance Somatic mutation

Any paroxysmal nocturnal hemoglobinuria in which the cause of the disease is a mutation in the PIGT gene.

168
(59.9%)

Fabry disease

Anemia Angiokeratoma Proteinuria

X-linked inheritance X-linked recessive inheritance

Fabry disease (FD) is a progressive, inherited, multisystemic lysosomal storage disease characterized by specific neurological, cutaneous, renal, cardiovascular, cochleo-vestibular and cerebrovascular manifestations.

168
(59.9%)

Wiskott-Aldrich syndrome

Decreased specific anti-polysaccharide antibody level Hemolytic anemia Petechiae

X-linked recessive inheritance

Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disease characterized by microthrombocytopenia, eczema, infections and an increased risk for autoimmune manifestations and malignancies.

168
(59.9%)

Fanconi anemia complementation group C

Anemia Bruising susceptibility Deficient excision of UV-induced pyrimidine dimers in DNA Reticulocytopenia

Autosomal recessive inheritance

Fanconi anemia caused by mutations of the FANCC gene. This gene provides instructions for making a protein that delays the onset of apoptosis and promotes homologous recombination repair of damaged DNA.

168
(59.9%)

Fanconi anemia complementation group E

Anemia Bruising susceptibility Deficient excision of UV-induced pyrimidine dimers in DNA Reticulocytopenia

Autosomal recessive inheritance

Fanconi anemia caused by mutations of the FANCE gene. This is a protein coding gene. It is required for the nuclear accumulation of FANCC and provides a critical bridge between the FA complex and FANCD2.

168
(59.9%)

Fanconi anemia complementation group A

Anemia Bruising susceptibility Deficient excision of UV-induced pyrimidine dimers in DNA Reticulocytopenia

Autosomal recessive inheritance

Fanconi anemia caused by mutations of the FANCA gene. FANCA gene mutations are the most common cause of Fanconi anemia. This gene provides instructions for making a protein that is involved in the Fanconi anemia (FA) pathway.

168
(59.9%)

Fanconi anemia complementation group D2

Anemia Bruising susceptibility Deficient excision of UV-induced pyrimidine dimers in DNA Reticulocytopenia

Autosomal recessive inheritance

Fanconi anemia caused by mutations of the FANCD2 gene. This gene is involved in the repair of DNA double-strand breaks, both by homologous recombination and single-strand annealing.

175
(59.8%)

congenital disorder of glycosylation type 1E

Reduced antithrombin III activity Splenomegaly Telangiectasia Type I transferrin isoform profile

Autosomal recessive inheritance

The CDG (Congenital Disorders of Glycosylation) syndromes are a group of autosomal recessive disorders affecting glycoprotein synthesis. CDG syndrome type Ie is characterised by psychomotor delay, seizures, hypotonia, facial dysmorphism and microcephaly. Ocular anomalies are also very common.

176
(59.7%)

juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome

Anemia Epistaxis Hepatic arteriovenous malformation Telangiectasia

Autosomal dominant inheritance

176
(59.7%)

dyskeratosis congenita, autosomal dominant 1

Anemia Carious teeth Cirrhosis Premature graying of hair

Autosomal dominant inheritance

A dyskeratosis congenita that has material basis in an autosomal dominant mutation of TERC on chromosome 3q26.2.

176
(59.7%)

dyskeratosis congenita, X-linked

Anemia Cirrhosis Cryptorchidism Premature graying of hair

X-linked recessive inheritance

X-linked form of dyskeratosis congenita.

179
(59.6%)

hyper-IgM syndrome type 4

Absence of lymph node germinal center Autoimmune hemolytic anemia Impaired Ig class switch recombination Recurrent infection of the gastrointestinal tract

Autosomal recessive inheritance

A form of Hyper IgM syndrome which is a defect in class switch recombination downstream of the AICDA gene that does not impair somatic hypermutation.

179
(59.6%)

combined immunodeficiency due to LRBA deficiency

Autoimmune hemolytic anemia Chronic diarrhea Decreased circulating IgA level Lymphadenopathy

Autosomal recessive inheritance

181
(59.4%)

progressive familial intrahepatic cholestasis type 1

Conjugated hyperbilirubinemia Jaundice Splenomegaly

Autosomal recessive inheritance

PFIC1, a type of progressive familial intrahepathic cholestasis (PFIC), is an infantile hereditary disorder in bile formation that is hepatocellular in origin and associated with extrahepatic features.

181
(59.4%)

Aagenaes syndrome

Jaundice Lymphedema Splenomegaly

Autosomal recessive inheritance

Cholestasis-lymphedema syndrome is a rare genetic disorder characterized by neonatal intrahepatic cholestasis, often lessening and becoming intermittent with age, and severe chronic lymphedema which mainly affects the lower limbs. Patients often present with fat malabsorption leading to failure to thrive, fat soluble vitamin deficiency with bleeding, rickets, and neuropathy. In 25% of cases, cirrhosis occurs during childhood or later in life.

181
(59.4%)

familial lipoprotein lipase deficiency

Hyperlipidemia Jaundice Lipemia retinalis Splenomegaly

Autosomal recessive inheritance

Familial lipoprotein 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. Familial lipoprotein lipase deficiency is caused by changes (mutations) in the LPL gene. It is inherited in an autosomal recessive pattern. Treatment aims to control symptoms and blood triglyceride levels with a very low-fat diet. Treatment for individual symptoms (i.e. pancreatitis) involves following established treatment guidelines.

181
(59.4%)

galactose epimerase deficiency

Aminoaciduria Jaundice Sensorineural hearing impairment Splenomegaly

Autosomal recessive inheritance

Galactose epimerase deficiency is a very rare, moderate to severe form of galactosemia characterized by moderate to severe signs of impaired galactose metabolism.

181
(59.4%)

progressive familial intrahepatic cholestasis type 2

Conjugated hyperbilirubinemia Intermittent jaundice Pruritus Splenomegaly

Autosomal recessive inheritance

Progressive familial intrahepatic cholestasis type 2 (PFIC2), a type of progressive familial intrahepatic cholestasis (PFIC), is a severe, neonatal, hereditary disorder in bile formation that is hepatocellular in origin and not associated with extrahepatic features. Initially, PFIC2 was reported under the name Byler syndrome.

181
(59.4%)

cholestasis-pigmentary retinopathy-cleft palate syndrome

Hyperbilirubinemia Jaundice Recurrent urinary tract infections Splenomegaly

Sporadic

Cholestasis- pigmentary retinopathy- cleft palate is a syndrome of multiple congenital malformations, characterized by an association of cleft lip and palate, patchy pigmentary retinopathy (cat's paw), obstructive liver disease (cholestasis, portal hypertension etc.) and obstructive renal disease (ectopic ureteric insertion, obstruction, vesicouretral reflux and hydronephrosis). Gastrointestinal tract involvement (malrotation, gastresophageal reflux etc.) and cardiac involvement (coarctation of aorta, pulmonary artery stenosis etc) have also been reported. An overlap with Kabuki syndrome is debated.

181
(59.4%)

peroxisome biogenesis disorder 5A (Zellweger)

Cryptorchidism Jaundice Palpebral edema Splenomegaly

Autosomal recessive inheritance

181
(59.4%)

COG7-CDG

Hypoglycemia Jaundice Neurogenic bladder Splenomegaly

Autosomal recessive inheritance

COG7-CDG is a congenital disorder of glycosylation characterised by dysmorphism, skeletal dysplasia, hypotonia, hepatosplenomegaly, jaundice, cardiac insufficiency, recurrent infections and epilepsy. To date, it has been described in two infants, both of whom died within the first three months of life. The syndrome is caused by a mutation in the gene encoding COG-7 (chromosome 16), a subunit of the oligomeric Golgi complex.

189
(59.4%)

microcytic anemia with liver iron overload

Abnormality of metabolism/homeostasis Abnormality of the liver Decreased mean corpuscular volume Hypochromia

Autosomal recessive inheritance

Congenital hypochromic microcytic anemia with progressive liver iron overload paradoxically associated with normal to moderately elevated serum ferritin levels has been described in three unrelated patients.

189
(59.4%)

atransferrinemia

Abnormality of the liver Atransferrinemia Hypochromic anemia

Autosomal recessive inheritance

Congenital atransferrinemia is a very rare hematologic disease caused by a transferrin (TF) deficiency and characterized by microcytic, hypochromic anemia (manifesting with pallor, fatigue and growth retardation) and iron overload, and that can be fatal if left untreated.

189
(59.4%)

3-methylglutaconic aciduria type 5

Glutaric aciduria Microvesicular hepatic steatosis Normochromic microcytic anemia

Autosomal recessive inheritance

Dilated cardiomyopathy with ataxia (DCMA) is characterized by severe early onset (before the age of three years) dilated cardiomyopathy (DCM) with conduction defects (long QT syndrome), non-progressive cerebellar ataxia, testicular dysgenesis, and 3-methylglutaconic aciduria.

192
(58.9%)

autoimmune pulmonary alveolar proteinosis

Cyanosis Pneumonia Polycythemia

Sporadic

Pulmonary alveolar proteinosis (PAP) is a rare lung disease characterized by the accumulation of a lipoproteinaceous substance in the distal air spaces which positively stains with periodic acid-Schiff (PAS).

193
(58.8%)

retinitis pigmentosa and erythrocytic microcytosis

Anemia Decreased serum iron Elliptocytosis Optic disc pallor Pallor

Autosomal recessive inheritance

194
(58.6%)

neonatal ichthyosis-sclerosing cholangitis syndrome

Abnormality of blood and blood-forming tissues Hepatomegaly Jaundice Sparse eyelashes

Autosomal recessive inheritance

Neonatal ichthyosis-sclerosing cholangitis (NISCH syndrome) is a very rare complex ichthyosis syndrome characterized by scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis.

195
(58.5%)

Seckel syndrome 10

Diabetes mellitus Elevated hemoglobin A1c Hepatic steatosis

Autosomal recessive inheritance

Any Seckel syndrome in which the cause of the disease is a mutation in the NSMCE2 gene.

196
(58.4%)

primary myelofibrosis

Fever Purpura Splenomegaly

Somatic mutation

Myelofibrosis with myeloid metaplasia is a myeloproliferative disease with annual incidence of approximately 1 case per 100,000 individuals and age at diagnosis around 60 (an increased prevalence is noted in Ashkenazi Jews). Clinical manifestations depend on the type of blood cell affected and may include anemia, pallor, splenomegaly, hypermetabolic state, petechiae, ecchymosis, bleeding, lymphadenopathy, hepatomegaly, portal hypertension.

196
(58.4%)

familial cold autoinflammatory syndrome 2

Lymphocytosis Recurrent fever Splenomegaly Urticaria

Autosomal dominant inheritance

An autoinflammatory disease caused by mutations in the NLRP12 gene. It is characterized by periodic fevers beginning in the first year of life that are triggered by cold exposure. Episodes occur more than once per month.

196
(58.4%)

GM1 gangliosidosis type 1

Angiokeratoma corporis diffusum Decreased beta-galactosidase activity Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

GM1 gangliosidosis type 1 is the severe infantile form of GM1 gangliosidosis with variable neurological and systemic manifestations.

196
(58.4%)

fucosidosis

Angiokeratoma Oligosacchariduria Splenomegaly Vacuolated lymphocytes

Autosomal recessive inheritance

Fucosidosis is an extremely rare lysosomal storage disorder characterized by a highly variable phenotype with common manifestations including neurologic deterioration, coarse facial features, growth retardation, and recurrent sinopulmonary infections, as well as seizures, visceromegaly, angiokeratoma and dysostosis.

200
(58.1%)

Pearson syndrome

Diabetes mellitus Pancreatic fibrosis Refractory sideroblastic anemia

Mitochondrial inheritance

Pearson syndrome is characterized by refractory sideroblastic anemia, vacuolization of bone marrow precursors and exocrine pancreatic dysfunction.