Hirschsprung disease

Summary

Hirschsprung disease (MONDO:0018309) is a disease with 61 cohort genes (25 GWAS associations across 7 studies) and 53 clinical trials. The dominant Reactome pathway is ERBB2 Activates PTK6 Signaling (4 cohort genes). Top therapeutic interventions include indocyanine green acid form.

At a glance

• Prevalence: 1-5 / 10 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 61
• GWAS associations: 25
• ClinVar variants: 81
• Phenotypes (HPO): 19
• Clinical trials: 53

Clinical features

Epidemiology

Prevalence records

6 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-5 / 10 000	15	Worldwide	Validated
Prevalence at birth	1-5 / 10 000	15	Worldwide	Validated
Point prevalence	1-5 / 10 000	13.2	Europe	Validated
Prevalence at birth	1-5 / 10 000	13.2	Europe	Validated
Prevalence at birth	1-5 / 10 000	21	United States	Validated
Prevalence at birth	1-5 / 10 000	22	Taiwan, Province of China	Validated

Signs & symptoms

Clinical features (HPO)

19 HPO clinical features (Orphanet curated; top 19 by frequency):

HPO ID	Term	Frequency
HP:0002251	Aganglionic megacolon	Very frequent (80-99%)
HP:0005214	Intestinal obstruction	Very frequent (80-99%)
HP:0012719	Functional abnormality of the gastrointestinal tract	Very frequent (80-99%)
HP:0002017	Nausea and vomiting	Very frequent (80-99%)
HP:0002019	Constipation	Very frequent (80-99%)
HP:0002027	Abdominal pain	Very frequent (80-99%)
HP:0001824	Weight loss	Frequent (30-79%)
HP:0003270	Abdominal distention	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0034754	Bilious emesis	Frequent (30-79%)
HP:6000224	Delayed passage of meconium	Frequent (30-79%)
HP:0002014	Diarrhea	Occasional (5-29%)
HP:0004322	Short stature	Occasional (5-29%)
HP:0004387	Enterocolitis	Occasional (5-29%)
HP:0031369	Colon perforation	Occasional (5-29%)
HP:0100806	Sepsis	Occasional (5-29%)
HP:0001531	Failure to thrive in infancy	Occasional (5-29%)
HP:0001510	Growth delay	Occasional (5-29%)
HP:0001561	Polyhydramnios	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Hirschsprung disease
Mondo ID	MONDO:0018309
MeSH	D006627
OMIM	142623
Orphanet	388
DOID	DOID:10487
ICD-10-CM	Q43.1
ICD-11	1772690306
NCIT	C34700
SNOMED CT	204739008
UMLS	C0019569
MedGen	5559
GARD	0006660
MedDRA	10010539
NORD	1244
Is cancer (heuristic)	no

Also known as: aganglionic megacolon · congenital intestinal aganglionosis · congenital megacolon · Hirschsprung disease · Hirschsprung disease susceptibility · Hirschsprung’s disease · HSCR · pelvirectal achalasia

Data availability: 81 ClinVar variants · 25 GWAS associations (7 studies) · 8 GenCC gene-disease records · 9 cell lines.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › Hirschsprung disease

Related subtypes (1923): inherited bleeding disorder, platelet-type, infantile liver failure, febrile seizures, familial, hereditary hypophosphatemic rickets, hypothyroidism, congenital, nongoitrous, isolated microphthalmia, nephrolithiasis/osteoporosis, hypophosphatemic, anemia, hypochromic microcytic with iron overload, camptodactyly syndrome, Guadalajara, cerebelloparenchymal disorder, Chiari malformation, developmental dysplasia of the hip, bone marrow failure syndrome, Zimmermann-Laband syndrome, autoimmune disease, multisystem, infantile-onset, multinodular goiter, orofacial cleft, spondylocostal dysostosis, X-linked disease, Y-linked disease, autosomal genetic disease, cornea plana, epithelial-stromal TGFBI dystrophy, congenital diarrhea, Klippel-Feil syndrome, familial polycythemia, myopia, inherited aplastic anemia, FG syndrome, hypotrichosis, hereditary Wilms tumor, familial hemolytic anemia, hereditary fallopian tube carcinoma, ariboflavinosis, bronchiectasis, spermatogenic failure, preeclampsia, cataract, celiac disease, inflammatory bowel disease, ciliopathy, Fuchs’ endothelial dystrophy, hypospadias, bone Paget disease, visceral leishmaniasis, tooth agenesis, nanophthalmia, hydatidiform mole, fibromuscular dysplasia, familial abdominal aortic aneurysm, Adams-Oliver syndrome, Achard syndrome, Achoo syndrome, acroleukopathy, symmetric, acromegaloid changes, cutis verticis gyrata, and corneal leukoma, acromial dimples, adenosine triphosphatase deficiency, anemia due to, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, amastia, bilateral, with ureteral triplication and dysmorphism, amelia and terminal transverse hemimelia, amenorrhea-galactorrhea syndrome, amyotrophic dystonic paraplegia, anal sphincter dysplasia, anal sphincter myopathy, internal, isolated aniridia, aniridia-absent patella syndrome, aniridia, microcornea, and spontaneously Reabsorbed cataract, anisocoria, ankyloglossia, diffuse idiopathic skeletal hyperostosis, annular erythema, anonychia-ectrodactyly, anonychia-onychodystrophy with brachydactyly type b and ectrodactyly, aortic arch interruption, facial palsy, and retinal coloboma, arcus senilis, arms, malformation of, arteries, anomalies of, arteriovenous malformations of the brain, arteritis, familial granulomatous, with juvenile polyarthritis, arthritis, sacroiliac, asymmetric short stature syndrome, PR interval, variation in, aurocephalosyndactyly, Axenfeld-Rieger anomaly with partially absent eye muscles, distinctive face, hydrocephaly, and skeletal abnormalities, azotemia, familial, gastroesophageal reflux disease, beta-amino acids, renal transport of, bladder diverticulum, blepharochalasis, superior, bone pain, periodic, Brachmann-de Lange-like facial changes with microcephaly, metatarsus adductus, and developmental delay, brachymesomelia-renal syndrome, Brachymetatarsus 4, Brachymorphism-onychodysplasia-dysphalangism syndrome, branchial myoclonus with spastic paraparesis and cerebellar ataxia, familial juvenile hypertrophy of the breast, bundle branch block, familial isolated complete right, butyrylesterase 1, Burkitt lymphoma, calcific aortic disease with immunologic abnormalities, familial, cancer, familial, with in vitro Radioresistance, canine teeth, absence of upper permanent, Car factor deficiency, Carabelli anomaly of maxillary molar teeth, carpal displacement, cervical hypertrichosis with underlying kyphoscoliosis, cervical rib disease, cervical vertebral Bridge, cervical vertebral dysplasia, chemodectoma, intraabdominal, with cutaneous angiolipomas, Chondronectin, choroidal osteoma, bilateral, cirrhosis, familial, congenital pseudoarthrosis of clavicle, aorta coarctation, coloboma, ocular, autosomal dominant, uveal coloboma-cleft lip and palate-intellectual disability, colonic varices without portal hypertension, comedones, familial Dyskeratotic, commissural lip pits, coracoclavicular joint, anomalous, cornea guttata with anterior polar cataracts, corneal degeneration, ribbonlike, with deafness, Schnyder corneal dystrophy, fleck corneal dystrophy, Meesmann corneal dystrophy, epithelial recurrent erosion dystrophy, coumarin resistance, coxa vara, cranioacrofacial syndrome, craniofacial-deafness-hand syndrome, craniorhiny, creatine phosphokinase, elevated serum, cryofibrinogenemia, familial primary, cryptotia, familial, isolated cryptophthalmia, Darwinian tubercle of pinna, autosomal dominant deafness - onychodystrophy syndrome, deafness-ear malformation-facial palsy syndrome, keratoderma hereditarium mutilans, deafness, mid-tone neural, deafness, sensorineural, with peripheral neuropathy and arterial disease, deafness, unilateral, deafness with anhidrotic ectodermal dysplasia, dens evaginatus, dens in dente and palatal invaginations, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, dementia/parkinsonism with non-Alzheimer amyloid plaques, primary failure of tooth eruption, dentin dysplasia type I, dentin dysplasia type II, dentin dysplasia-sclerotic bones syndrome, deoxyribose-5-phosphate aldolase deficiency, dentinogenesis imperfecta type 2, dentinogenesis imperfecta type 3, dermal Ridges, patternless, diarrhea, glucose-stimulated secretory, with common variable immunodeficiency, diastema, dental medial, dilution, pigmentary, discrimination, Two-point, reduction 1N, distal osteosclerosis, distichiasis with congenital anomalies of the heart and peripheral vasculature, DNA, satellite, 3, DNA, low-repetitive sequences of, double nail for fifth toe, duodenal ulcer due to antral G-cell hyperfunction, duodenal ulcer, hyperpepsinogenemic 1, dwarfism, Levi type, dwarfism with stiff joints and ocular abnormalities, dystelephalangy, ear antitragus, tag at base of, ear exostoses, ear folding, ear malformation, preauricular fistulae, congenital, ear pits, posterior helical, thickened earlobes-conductive deafness syndrome, ectodermal dysplasia syndrome with distinctive facial appearance and preaxial polydactyly of feet, ectodermal dysplasia with adrenal cyst, ectopia lentis 1, isolated, autosomal dominant, ectopia pupillae, ectrodactyly and ectodermal dysplasia without cleft lip/palate, ectrodactyly-cleft palate syndrome, edema, familial idiopathic, prepubertal, electroencephalographic peculiarity: 14 and 6 per sec. positive spike phenomenon, electroencephalographic peculiarity: fronto-precentral beta wave groups, emphysema, hereditary pulmonary, eosinophilia, familial, Eosinophilopenia, epidermoid cysts, epidermolysis bullosa with deficiency of galactosylhydroxylysyl glucosyltransferase, epidermolysis bullosa with congenital localized absence of skin and deformity of nails, erythema nodosum, familial, esophageal ring, lower, exchondrosis of pinna, posterior, exostoses-anetodermia-brachydactyly type E syndrome, facial spasm, factor VIII and Factor IX, combined deficiency of, factors VIII, IX and XI, combined deficiency of, factor 9 and Factor XI, combined deficiency of, fibrinolytic defect, fibrodysplasia ossificans progressiva, fibula, recurrent dislocation of head of, Floating-Harbor syndrome, flushing of ears and somnolence, focal epithelial hyperplasia of the oral mucosa, fragile site 10Q23, Friedreich ataxia, so-called, with optic atrophy and sensorineural deafness, intellectual disability, FRA12A type, fucosidase regulator, gamma-A-globulin, defect in assembly of, Gamstorp-Wohlfart syndrome, gastric volvulus, intrathoracic, MALT lymphoma, gastric mucosal hypertrophy, genu valgum, st. Helena familial, giant neutrophil leukocytes, globulin anomaly involving beta (2A)-globulin, glomuvenous malformation, Glucoglycinuria, glucose-6-phosphate dehydrogenase-like, glutamic acid decarboxylase, brain, membrane form, glutathione transferase activity toward trans-stilbene oxide, hyperglycinuria, granddad syndrome, Grant syndrome, granulosis rubra nasi, graying of hair, precocious, guanylate kinase 3, hairy nose tip, hairy palms and soles, hand clasping pattern, cavernous hemangiomas of face-supraumbilical midline raphe syndrome, Kasabach-Merritt syndrome, oculoauriculovertebral spectrum with radial defects, hemolytic poikilocytic anemia due to reduced ankyrin binding sites, hemoglobin–variants for which the chain carrying the mutation 1S unknown or uncertain, hepatic adenomas, familial, hernia, double inguinal, heterochromia iridis, histiocytic dermatoarthritis, humeroradial synostosis, 5-hydroxytryptamine oxygenase regulator, orthostatic hypotensive disorder, Streeten type, hypercalciuria, absorptive, 2, hyperheparinemia, hyperhidrosis palmaris ET plantaris, hyperimmunoglobulin G1(A1) syndrome, hyperlipoproteinemia, type II, and deafness, hyperostosis cranialis interna, hyperpigmentation of eyelid, hyperpigmentation of Fuldauer and Kuijpers, hyperproglucagonemia, hyperreflexia, hypersecretion of adrenal androgens, familial, hypotaurinemic retinal degeneration and cardiomyopathy, essential hypertension, genetic, hyperthermia, cutaneous, with headaches and nausea, hyperthyroxinemia, dystransthyretinemic, hypertrophia musculorum vera, hypoparathyroidism-deafness-renal disease syndrome, hypophosphatemic bone disease, hypoxanthine guanine phosphoribosyltransferase suppressor, ichthyosis-cheek-eyebrow syndrome, IgE responsiveness, atopic, fused mandibular incisors, incisors, lower central, absence of, incisors, rotation of upper central, incisors, shovel-shaped, insensitivity to pain with hyperplastic Myelinopathy, insect Stings, hypersensitivity to, interferon antiviral depressor, iris pigment layer, cleavage of, islet cell adenomatosis, intussusception, IVIC syndrome, internal carotid artery, spontaneous dissection of, keloid formation, keratitis fugax hereditaria, keratosis, familial actinic, angioosteohypertrophic syndrome, knuckle pads, Kyrle disease, labia minora, incomplete adhesion of, lactic acidosis, chronic adult form, laryngeal adductor paralysis, lattice degeneration of retina leading to retinal detachment, periodic fever, immunodeficiency, and thrombocytopenia syndrome, leg ulcers, familial, of juvenile onset, lentiginosis, centrofacial neurodysraphic, leukocyte nuclear appendages, hereditary prevalence of, levator-medial rectus synkinesis, lip, hamartomatous, lipoprotein types–Lt system, lipoprotein, variant of beta, lithium transport, low density lipoprotein, variation in molecular weight of, lumbar stenosis, familial, macrocephaly, benign familial, myelodysplastic syndrome associated with isolated del(5q), malocclusion due to protuberant upper front teeth, Mammastatin, mannose 6-phosphate receptor recognition defect, Lebanese type, marfanoid hypermobility syndrome, masticatory muscles, hypertrophy of, maxillofacial dysostosis, Meckel diverticulum, mediosternal depigmentation line, megalodactyly, melanoma tumor antigen Gp90, mental and growth retardation with amblyopia, mesomelic dwarfism of hypoplastic tibia and radius type, metachondromatosis, metachromasia of fibroblasts, metatarsus varus, type 1, microphthalmia, isolated, with corectopia, microspherophakia with hernia, microspherophakia-metaphyseal dysplasia syndrome, milia, multiple eruptive, tooth ankylosis, MOMO syndrome, antigen defined by monoclonal antibody Aj9, antigen defined by monoclonal antibody T87, Monophalangy of great toe, nondisjunction, mullerian aplasia and hyperandrogenism, multiple exostoses with spastic tetraparesis, muscle cramps, familial, muscular atrophy, malignant neurogenic, muscular hypoplasia, congenital universal, of Krabbe, myelinated optic nerve fibers, myopathy with storage of glycoproteins and Glycosaminoglycans, nasal alar collapse, bilateral, nasal bones, absence of, nasal groove, familial transverse, nasal hyperpigmentation, familial transverse, neurofibromatosis-pheochromocytoma-duodenal carcinoid syndrome, neuropathy, congenital, with arthrogryposis multiplex, neuropathy, with paraprotein in serum, cerebrospinal fluid and urine, neutropenia, chronic familial, hereditary neutrophilia, nevus anemicus, nevus flammeus of nape of neck, nipples inverted, familial supernumerary nipples, noduli Cutanei, multiple, with urinary tract abnormalities, nose, anomalous shape of, onychogryposis, pedal, with keratosis plantaris and coarse hair, omphalocele, autosomal, ophthalmomandibulomelic dysplasia, ophthalmoplegia, familial static, ophthalmoplegia, familial total, with iris transillumination, ossified ear cartilages, ossicular malformations, familial, osteosclerosis with ichthyosis and fractures, otofaciocervical syndrome, ovalocytosis, hereditary hemolytic, with defective erythropoiesis, osteochondrodysplasia, rhizomelic, with callosal agenesis, thrombocytopenia, hydrocephalus, and hypertension, palmaris longus muscle, absence of, hereditary chronic pancreatitis, pancytopenia and occlusive vascular disease, papillomatosis, confluent and reticulated, papillomatosis, florid, of nipple, Paramolar tubercle of bolk, Parotidomegaly, hereditary bilateral, Passovoy factor defect, patella aplasia/hypoplasia, patella, familial recurrent dislocation of, Pechet factor deficiency, pectus excavatum, pelvic lipomatosis with crossed renal ectopia, pernicious anemia, peroneal nerve, accessory deep, peroxidase, salivary, phagocytosis, plasma-related defect 1N, pheochromocytoma-islet cell tumor syndrome, phlebectasia of lips, phocomelia-ectrodactyly-deafness-sinus arrhythmia syndrome, phosphatase, acid, of tissues, phosphoglucomutase 4, 6-phosphogluconolactonase deficiency, phosphoglycoprotein 1, photomyoclonus, diabetes mellitus, deafness, nephropathy, and cerebral dysfunction, Robin sequence-oligodactyly syndrome, pigmented purpuric eruption, pilonidal sinus, platelet adenylate cyclase activity, platelet aggregation, spontaneous, platelet disorder, undefined, platelet factor 3 deficiency, platelet membrane fluidity, platelet responsiveness to adrenaline, depressed, platelet signal processing defect, familial spontaneous pneumothorax, polyposis, intestinal, scattered and discrete, polyposis, intestinal, with multiple exostoses, polyps, multiple and recurrent inflammatory fibroid, gastrointestinal, popliteal cyst, postaxial tetramelic oligodactyly, posterior column ataxia, Guttmacher syndrome, familial male-limited precocious puberty, premature chromatid separation trait, presenile dementia, Kraepelin type, priapism, familial idiopathic, pronation-supination of the forearm, impairment of, proteolytic capacity of plasma, Protrusio acetabuli, pruritus, hereditary localized, pseudoarthrogryposis, Pseudoatrophoderma colli, pseudomonilethrix, pseudoxanthoma elasticum, forme fruste, pterygium colli, isolated, pubic bone dysplasia, pulmonary atresia with ventricular septal defect, pulmonic stenosis, atrial septal defect, and unique electrocardiographic abnormalities, pulmonic stenosis and deafness, pupillary membrane, persistence of, purpura simplex, radial heads, posterior dislocation of, radio-renal syndrome, radius, aplasia of, with cleft lip/palate, ragweed sensitivity, raindrop hypopigmentation, Raynaud disease, recombinant 8 syndrome, red cell permeability defect, red cell phospholipid defect with hemolysis, retinal venous beading, rhiny, ring dermoid of cornea, Rombo syndrome, Robinow-Sorauf syndrome, Roussy-Levy syndrome, Silver-Russell syndrome, aplasia of lacrimal and salivary glands, salivary substance, Clostridium botulinum type, salivary duct calculi, pleomorphic adenoma, cleft palate-large ears-small head syndrome, sella turcica, bridged, sister chromatid exchange, frequency of, skeletal dysplasia with delayed epiphyseal and carpal bone ossification, Somatomedin, embryonic, spastic paraplegia with associated extrapyramidal signs, spastic paraplegia, optic atrophy, and dementia, sperm protamine P4, spinocerebellar ataxia with rigidity and peripheral neuropathy, spinocerebellar atrophy with pupillary paralysis, splenogonadal fusion-limb defects-micrognathia syndrome, splenomegaly syndrome with splenic Germinal center hypoplasia and reduced circulating T helper cells, split lower lip, split-hand and split-foot with hypodontia, Karsch-Neugebauer syndrome, spondylolisthesis, spondylosis, cervical, polycystic ovary syndrome, sternum, premature obliteration of sutures of, storm syndrome, striae distensae, familial, surface antigen, glycoprotein 75, symphalangism of toes, surface polypeptides, anonymous, symphalangism, C. S. Lewis type, distal symphalangism, symphalangism with multiple anomalies of hands and feet, synovial chondromatosis, familial, with dwarfism, syringomas, multiple, talonavicular coalition, tarsal coalition, tear protein, anodal, T-cell Subgroups, non-HLA-linked, teeth, odd shapes of, teeth present at birth, teeth, supernumerary, temperature-sensitive lethal mutation, spermatic cord torsion, tetralogy of fallot and glaucoma, tetramelic monodactyly, thumb deformity, thyroid hormone plasma membrane transport defect, tibial torsion, bilateral medial, toe, fifth, number of phalanges 1N, toe, misshapen, toe, rotated fifth, toes, relative length of first and second, toes, space between first and second, malposition of teeth with or without hypodontia/oligodontia, torus palatinus and torus mandibularis, tremor of intention, ataxia, and lipofuscinosis, trichomegaly, trichoepitheliomas, multiple desmoplastic, trigger thumb, triphalangeal thumb with double phalanges, triphalangeal thumb, Nonopposable, Tristichiasis, humerus trochlea aplasia, Tuftsin deficiency, suppressor of tumorigenicity 3, tune deafness, Undritz anomaly, Upington disease, ureter, bifid or double, ureterocele, urolithiasis, uric acid, autosomal dominant, urinary bladder, atony of, uterine anomalies, vascular helix of umbilical cord, veins, pattern of, on anterior thorax, venular insufficiency, systemic, vertebral hypoplasia with lumbar kyphosis, congenital vertical talus, vestibulocochlear dysfunction, progressive, volvulus of midgut, Woronets trait, ablepharon macrostomia syndrome, familial glucocorticoid deficiency, aganglionosis, total intestinal, agenesis of cerebral white matter, agnathia-otocephaly complex, Moynahan syndrome, alopecia - intellectual disability syndrome, amino aciduria with mental deficiency, dwarfism, muscular dystrophy, osteoporosis, and acidosis, Amobarbital, deficient N-hydroxylation of, amyloidosis of gingiva and conjunctiva, with intellectual disability, gelatinous drop-like corneal dystrophy, amyloidosis, cutaneous bullous, angiomatosis, diffuse Corticomeningeal, of Divry and van Bogaert, aniridia-renal agenesis-psychomotor retardation syndrome, anodontia, anosmia for isobutyric acid, antithrombin, familial hemorrhagic diathesis due to, Aphalangy-hemivertebrae-urogenital-intestinal dysgenesis syndrome, arteriosclerosis, severe juvenile, arthrogryposis, distal, with intellectual disability and characteristic facies, asthma, nasal polyps, and aspirin intolerance, asthma, short stature, and elevated IgA, ataxia with myoclonic epilepsy and presenile dementia, ataxia, deafness, and cardiomyopathy, ataxia-microcephaly-cataract syndrome, atherosclerosis-deafness-diabetes-epilepsy-nephropathy syndrome, Athrombia, essential, atonic-astatic syndrome of Foerster, atrichia with papular lesions, berry aneurysm, cirrhosis, pulmonary emphysema, and cerebral calcification, beta-aminoisobutyric acid, urinary excretion of, biliary malformation with renal tubular insufficiency, Bowen syndrome of multiple malformations, brachydactyly, type A2, with microcephaly, Elsahy-Waters syndrome, Sabinas brittle hair syndrome, hereditary arterial and articular multiple calcification syndrome, camptodactyly-ichthyosis syndrome, congenital disorder of glycosylation, type i/IIx, carboxypeptidase N deficiency, cardiac septal defects with coarctation of the aorta, cardioauditory syndrome of Sanchez Cascos, cardiomyopathy associated with myopathy and sudden death, carnitine deficiency, myopathic, colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, premature centromere division, cephalin lipidosis, cerebellar ataxia and neurosensory deafness, cerebellar ataxia, benign, with thermoanalgesia, cerebral angiopathy, dysphoric, cerebral malformation, seizures, hypertrichosis, and overlapping fingers, cerebrocortical degeneration of infancy, cervical vertebrae, agenesis of, CHAND syndrome, Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome, cholestasis with gallstone, ataxia, and visual disturbance, cholesterol pneumonia, chondroitin-6-sulfaturia, defective cellular immunity, nephrotic syndrome, central areolar choroidal dystrophy, chromosomal instability with tissue-specific radiosensitivity, circumvallate placenta syndrome, citrulline transport defect, Juberg-Hayward syndrome, coloboma, ocular, autosomal recessive, Jalili syndrome, convulsive disorder, familial, with prenatal or early onset, corneal dystrophy-perceptive deafness syndrome, corneal degeneration, band-shaped spheroid, congenital hereditary endothelial dystrophy of cornea, Crane-Heise syndrome, cranial nerves, congenital paresis of, cranial nerves, recurrent paresis of, temtamy syndrome, craniosynostosis with anomalies of the cranial base and digits, craniosynostosis-intellectual disability syndrome of 51N and Gettig, craniosynostosis-intellectual disability-clefting syndrome, cryptorchidism, curved nail of fourth toe, Cushing syndrome due to macronodular adrenal hyperplasia, cutis verticis gyrata and intellectual disability, cyanosis and hepatic disease, cysteine Peptiduria, cystic disease of lung, ventriculomegaly-cystic kidney disease, deafness, congenital, and familial myoclonic epilepsy, DOORS syndrome, high myopia-sensorineural deafness syndrome, conductive deafness-malformed external ear syndrome, deafness-vitiligo-achalasia syndrome, deafness-small bowel diverticulosis-neuropathy syndrome, deafness, neural, congenital moderate, deafness, neural, with atypical atopic dermatitis, dextrocardia with unusual facies and microphthalmia, diaminopentanuria, disseminated sclerosis with narcolepsy, Dohle bodies and leukemia, dwarfism, low-birth-weight type, with unresponsiveness to growth hormone, dwarfism, intellectual disability, and eye abnormality, dwarfism, proportionate, with hip dislocation, dysautonomia-like disorder, dysmyelination with jaundice, dystonia with Ringbinden, ectopia lentis 2, isolated, autosomal recessive, ectopia lentis et pupillae, encephalomalacia, multilocular, Fowler syndrome, endocardial fibroelastosis and coarctation of abdominal aorta, endothelial dystrophy, congenital hereditary, with nail hypoplasia, enterocolitis, congenital enteropathy due to enteropeptidase deficiency, protein-losing enteropathy, epidermolysis bullosa with diaphragmatic hernia, epilepsy, photogenic, with spastic diplegia and intellectual disability, celiac disease-epilepsy-cerebral calcification syndrome, epiphyseal dysplasia of femoral head, myopia, and deafness, epithelial squamous dysplasia, keratinizing desquamative, of urinary tract, immunodeficiency 32B, erythema of acral regions, ethanolaminosis, facial abnormalities, kyphoscoliosis, and intellectual disability, lethal faciocardiomelic dysplasia, faciothoracogenital syndrome, Fanconi-like syndrome, fever, familial lifelong persistent, fibrosclerosis, multifocal, focal epithelial hyperplasia, Fraser-like syndrome, Freesia Flowers, inability to smell, Friedreich ataxia and congenital glaucoma, fructose and galactose intolerance, monosodium glutamate sensitivity, gluteal muscles, absence of, GOMBO syndrome, granulocytopenia with immunoglobulin abnormality, grouped pigmentation of the retina, Halothane hepatitis, hemangiomatosis, cutaneous, with associated features, hepatic veno-occlusive disease-immunodeficiency syndrome, Hirschsprung disease with ulnar polydactyly, polysyndactyly of big toes, and ventricular septal defect, familial lipochrome histiocytosis, classic Hodgkin lymphoma, Hooft disease, Hutterite cerebroosteonephrodysplasia syndrome, hydroxyprolinemia, hymen, imperforate, Leydig cell hypoplasia, type 1, hyperleucine-Isoleucinemia, hyperlysinuria with hyperammonemia, hypermetabolism due to defect in mitochondria, hyperopia, high, hyperparathyroidism, neonatal self-limited primary, with hypercalciuria, hyperphosphatemia, polyuria, and seizures, hypertelorism and tetralogy of fallot, hypertrophic neuropathy and cataract, hyperuricemia, infantile, with abnormal behavior and normal hypoxanthine guanine phosphoribosyltransferase, hypoglycemia, leucine-induced, hypoinsulinemic hypoglycemia and body hemihypertrophy, hypogonadism with low-grade mental deficiency and microcephaly, hypogonadism, male, hypohidrosis with abnormal palmar dermal Ridges, hypokalemic alkalosis, familial, with specific renal tubulopathy, hypophosphatemia, renal, with intracerebral calcifications, hypopituitarism, congenital, with central diabetes insipidus, Bamforth-Lazarus syndrome, ichthyosis congenita with biliary atresia, ichthyosis-intellectual disability-dwarfism-renal impairment syndrome, ichthyosis, split hairs, and amino aciduria, immunoglobulin d level in plasma, low, channelopathy-associated congenital insensitivity to pain, autosomal recessive, indolylacroyl glycinuria with intellectual disability, inosine phosphorylase deficiency, immune defect due to, internal carotid arteries, hypoplasia of, immunodeficiency with defective T-cell response to interleukin 1, acetylation, slow, isovaleric acid, inability to smell, Jumping Frenchmen of Maine, oculocerebrofacial syndrome, Kaufman type, keratoconus and congenital hip dysplasia, keratoconus posticus circumscriptus, Kniest-like dysplasia with pursed lips and ectopia lentis, Kifafa seizure disorder, specific granule deficiency, Lambotte syndrome, absence deformity of leg-cataract syndrome, leukemia, acute myelocytic, with polyposis coli and colon cancer, lymphoid system deterioration, progressive, lymphopenic hypergammaglobulinemia, antibody deficiency, autoimmune hemolytic anemia, and glomerulonephritis, lysine malabsorption syndrome, macroepiphyseal dysplasia with osteoporosis, wrinkled skin, and aged appearance, macrosomia adiposa congenita, magnesium, elevated red cell, malocclusion and short stature, mandibulofacial dysostosis with mental deficiency, oculotrichoanal syndrome, megaepiphyseal dwarfism, megalencephaly with dysmyelination, megalocornea, mesoaxial hexadactyly and cardiac malformation, metaphyseal chondrodysplasia, Pena type, metaphyseal dysplasia, anetoderma, and optic atrophy, metaphyseal modeling abnormality, skin lesions, and spastic paraplegia, methionine malabsorption syndrome, microcephaly-micromelia syndrome, Jawad syndrome, microphthalmia with hyperopia, retinal degeneration, macrophakia, and dental anomalies, microtia with meatal atresia and conductive deafness, mucus inspissation of respiratory tract, muscular dystrophy, adult-onset, with leukoencephalopathy, muscular hypertonia, lethal, musk, inability to smell, myeloperoxidase deficiency, myopathy, granulovacuolar lobular, with electrical myotonia, myopathy due to malate-aspartate shuttle defect, myopathy with giant abnormal mitochondria, Keipert syndrome, nephropathy - deafness - hyperparathyroidism syndrome, neuroectodermal melanolysosomal disease, neurologic disease, infantile multisystem, with osseous fragility, neuropathy, hereditary motor and sensory, with excessive myelin folding complex, autosomal recessive, neuropathy, painful, obesity-hypoventilation syndrome, ocular myopathy with curare sensitivity, oculocerebral hypopigmentation syndrome of Preus, oculorenocerebellar syndrome, olivopontocerebellar atrophy II, autosomal recessive, Onychotrichodysplasia and neutropenia, ophthalmoplegia totalis with ptosis and miosis, ophthalmoplegic neuromuscular disorder with abnormal mitochondria, optic atrophy, hearing loss, and peripheral neuropathy, autosomal recessive, Opticocochleodentate degeneration, oral sensibility, disturbance of, Primrose syndrome, osteodysplasty, precocious, of Danks, Mayne, and Kozlowski, congenital osteogenesis imperfecta-microcephaly-cataracts syndrome, osteoma of middle ear, otoonychoperoneal syndrome, palant cleft palate syndrome, pancreatic agenesis, pancreatitis, sclerosing cholangitis, and sicca complex, Partington-Anderson syndrome, pellagra-like syndrome, periodontitis, chronic, adult, peripheral neuropathy, ataxia, focal necrotizing encephalopathy, and spongy degeneration of brain, peroneus tertius muscle, absence of, phenformin 4-hydroxylation, Rabson-Mendenhall syndrome, pituitary dwarfism with large sella turcica, plasma clot retraction factor, deficiency of, platelet prostacyclin receptor defect, pleoconial myopathy with salt craving, polycystic kidney, cataract, and congenital blindness, polymyoclonus, infantile, polysaccharide, storage of unusual, polyhydramnios, chronic idiopathic, Prepapillary vascular loops, progesterone resistance, prolactin deficiency, isolated, prolactin deficiency with obesity and enlarged testes, prune belly syndrome with pulmonic stenosis, intellectual disability, and deafness, 46,XY disorder of sex development due to 17-beta-hydroxysteroid dehydrogenase 3 deficiency, Pseudouridinuria and mental defect, pulmonary alveolar microlithiasis, pulmonary atresia-intact ventricular septum syndrome, pulmonary bullae causing pneumothorax, pulmonary venoocclusive disease, pulmonic stenosis, pulmonic stenosis and congenital nephrosis, pyloric atresia, pyropoikilocytosis, hereditary, radiculoneuropathy, fatal neonatal, Ramon syndrome, red skin pigment anomaly of new guinea, Reese retinal dysplasia, renal and mullerian duct hypoplasia, Perlman syndrome, respiratory underresponsiveness to hypoxia and hypercapnia, retinal degeneration and epilepsy, retinal telangiectasia and hypogammaglobulinemia, retinitis pigmentosa inversa with deafness, retinitis pigmentosa-intellectual disability-deafness-hypogenitalism syndrome, retinopathy, pigmentary, and intellectual disability, rod-cone dystrophy, sensorineural deafness, and Fanconi-type renal dysfunction, Rowley-Rosenberg syndrome, second metatarsal-metacarpal syndrome, senile plaque formation, short stature-obesity syndrome, Sjogren-Larsson-like ichthyosis without CNS or eye involvement, sodium-potassium-ATPase activity of red cell, growth delay due to insulin-like growth factor I resistance, ataxia, spastic, childhood-onset, autosomal recessive, with optic atrophy and intellectual disability, spastic diplegia and intellectual disability, spastic paraplegia with myoclonic epilepsy, spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome, spinal muscular atrophy with intellectual disability, spinal muscular atrophy with microcephaly and mental subnormality, familial isolated congenital asplenia, splenoportal vascular anomalies, spondylocostal dysostosis-anal and genitourinary malformations syndrome, subaortic stenosis, membranous, sucrosuria, hiatus hernia and intellectual disability, syndesmodysplasic dwarfism, tardive dyskinesia, taurodontism, teeth, fused, testes, rudimentary, tetraamelia with ectodermal dysplasia and lacrimal duct abnormalities, tetraamelia-multiple malformations syndrome, thalamic degeneration, symmetric infantile, thumb, distal hyperextensibility of, thymic aplasia with fetal death, thymoma, familial, tiglic acidemia, tibia, absence of, with congenital deafness, tongue, pigmented fungiform papillae of, Tryptophanuria with dwarfism, T-substance anomaly, Tyrosinosis, ulna hypoplasia-intellectual disability syndrome, ulnar agenesis and endocardial fibroelastosis, Valinemia, van Bogaert-Hozay syndrome, vascular hyalinosis, isolated right ventricular hypoplasia, vitiligo, progressive, with intellectual disability and urethral duplication, de Sanctis-Cacchione syndrome, xylosidase deficiency, Young syndrome, corpus callosum agenesis-abnormal genitalia syndrome, intestinal pseudoobstruction, neuronal, chronic idiopathic, X-linked, CGF1, arthrogryposis, congenital, lower limb, X-linked, hypotonia, congenital nystagmus, ataxia, and abnormal auditory brainstem responses, Simpson-Golabi-Behmel syndrome type 2, episodic muscle weakness, X-linked, radioulnar synostosis, radial ray abnormalities, and severe malformations in the male, Christianson syndrome, Armfield syndrome, radial ray deficiency, X-linked, alpha-thalassemia-myelodysplastic syndrome, cataract, ataxia, short stature, and intellectual disability, Tn polyagglutination syndrome, fragile X syndrome, deafness, cataract, retinitis pigmentosa, and sperm abnormalities, Lisch epithelial corneal dystrophy, synovial sarcoma, cardiomyopathy, fatal fetal, due to myocardial calcification, X-linked dominant chondrodysplasia, Chassaing-Lacombe type, immunodeficiency 47, Meester-Loeys syndrome, midface hypoplasia, hearing impairment, elliptocytosis, and nephrocalcinosis, Arts syndrome, tubulin, beta, bullous dystrophy, macular type, Nance-Horan syndrome, central incisors, absence of, Charcot-Marie-Tooth peroneal muscular atrophy, X-linked, with aplasia cutis congenita, Abruzzo-Erickson syndrome, X-linked complicated corpus callosum dysgenesis, cutis verticis gyrata, thyroid aplasia, and intellectual disability, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, focal dermal hypoplasia, glutamyl ribose-5-phosphate storage disease, granulomas, congenital cerebral, hemopoietic proliferation, Hhhh syndrome, ichthyosis and male hypogonadism, immunodeficiency, X-linked, with deficiency of 115,000 Dalton surface glycoprotein, immunoglobulin M, level of, impacted teeth, multiple, imprinting gene related to retinoblastoma, jaundice, familial obstructive, of infancy, Kallmann syndrome with spastic paraplegia, modifier, X-linked, for Neurofunctional defects, myelolymphatic insufficiency, nuclear ribonucleic acid, occipital hair, white lock of, omphalocele, X-linked, ophthalmoplegia, external, and myopia, optic atrophy–spastic paraplegia syndrome, Paine syndrome, Pierre Robin syndrome-faciodigital anomaly syndrome, properdin deficiency, X-linked, absent radius-anogenital anomalies syndrome, radiation sensitivity of natural killer activity, reticuloendotheliosis, X-linked, spastic paraparesis-deafness syndrome, spatial visualization, aptitude for, Taqi polymorphism, taurodontism, microdontia, and dens invaginatus, thrombocytopenia with elevated serum IgA and renal disease, thumbs, congenital Clasped, ulnar hypoplasia-split foot syndrome, unique green phenomenon, VACTERL association, X-linked, with or without hydrocephalus, widow’s peak syndrome, hairy ears, Y-linked, ubiquitin-activating enzyme, Y-linked, hypomagnesemia, hypertension, and hypercholesterolemia, mitochondrial, cardiomyopathy, infantile hypertrophic, chloramphenicol toxicity, nephropathy, chronic tubulointerstitial, pancreatic hypoplasia-diabetes-congenital heart disease syndrome, macrocytosis, familial, pancreatic beta cell agenesis with neonatal diabetes mellitus, chondrodysplasia-pseudohermaphroditism syndrome, familial caudal dysgenesis, gonadal agenesis, succinic acidemia, parotid salivary glands, polycystic dysgenetic disease of, enteropathy, familial, with villous edema and immunoglobulin G2 deficiency, pachydermodactyly, familial, angiokeratoma corporis diffusum with arteriovenous fistulas, pigment dispersion syndrome, setting-Sun phenomenon, familial benign, enuresis, nocturnal, 1, varicella, severe recurrent, dwarfism, familial, with muscle spasms, isoproterenol-mediated vasodilatation, nocturnal enuresis, 2, mitochondrial import-stimulating factor, hereditary hyperferritinemia with congenital cataracts, ectodermal dysplasia with intellectual disability and syndactyly, enamel hypoplasia, cataracts, and aqueductal stenosis, protocadherin 3, cardiac malformation, cleft lip/palate, microcephaly, and digital anomalies, portal vein, cavernous transformation of, midline malformations, multiple, with limb abnormalities and hypopituitarism, ichthyosis-intellectual disability syndrome with large keratohyalin granules in the skin, Ayme-Gripp syndrome, guanylate cyclase 2E, trisomy 18-like syndrome, muscular dystrophy, congenital, with severe central nervous system atrophy and absence of large myelinated fibers, osteoporosis-oculocutaneous hypopigmentation syndrome, myeloid tumor suppressor, epithelial basolateral chloride conductance regulator, rabbit, homolog of, atrophia maculosa varioliformis cutis, familial, spinal dysplasia, Anhalt type, Martinez-Frias syndrome, myelodysplasia, immunodeficiency, facial dysmorphism, short stature, and psychomotor delay, ectrodactyly of lower limbs, congenital heart defect, and micrognathia, short stature, Brussels type, deafness-epiphyseal dysplasia-short stature syndrome, amelia cleft lip palate hydrocephalus iris coloboma, distal monosomy 10p, cervical ribs, Sprengel anomaly, anal atresia, and urethral obstruction, microcephaly, corpus callosum dysgenesis, and cleft lip/palate, anterior chamber cleavage disorder, cerebellar hypoplasia, hypothyroidism, and tracheal stenosis, progressive deafness with stapes fixation, patent ductus venosus, ribbing disease, microcephaly, retinitis pigmentosa, and sutural cataract, facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome, spastic paraplegia and Evans syndrome, iris pigment epithelium anomalies, acute insulin response, sebaceous gland hyperplasia, familial presenile, superior transverse scapular ligament, calcification of, familial, Spondylospinal thoracic dysostosis, acroosteolysis-keloid-like lesions-premature aging syndrome, vacuolar Neuromyopathy, sperm-specific antigen 1, otofacioosseous-gonadal syndrome, broad terminal phalanges, familial, capillary infantile hemangioma, medium chain 3-ketoacyl-Coa thiolase deficiency, ventriculomegaly with defects of the radius and kidney, mitochondrial intermembrane space protein Tim12, yeast, homolog of, sensorineural hearing loss, retinal pigment epithelium lesions, discolored teeth, Weyers ulnar ray/oligodactyly syndrome, creases, infra-auricular cutaneous, with tall stature and advanced bone age, pseudoacromegaly with severe insulin resistance, grange syndrome, jejunal atresia with renal adysplasia, microcephaly, macrotia, and intellectual disability, facial dysmorphism, cleft palate, hearing loss, and camptodactyly, brachydactyly, intraventricular septal defect, and deafness, emphysema, congenital, with deafness, penoscrotal web, and intellectual disability, pancreatic lymphoma, familial, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, skeletal dysplasia and progressive central nervous system degeneration, lethal, intellectual disability, severe, with spasticity and pigmentary tapetoretinal degeneration, tumor suppressor gene on chromosome 11, spastic paraplegia, optic atrophy, microcephaly, and 10Y sex reversal, apraxia of eyelid opening, dislocated elbows, bowed tibias, scoliosis, deafness, cataract, microcephaly, and intellectual disability, muscular dystrophy, congenital, with cerebellar atrophy, GRACILE syndrome, familial gestational hyperthyroidism, long chain fatty acids, defect in transport of, Osebold skeletal dysplasia/osteolysis syndrome, osteosclerotic chondrodysplasia, lethal, with intracellular inclusions, microcephaly, severe, with skeletal anomalies including posterior rib-Gap defects, Tonoki syndrome, expansile bone lesions, Oroacral syndrome, Verloes-Koulischer type, Dyserythropoiesis, congenital, with ultrastructurally normal erythroblast heterochromatin, microcephaly, facial abnormalities, micromelia, and intellectual disability, follicular atrophoderma, perioral pigmented, with milia and epidermoid cysts, parotitis, juvenile recurrent, facial dysmorphism, selective tooth agenesis, and choroid calcification, osteoma of cranial vault, familial, neuroendocrine carcinoma of salivary glands, sensorineural hearing loss, and enamel hypoplasia, atrial septal defect, secundum, with various cardiac and Noncardiac defects, exostosis, Dupuytren subungual, eccrine syringofibroadenomatosis with eyelid abnormalities, blue nevi, familial multiple, blepharophimosis - intellectual disability syndrome, SBBYS type, Acrodysplasia with ossification abnormalities, short stature, and fibular hypoplasia, intervertebral disk degenerative disorder, Caronte, cholesteatoma, congenital, Hirschsprung disease with heart defects, laryngeal anomalies, and preaxial polydactyly, Chudley-McCullough syndrome, camera-Marugo-Cohen syndrome, anemia, congenital hypoplastic, with multiple congenital anomalies/intellectual disability syndrome, myoclonic epilepsy, congenital deafness, macular dystrophy, and psychiatric disorders, ulnar ray dysgenesis with postaxial polydactyly and renal cystic dysplasia, lissencephaly, familial, with cleft palate and cerebellar hypoplasia, polyneuropathy, lethal neonatal, axonal sensorimotor, autosomal recessive, growth and developintellectual disability, ocular ptosis, cardiac defect, and anal atresia, polycystic bone disease, mandibulofacial dysostosis syndrome, Bauru type, hyaluronan metabolism, defect 1N, wormian bone-multiple fractures-dentinogenesis imperfecta-skeletal dysplasia, Wolfram syndrome 2, diabetes mellitus, congenital autoimmune, low density lipoprotein cholesterol, mild elevation of, clavicular hypoplasia, zygomatic arch hypoplasia, and micrognathia, early response to neural induction gene, pseudohyperaldosteronism type 2, Wiedemann-Steiner syndrome, frontoocular syndrome, fibromatosis, gingival, with hypertrichosis and intellectual disability, tetralogy of fallot syndrome, autosomal recessive, anisomastia, ovarian dysgenesis, hypergonadotropic, with short stature and recurrent metabolic acidosis, short stature, intellectual disability, callosal agenesis, Heminasal hypoplasia, microphthalmia, and atypical clefting, arthropathy, erosive, liver fibrocystic disease and polydactyly, crumpled helices and small mouth, acromegaloid features, overgrowth, cleft palate, and hernia, Sener syndrome, baculum, congenital absence of, carnitine acetyltransferase deficiency, laryngeal abductor paralysis with cerebellar ataxia and motor neuropathy, intellectual disability, short stature, facial anomalies, and joint dislocations, Phelan-McDermid syndrome, intellectual disability, microcephaly, growth retardation, joint contractures, and facial dysmorphism, alveolar soft part sarcoma, pathological gambling, Megarbane syndrome, partial lipodystrophy, congenital cataracts, and neurodegeneration syndrome, gastrointestinal stromal tumor, hemifacial myohyperplasia, peripheral arterial occlusive disease 1, parasomnia, sleep bruxism type, Cardioneuromyopathy with hyaline masses and nemaline rods, Cree intellectual disability syndrome, primary intraosseous venous malformation, duodenojejunal atresia with volvulus, absent dorsal mesentery, and absent superior mesenteric artery, symphalangism, distal, with microdontia, dental pulp stones, and narrowed zygomatic arch, COPD, severe early onset, laryngeal atresia, encephalocele, and limb deformities, epilepsy, partial, with pericentral spikes, hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration, horizontal gaze palsy with progressive scoliosis, streptococcus, group A, severity of infection by, thyroid Hurthle cell carcinoma, headache associated with sexual activity, Camptosynpolydactyly, complex, secretory diarrhea, myopathy, and deafness, spastic paraplegia, ataxia, and intellectual disability, breath-holding Spells, prostate cancer aggressiveness quantitative trait locus on chromosome 19, microphthalmia with cyst, bilateral facial clefts, and limb anomalies, cataract, congenital, with mental impairment and dentate gyrus atrophy, craniolenticulosutural dysplasia, nonimmune chronic idiopathic neutropenia of adults, caudal duplication, Thai symphalangism syndrome, bile and pancreatic ducts, complete absence of, ovarian hyperstimulation syndrome, zinc deficiency, transient neonatal, aspirin resistance, mandibulofacial dysostosis with ptosis, autosomal dominant, parathyroid gland carcinoma, growth failure, microcephaly, intellectual disability, cataracts, large joint contractures, osteoporosis, cortical dysplasia, and cerebellar atrophy, scimitar anomaly, multiple cardiac malformations, and craniofacial and central nervous system abnormalities, capillary malformation-arteriovenous malformation syndrome, speech-sound disorder, alopecia universalis congenita, 10Y gonadal dysgenesis, and laryngomalacia, choanal atresia-hearing loss-cardiac defects-craniofacial dysmorphism syndrome, brachial palsy, familial congenital, oligodontia-cancer predisposition syndrome, midface hypoplasia, obesity, developmental delay, and neonatal hypotonia, ichthyosis prematurity syndrome, intellectual disability-brachydactyly-Pierre Robin syndrome, neuropathy, hereditary sensory and autonomic, adult-onset, with anosmia, growth delay due to insulin-like growth factor type 1 deficiency, sudden infant death-dysgenesis of the testes syndrome, leukoencephalopathy, arthritis, colitis, and hypogammaglobulinema, metaphyseal undermodeling, spondylar dysplasia, and overgrowth, lateral semicircular canal malformation, familial, with external and middle ear abnormalities, Meacham syndrome, marfanoid habitus with situs inversus, peripheral cone dystrophy, Emanuel syndrome, intellectual disability with optic atrophy, facial dysmorphism, microcephaly, and short stature, skeletal dysplasia, rhizomelic, with retinitis pigmentosa, familial hyperthyroidism due to mutations in TSH receptor, umbilicus, familial flat, dandy-walker malformation with occipital cephalocele, autosomal dominant, hypotrichosis, progressive patterned scalp, with wiry hair, onycholysis, and cleft lip/palate, syncope, familial vasovagal, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, chromosome 18 pericentric inversion, colloid cysts of third ventricle, intellectual disability, keratoconus, febrile seizures, and sinoatrial block, Goldberg-Shprintzen syndrome, cleft palate, midfacial hypoplasia, triangular facies, and sensorineural hearing loss, nephropathy, progressive, with deafness, iridogoniodysgenesis and skeletal anomalies, omphalocele, diaphragmatic hernia, and radial ray defects, spondylomegaepiphyseal dysplasia with upper limb mesomelia, punctate calcifications, and deafness, Nguyen syndrome, trichilemmal cyst, short stature and Facioauriculothoracic malformations, 7q11.23 microduplication syndrome, hamartoma, Precalcaneal congenital fibrolipomatous, vasculitis, lymphocytic, cutaneous small vessel, ectodermal dysplasia, sensorineural hearing loss, and distinctive facial features, brachyphalangy, polydactyly, and tibial aplasia/hypoplasia, metaphyseal chondrodysplasia with cone-shaped epiphyses, normal hair, and normal hands, trichoscyphodysplasia, arthrogryposis multiplex with deafness, inguinal hernias, and early death, brachydactyly, coloboma, and anterior segment dysgenesis, congenital stromal corneal dystrophy, Devriendt syndrome, MORM syndrome, kyphoscoliosis 1, esophagitis, eosinophilic, 1, alcohol sensitivity, acute, Kleefstra syndrome, rhizomelic dysplasia, scoliosis, and retinitis pigmentosa, right pulmonary artery, anomalous origin of, familial, preauricular tag, isolated, autosomal dominant, 1, testicular microlithiasis, Koolen-de Vries syndrome, preterm premature rupture of the membranes, insulin-resistance syndrome type A, corticosterone methyloxidase type 2 deficiency, holoprosencephaly, recurrent infections, and monocytosis, deafness with labyrinthine aplasia, microtia, and microdontia, iris pattern, epiphyseal dysplasia, Baumann type, Polyosteolysis-hyperostosis syndrome, Sakoda complex, Potocki-Lupski syndrome, hereditary pulmonary alveolar proteinosis, craniofacial dysplasia - osteopenia syndrome, Mungan syndrome, Tented eyebrows, corticosteroid-binding globulin deficiency, familial cavitary optic disk anomaly, renal tubular acidosis, distal, with nephrocalcinosis, short stature, intellectual disability, and distinctive facies, peripapillary atrophy, beta type, dystonia with cerebellar atrophy, Dauwerse-Peters syndrome, tremor, hereditary essential, and idiopathic normal pressure hydrocephalus, mesomelic dysplasia, camera type, Stevenson-Carey syndrome, Hunter-Macdonald syndrome, hypophosphatemic rickets and hyperparathyroidism, deafness, unilateral, with delayed endolymphatic hydrops, histiocytoma, Angiomatoid fibrous, diastasis recti and weakness of the linea alba, Ewing sarcoma, extraskeletal myxoid chondrosarcoma, bilateral microtia-deafness-cleft palate syndrome, Pseudofolliculitis barbae, skeletal defects, genital hypoplasia, and intellectual disability, endocrine-cerebro-osteodysplasia syndrome, cholestasis-pigmentary retinopathy-cleft palate syndrome, faciocardiomelic syndrome, hypotonia, seizures, and precocious puberty, Megarbane-Jalkh syndrome, Giacheti syndrome, lethal polymalformative syndrome, Boissel type, microcephaly, growth retardation, cataract, hearing loss, and unusual appearance, Stargardt macular degeneration, absent or hypoplastic corpus callosum, intellectual disability, and dysmorphic features, Santos syndrome, CLAPO syndrome, hereditary hypotrichosis with recurrent skin vesicles, hydrops fetalis, nonimmune, with gracile bones and dysmorphic features, trichotillomania, Pseudopili annulati, bile acid malabsorption, primary, 1, syndromic multisystem autoimmune disease due to ITCH deficiency, Birbeck granule deficiency, Warsaw breakage syndrome, chromosome 15q24 deletion syndrome, esophagitis, eosinophilic, 2, Reynolds syndrome, early repolarization associated with ventricular fibrillation, chromosome 4Q32.1-q32.2 triplication syndrome, forsythe-wakeling syndrome, lymphedema-posterior choanal atresia syndrome, agenesis of the corpus callosum and congenital lymphedema, brachydactyly, type A1, with short stature, scoliosis, microcephaly, ptosis, hearing loss, and intellectual disability, odontoid hypoplasia, cocoon syndrome, tuberculin skin test reactivity, absence of, intellectual disability, anterior maxillary protrusion, and strabismus, THOC6-related developmental delay-microcephaly-facial dysmorphism syndrome, mammary-digital-nail syndrome, supernumerary der(22)t(8;22) syndrome, porencephaly-microcephaly-bilateral congenital cataract syndrome, chromosome 1p32-p31 deletion syndrome, Congenital adrenal insufficiency with 46, XY sex reversal OR 46,XY disorder of sex development-adrenal insufficiency due to CYP11A1 deficiency, multisystemic smooth muscle dysfunction syndrome, inosine triphosphatase deficiency, fucosyltransferase 6 deficiency, Hirschsprung disease, cardiac defects, and autonomic dysfunction, obesity, hyperphagia, and developmental delay, lipodystrophy, partial, acquired, with low complement component c3, with or without glomerulonephritis, acetyl-coa carboxylase deficiency, Okt4 epitope deficiency, cyanosis, transient neonatal, protein Z deficiency, hydroxyacyl glutathione hydrolase deficiency, trypsinogen deficiency, acetyl-CoA acetyltransferase-2 deficiency, N-acetylaspartate deficiency, anhaptoglobinemia, plasma fibronectin deficiency, recurrent infections associated with rare immunoglobulin isotypes deficiency, hyperbiliverdinemia, myostatin-related muscle hypertrophy, hypertelorism-preauricular sinus-punctual pits-deafness syndrome, craniofacial anomalies and anterior segment dysgenesis syndrome, microcephaly-capillary malformation syndrome, arthrogryposis, Perthes disease, and upward gaze palsy, platelet-activating factor acetylhydrolase deficiency, tetrasomy 18p, EDICT syndrome, cognitive impairment with or without cerebellar ataxia, peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome, glucocorticoid therapy, response to, transient infantile hypertriglyceridemia and hepatosteatosis, Huppke-Brendel syndrome, psychomotor retardation, epilepsy, and craniofacial dysmorphism, encephalomyopathy, mitochondrial, due to voltage-dependent anion channel deficiency, intestinal obstruction in the newborn due to guanylate cyclase 2C deficiency, hypertelorism and other facial dysmorphism, brachydactyly, genital abnormalities, intellectual disability, and recurrent inflammatory episodes, alar cleft, isolated, facial paresis, hereditary congenital, 3, Malan overgrowth syndrome, metaphyseal chondromatosis with D-2-hydroxyglutaric aciduria, immunodeficiency 28, retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome, phosphohydroxylysinuria, facial dysmorphism-immunodeficiency-livedo-short stature syndrome, intellectual disability-strabismus syndrome, estrogen resistance syndrome, severe feeding difficulties-failure to thrive-microcephaly due to ASXL3 deficiency syndrome, severe dermatitis-multiple allergies-metabolic wasting syndrome, severe intellectual disability-short stature-behavioral abnormalities-facial dysmorphism syndrome, testicular anomalies with or without congenital heart disease, multiple fibroadenoma of the breast, complement factor b deficiency, microcephaly-thin corpus callosum-intellectual disability syndrome, L-ferritin deficiency, macrocephaly-developmental delay syndrome, autosomal recessive primary immunodeficiency with defective spontaneous natural killer cell cytotoxicity, chromosome 16 inversion, 0.45-Mb, short stature due to GHSR deficiency, Webb-Dattani syndrome, kallikrein, decreased urinary activity of, short stature due to primary acid-labile subunit deficiency, hyperthyroxinemia, familial dysalbuminemic, congenital analbuminemia, immunodeficiency 37, retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, chronic atrial and intestinal dysrhythmia, hyperproinsulinemia, Tenorio syndrome, congenital contractures of the limbs and face, hypotonia, and developmental delay, mitochondrial short-chain Enoyl-Coa hydratase 1 deficiency, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, immunodeficiency 39, mandibulofacial dysostosis with alopecia, congenital cataract-microcephaly-nevus flammeus simplex-severe intellectual disability syndrome, BENTA disease, microcephaly-intellectual disability-sensorineural hearing loss-epilepsy-abnormal muscle tone syndrome, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, primary immunodeficiency with post-measles-mumps-rubella vaccine viral infection, PMP22-RAI1 contiguous gene duplication syndrome, DeSanto-Shinawi syndrome due to WAC point mutation, familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome, palatal anomalies-widely spaced teeth-facial dysmorphism-developmental delay syndrome, wooly hair, autosomal recessive 3, leukodystrophy and acquired microcephaly with or without dystonia;, inherited oocyte maturation defect, Lamb-Shaffer syndrome, Luscan-Lumish syndrome, exercise intolerance, riboflavin-responsive, split-foot malformation-mesoaxial polydactyly syndrome, heart and brain malformation syndrome, chorea, childhood-onset, with psychomotor retardation, retinitis pigmentosa and erythrocytic microcytosis, macrocephaly, dysmorphic facies, and psychomotor retardation, MIRAGE syndrome, tall stature-intellectual disability-renal anomalies syndrome, Alazami-Yuan syndrome, ZTTK syndrome, Sifrim-Hitz-Weiss syndrome, short stature, rhizomelic, with microcephaly, micrognathia, and developmental delay, Chitayat syndrome, language delay and attention deficit-hyperactivity disorder/cognitive impairment with or without cardiac arrhythmia, Shashi-Pena syndrome, sudden cardiac failure, infantile, sudden cardiac failure, alcohol-induced, cone-rod dystrophy and hearing loss, lung disease, immunodeficiency, and chromosome breakage syndrome;, uncombable hair syndrome 2, uncombable hair syndrome 3, global developmental delay, absent or hypoplastic corpus callosum, and dysmorphic facies, coloboma, osteopetrosis, microphthalmia, macrocephaly, albinism, and deafness, Yao syndrome, hypotonia, ataxia, and delayed development syndrome, FRAXF syndrome, arthrogryposis multiplex congenita, aniridia - intellectual disability syndrome, radial deficiency-tibial hypoplasia syndrome, familial pancreatic carcinoma, progeroid syndrome, 17q11.2 microduplication syndrome, hereditary sensory and autonomic neuropathy with deafness and global delay, hereditary neoplastic syndrome, orofaciodigital syndrome, lethal recessive chondrodysplasia, Coffin-Siris syndrome, craniosynostosis, keratoconus, congenital pseudoarthrosis of the limbs, hereditary hemophagocytic lymphohistiocytosis, hereditary dementia, advanced sleep phase syndrome, dysmorphism-cleft palate-loose skin syndrome, oculomaxillofacial dysostosis, isolated congenital breast hypoplasia/aplasia, primary pigmented nodular adrenocortical disease, shoulder and thorax deformity-congenital heart disease syndrome, erythromelalgia, Cornelia de Lange syndrome, familial clubfoot with or without associated lower limb anomalies, hereditary gingival fibromatosis, syndromic microphthalmia, progressive non-infectious anterior vertebral fusion, hereditary hypoparathyroidism, hereditary hyperparathyroidism, familial ovarian cancer, hereditary breast carcinoma, heart-hand syndrome, Kabuki syndrome, familial hyperaldosteronism, lymphoproliferative syndrome, split hand-foot malformation, dysraphism-cleft lip/palate-limb reduction defects syndrome, primary hypertrophic osteoarthropathy, Melhem-Fahl syndrome, hereditary anemia, limb transversal defect-cardiac anomaly syndrome, frontonasal dysplasia, familial visceral myopathy, osteochondrodysplatic nanism-deafness-retinitis pigmentosa syndrome, Opitz G/BBB syndrome, oromandibular-limb hypogenesis syndrome, heritable pulmonary arterial hypertension, imperforate oropharynx-costo vetebral anomalies syndrome, familial vesicoureteral reflux, Pilotto syndrome, celiac trunk compression syndrome, 3MC syndrome, hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome, renal-hepatic-pancreatic dysplasia, lethal congenital contracture syndrome, triphalangeal thumb-polysyndactyly syndrome, autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome, van Maldergem syndrome, sclerosteosis, diencephalic-mesencephalic junction dysplasia, familial nonmedullary thyroid carcinoma, multiple synostoses syndrome, T-cell immunodeficiency with epidermodysplasia verruciformis, syngnathia multiple anomalies, syngnathia-cleft palate syndrome, humero-radio-ulnar synostosis, severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, thrombocytopenia-Robin sequence syndrome, tibial aplasia-ectrodactyly syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, hereditary glaucoma, familial cervical artery dissection, bipartite talus, skeletal dysplasia, acrofacial dysostosis, chronic granulomatous disease, growth retardation-mild developmental delay-chronic hepatitis syndrome, osteonecrosis of genetic origin, global developmental delay - lung cysts - overgrowth - Wilms tumor syndrome, hereditary gastric cancer, severe congenital neutropenia, hypogonadotropic hypogonadism, GCGR-related hyperglucagonemia, autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome, visceral heterotaxy, hereditary neuroendocrine tumor of small intestine, hereditary otorhinolaryngologic disease, congenital bilateral absence of vas deferens, bile duct cyst, Caroli syndrome, isolated neonatal sclerosing cholangitis, arterial calcification of infancy, branchiootic syndrome, Mazabraud syndrome, familial melanoma, inherited hemoglobinopathy, inborn errors of metabolism, familial thrombocytosis, androgen insensitivity syndrome, central precocious puberty, familial long QT syndrome, inherited obesity, Axenfeld-Rieger syndrome, inherited isolated nail anomaly, lymphatic malformation, ischio-vertebral syndrome, fetal and neonatal alloimmune thrombocytopenia, anterior segment dysgenesis, amelogenesis imperfecta, van der Woude syndrome, familial thoracic aortic aneurysm and aortic dissection, inherited primary ovarian failure, distal arthrogryposis, Ehlers-Danlos syndrome, inherited sideroblastic anemia, posterior polymorphous corneal dystrophy, familial parathyroid adenoma, Simpson-Golabi-Behmel syndrome type 1, sex-linked disease, microcephaly, growth restriction and increased sister chromatid exchange, microcephaly, facial dysmorphism, renal agenesis, and ambiguous genitalia syndrome, autosomal dominant wooly hair, congenital short bowel syndrome, autosomal recessive, uncombable hair syndrome 1, Menke-Hennekam syndrome, dwarfism with tall vertebrae, pulmonary alveolar proteinosis with hypogammaglobulinemia, contractures, pterygia, and variable skeletal fusions syndrome, syndactyly, polydactyly, brachydactyly, RASopathy, immunodeficiency disease, laminopathy, inherited blood coagulation disorder, central centrifugal cicatricial alopecia, double fingernail of fifth finger, FRAXD syndrome, familial colorectal cancer, familial partial paralysis, Dursun syndrome, hereditary disorder of connective tissue, Marinesco-Sjogren-like syndrome, WHIM syndrome, visceral neuropathy, familial, neurologic, endocrine, and pancreatic disease, multisystem, infantile-onset, portal hypertension, noncirrhotic, multiple congenital anomalies-neurodevelopmental syndrome, X-linked, azoospermia, obstructive, with nephrolithiasis, megacystis-microcolon-intestinal hypoperistalsis syndrome, Mullegama-Klein-Martinez syndrome, Shukla-Vernon syndrome, Basilicata-Akhtar syndrome, serpinopathy, peripheral neuropathy, autosomal recessive, with or without impaired intellectual development, intellectual developmental disorder with hypertelorism and distinctive facies, Diets-Jongmans syndrome, autoinflammation with episodic fever and lymphadenopathy, retinal dystrophy with leukodystrophy, skeletal dysplasia, mild, with joint laxity and advanced bone age, Nizon-Isidor syndrome, seizures, early-onset, with neurodegeneration and brain calcifications, leukoencephalopathy, developmental delay, and episodic neurologic regression syndrome, leukoencephalopathy, motor delay, spasticity, and dysarthria syndrome, proteinuria, chronic benign, Liberfarb syndrome, microcephaly, developmental delay, and brittle hair syndrome, 46,xx sex reversal 5, intellectual developmental disorder with autistic features and language delay, with or without seizures, neurodevelopmental, jaw, eye, and digital syndrome, agenesis of corpus callosum, cardiac, ocular, and genital syndrome, retinitis pigmentosa 89, spondylometaphyseal dysplasia with corneal dystrophy, Teebi hypertelorism syndrome, leukoencephalopathy, hereditary diffuse, with spheroids, gastrointestinal defect and immunodeficiency syndrome, developmental delay, impaired growth, dysmorphic facies, and axonal neuropathy, intellectual developmental disorder with speech delay and axonal peripheral neuropathy, vertebral hypersegmentation and orofacial anomalies, cardiofacioneurodevelopmental syndrome, Kaya-Barakat-Masson syndrome, leukoencephalopathy, progressive, infantile-onset, with or without deafness, Lessel-Kreienkamp syndrome, intellectual developmental disorder with paroxysmal dyskinesia or seizures, Li-Campeau syndrome, neurofacioskeletal syndrome with or without renal agenesis, deafness, congenital, and adult-onset progressive leukoencephalopathy, oculomotor-abducens synkinesis, blistering, acantholytic, of oral and laryngeal mucosa, vertebral, cardiac, tracheoesophageal, renal, and limb defects, developmental delay with dysmorphic facies and dental anomalies, Kohlschutter-Tonz syndrome-like, bile acid conjugation defect 1, short stature, oligodontia, dysmorphic facies, and motor delay, global developmental delay with speech and behavioral abnormalities, vitreoretinopathy with phalangeal epiphyseal dysplasia, Baralle-Macken syndrome, dyskinesia with orofacial involvement, inherited interstitial lung disease, Bryant-Li-Bhoj neurodevelopmental syndrome, restrictive dermopathy, Stuve-Wiedemann syndrome, cardiac valvular defect, craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome, cardioacrofacial dysplasia, Tessadori-Van-Haaften neurodevelopmental syndrome, Carey-Fineman-Ziter syndrome, thyroid hormone metabolism, abnormal, short stature, facial dysmorphism, and skeletal anomalies with or without cardiac anomalies, developmental delay with short stature, dysmorphic facial features, and sparse hair, Braddock-Carey syndrome, ophthalmoplegia, external, with rib and vertebral anomalies, intellectual developmental disorder with macrocephaly, seizures, and speech delay, cardiac, facial, and digital anomalies with developmental delay, osteochondrodysplasia, brachydactyly, and overlapping malformed digits, warburg-cinotti syndrome, Snijders Blok-Campeau syndrome, inflammatory bowel disease, immunodeficiency, and encephalopathy, vertebral anomalies and variable endocrine and T-cell dysfunction, arthrogryposis, cleft palate, craniosynostosis, and impaired intellectual development, trichohepatoneurodevelopmental syndrome, mega-corpus-callosum syndrome with cerebellar hypoplasia and cortical malformations, fibrosis, neurodegeneration, and cerebral angiomatosis, cardiac-urogenital syndrome, visual impairment and progressive phthisis bulbi, microcephaly, cataracts, impaired intellectual development, and dystonia with abnormal striatum, macrocephaly, acquired, with impaired intellectual development, mucocutaneous ulceration, chronic, intellectual developmental disorder with cardiac defects and dysmorphic facies, global developmental delay with or without impaired intellectual development, infantile cataract, skin abnormalities, glutamate excess, and impaired intellectual development, intellectual developmental disorder with abnormal behavior, microcephaly, and short stature, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, microcephaly, growth deficiency, seizures, and brain malformations, short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis, turnpenny-fry syndrome, facial dysmorphism, hypertrichosis, epilepsy, intellectual/developmental delay, and gingival overgrowth syndrome, leukoencephalopathy, acute reversible, with increased urinary alpha-ketoglutarate, global developmental delay, progressive ataxia, and elevated glutamine, metabolic crises, recurrent, with variable encephalomyopathic features and neurologic regression, gonadal dysgenesis, dysmorphic facies, retinal dystrophy, and myopathy, intellectual developmental disorder with short stature and variable skeletal anomalies, developmental delay with or without dysmorphic facies and autism, Khan-Khan-Katsanis syndrome, cerebellar, ocular, craniofacial, and genital syndrome, hypotonia, hypoventilation, impaired intellectual development, dysautonomia, epilepsy, and eye abnormalities, congenital hypotonia, epilepsy, developmental delay, and digital anomalies, cerebellar atrophy with seizures and variable developmental delay, O’Donnell-Luria-Rodan syndrome, ichthyotic keratoderma, spasticity, hypomyelination, and dysmorphic facial features, hypopigmentation, organomegaly, and delayed myelination and development, glycosylphosphatidylinositol biosynthesis defect 21, spastic tetraplegia and axial hypotonia, progressive, snijders blok-fisher syndrome, intellectual developmental disorder with nasal speech, dysmorphic facies, and variable skeletal anomalies, lower urinary tract obstruction, congenital, Usher syndrome, type 1M, Siddiqi syndrome, oculopharyngeal myopathy with leukoencephalopathy 1, neurooculocardiogenitourinary syndrome, intellectual developmental disorder with impaired language and dysmorphic facies, hydrocephalus, congenital communicating, 1, intellectual developmental disorder with speech delay, autism, and dysmorphic facies, lessel-kubisch syndrome, intellectual developmental disorder with short stature and behavioral abnormalities, short stature and microcephaly with genital anomalies, megabladder, congenital, Heyn-Sproul-Jackson syndrome, intellectual developmental disorder with behavioral abnormalities and craniofacial dysmorphism with or without seizures, ectodermal dysplasia with facial dysmorphism and acral, ocular, and brain anomalies, Liang-Wang syndrome, neuromuscular disease and ocular or auditory anomalies with or without seizures, structural brain anomalies with impaired intellectual development and craniosynostosis, pachygyria, microcephaly, developmental delay, and dysmorphic facies, with or without seizures, intellectual developmental disorder with hypotonia and behavioral abnormalities, Catifa syndrome, CEBALID syndrome, congenital heart defects, multiple types, 7, Imagawa-Matsumoto syndrome, juvenile arthritis due to defect in LACC1, Beck-Fahrner syndrome, respiratory papillomatosis, juvenile recurrent, congenital, sandestig-stefanova syndrome, triokinase and FMN cyclase deficiency syndrome, T-cell lymphopenia, infantile, with or without nail dystrophy, autosomal dominant, intellectual developmental disorder with poor growth and with or without seizures or ataxia, pontocerebellar hypoplasia, hypotonia, and respiratory insufficiency syndrome, neonatal lethal, chromosome 1p36.33 duplication syndrome, atad3 gene cluster, autosomal dominant, genitourinary and/or brain malformation syndrome, rhizomelic limb shortening with dysmorphic features, Suleiman-El-Hattab syndrome, cone-rod synaptic disorder syndrome, congenital nonprogressive, Tolchin-Le Caignec syndrome, Li-Ghorbani-Weisz-Hubshman syndrome, autoinflammation, immune dysregulation, and eosinophilia, intellectual developmental disorder with seizures and language delay, mitochondrial complex 1 deficiency, nuclear type 35, deeah syndrome, combined oxidative phosphorylation deficiency 49, combined oxidative phosphorylation deficiency 50, Vissers-Bodmer syndrome, spinal muscular atrophy, infantile, James type, vitamin D-dependent rickets, type 3, cleft palate, proliferative retinopathy, and developmental delay, microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 1, congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome, microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome, early-onset familial hypoaldosteronism, chronic mast cell leukemia, DONSON-related microcephaly-short stature-limb abnormalities spectrum, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, CCNK-related neurodevelopmental disorder-severe intellectual disability-facial dysmorphism syndrome, cerebellar hypoplasia-intellectual disability-congenital microcephaly-dystonia-anemia-growth retardation syndrome, KLHL7-related Bohring-Opitz-like syndrome, oculogastrointestinal-neurodevelopmental syndrome, spastic paraparesis-cataracts-speech delay syndrome, inherited auditory system disease, Y chromosome infertility due to DAZ1 deletion, familial osteosclerosis, foveal hypoplasia, congenital heart defects, dysmorphic facial features, and intellectual developmental disorder, congenital heart defects and ectodermal dysplasia, brachycephaly, trichomegaly, and developmental delay, thrombocytopenia, anemia, and myelofibrosis, structural heart defects and renal anomalies syndrome, Rahman syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, familial monosomy 7 syndrome, menstrual cycle-dependent periodic fever, Gabriele de Vries syndrome, Lopes-Maciel-Rodan syndrome, Skraban-Deardorff syndrome, amyotonia congenita, cerebral sclerosis, diffuse, scholz type, autoinflammation with arthritis and dyskeratosis, retinal dystrophy with or without macular staphyloma, Cohen-Gibson syndrome, maleylacetoacetate isomerase deficiency, congenital heart defects and skeletal malformations syndrome, microcephaly, short stature, and limb abnormalities, congenital anomalies of kidney and urinary tract syndrome with or without hearing loss, abnormal ears, or developmental delay, cerebellar atrophy, developmental delay, and seizures, platelet abnormalities with eosinophilia and immune-mediated inflammatory disease, facial palsy, congenital, with ptosis and velopharyngeal dysfunction, immunodeficiency, developmental delay, and hypohomocysteinemia, Sweeney-Cox syndrome, combined immunodeficiency and megaloblastic anemia with or without hyperhomocysteinemia, Alkuraya-Kucinskas syndrome, Diamond-Blackfan anemia-like, hypotonia, ataxia, developmental delay, and tooth enamel defect syndrome, chromosome 1p35 deletion syndrome, hyperthyroxinemia, euthyroid, caused by generalized 5-prime-deiodinase deficiency, Jaberi-Elahi syndrome, deafness, congenital heart defects, and posterior embryotoxon, humerofemoral hypoplasia with radiotibial ray deficiency, intellectual developmental disorder with or without epilepsy or cerebellar ataxia, CDKL5 disorder, GATA1-Related X-Linked Cytopenia, focal segmental glomerulosclerosis and neurodevelopmental syndrome, hereditary skin disorder, AP-4 deficiency syndrome, inherited kidney disorder, Mendelian encephalopathy, X inactivation, familial skewed, growth hormone insensitivity syndrome with immune dysregulation, DICER1-related tumor predisposition, A20 haploinsufficiency, LTBP2-related ocular dysgenesis, inherited cutis laxa, inherited hypertrophic pyloric stenosis, inherited thrombocytopenia, multiple congenital anomalies-hypotonia-seizures syndrome, 46,XX sex reversal 1, microcephaly, epilepsy, and diabetes syndrome, SEC61A1 deficiency, achalasia, familial esophageal, MECOM-associated syndrome, TPM4-related platelet disorder, TRAF3 haploinsufficiency, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, hereditary neurological disease, cardiogenetic disease, hereditary narcolepsy, RNU4ATAC spectrum disorder, CTNNB1-related neurodevelopmental disorder and/or vitreoretinopathy, MTOR-related overgrowth spectrum, TOR1AIP1-related nuclear envelopathy, BMP4-related ocular growth disorder, CSF1R-related disorder, acinar dysplasia caused by mutation in FGF10, acinar dysplasia caused by mutation in FGFR2, acinar dysplasia caused by mutation in TBX4, EPHB4-associated vascular malformation spectrum, BAFopathy, hereditary skeletal muscle disorder, hereditary gallbladder disorder, prostate cancer, hereditary, POLR3A-related disorder, POLR3B-related disorder, POLR1C-related disorder, WFS1-related disorder, CACNA1C-related disorder, SMAD6-related disease, central hypoventilation syndrome, congenital, autoinflammatory-pancytopenia syndrome due to DNASE2 deficiency, alopecia universalis, microcornea, rod-cone dystrophy, cataract, and posterior staphyloma 2, myopathy, congenital, with excess of muscle spindles, pregnancy loss, recurrent, 4, urogenital adysplasia, yakut short stature syndrome, microcephaly, short stature, and impaired glucose metabolism, NR2F2 related multiple congenital anomalies/dysmorphic syndrome, ACD-related telomere biology disorder, AKT3-related overgrowth spectrum, rhabdomyosarcoma, embryonal, 2, blepharophimosis-impaired intellectual development syndrome, Radio-Tartaglia syndrome, Buratti-Harel syndrome, growth restriction, hypoplastic kidneys, alopecia, and distinctive facies, fibromuscular dysplasia, multifocal, dysostosis multiplex, Ain-Naz type, ataxia, intention tremor, and hypotonia syndrome, childhood-onset, deafness, cataract, impaired intellectual development, and polyneuropathy, onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome, Faundes-Banka syndrome, osteootohepatoenteric syndrome, hypokalemic tubulopathy and deafness, White-Kernohan syndrome, retinal dystrophy and microvillus inclusion disease, Luo-Schoch-Yamamoto syndrome, Usmani-Riazuddin syndrome, autosomal dominant, VISS syndrome, developmental delay, impaired speech, and behavioral abnormalities, bile acid malabsorption, primary, 2, DEGCAGS syndrome, Short stature, Dauber-Argente type, ventriculomegaly and arthrogryposis, Chopra-Amiel-Gordon syndrome, muscular dystrophy, congenital hearing loss, and ovarian insufficiency syndrome, neurodevelopmental-craniofacial syndrome with variable renal and cardiac abnormalities, biliary, renal, neurologic, and skeletal syndrome, Boudin-Mortier syndrome, Usmani-Riazuddin syndrome, autosomal recessive, intellectual developmental disorder with hypotonia, impaired speech, and dysmorphic facies, short stature, impaired intellectual development, microcephaly, hypotonia, and ocular anomalies, developmental delay with or without intellectual impairment or behavioral abnormalities, cerebellar ataxia, brain abnormalities, and cardiac conduction defects, developmental delay, hypotonia, musculoskeletal defects, and behavioral abnormalities, fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies, delayed puberty, self-limited, Hengel-Maroofian-Schols syndrome, Zaki syndrome, dystonia, early-onset, and/or spastic paraplegia, developmental delay with variable neurologic and brain abnormalities, Rauch-Steindl syndrome, intellectual disability and myopathy syndrome, cerebellar dysfunction, impaired intellectual development, and hypogonadotropic hypogonadism, Kury-Isidor syndrome, macrocephaly, neurodevelopmental delay, lymphoid hyperplasia, and persistent fetal hemoglobin, intellectual developmental disorder with or without peripheral neuropathy, neurocardiofaciodigital syndrome, corneal dystrophy, punctiform and polychromatic pre-descemet, osteoporosis, childhood- or juvenile-onset, with developmental delay, hepatorenocardiac degenerative fibrosis, ACCES syndrome, developmental delay, impaired speech, and behavioral abnormalities, with or without seizures, liver disease, severe congenital, primordial dwarfism-immunodeficiency-lipodystrophy syndrome, intellectual developmental disorder with muscle tone abnormalities and distal skeletal defects, keratoderma-ichthyosis-deafness syndrome, autosomal recessive, developmental delay, hypotonia, and impaired language, intellectual developmental disorder with autism and dysmorphic facies, bone marrow failure and diabetes mellitus syndrome, developmental delay, behavioral abnormalities, and neuropsychiatric disorders, hypermetabolism due to uncoupled mitochondrial oxidative phosphorylation 2, intellectual developmental disorder with ocular anomalies and distinctive facial features, developmental delay with variable intellectual disability and dysmorphic facies, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 1, developmental delay, language impairment, and ocular abnormalities, Rabin-Pappas syndrome, muscular dystrophy, congenital, with or without seizures, obesity and hypopigmentation, joint contractures, osteochondromas, and B-cell lymphoma, respiratory infections, recurrent, and failure to thrive with or without diarrhea, developmental delay with hypotonia, myopathy, and brain abnormalities, Atelis syndrome, hereditary neuro-ophthalmological disease, autoinflammation with pulmonary and cutaneous vasculitis, neurooculorenal syndrome, combined low LDL and fibrinogen, hypersulfaturia, woolly hair-skin fragility syndrome, hematuria, benign familial, cataracts, hearing impairment, nephrotic syndrome, and enterocolitis, disabling pansclerotic morphea of childhood, Houge-Janssens syndrome, hearing loss, noise-induced, susceptibility to, encephalitis, acute, infection-induced, susceptibility to, 12, cranial dysinnervation disorder, congenital, with absent corneal reflex and developmental delay, congenital smooth muscle hamartoma, with or without hemihypertrophy, amegakaryocytic thrombocytopenia, congenital, 2, epilepsy, early-onset, xerosis and growth failure with immune and pulmonary dysfunction syndrome, Fliedner-Zweier syndrome, immune dysregulation, autoimmunity, and autoinflammation, arrhythmogenic cardiomyopathy with variable ectodermal abnormalities, developmental delay, dysmorphic facies, and brain anomalies, developmental delay with or without epilepsy, craniometadiaphyseal osteosclerosis with hip dysplasia, Lui-Jee-Baron syndrome, Long-Olsen-Distelmaier syndrome, Tan-Almurshedi syndrome, diabetes, deafness, developmental delay, and short stature syndrome, Alfadhel syndrome, Hoxha-Aliu syndrome, congenital insensitivity to pain syndrome, Marsili type, Yuksel-Vogel-Bauer syndrome, polydactyly-macrocephaly syndrome, isolated hyperferritinemia, megalencephaly-polydactyly syndrome, autoinflammation with episodic fever and immune dysregulation, autoinflammation with arthritis and vasculitis, myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, brain malformation renal syndrome, short stature with nonspecific skeletal abnormalities, bronchiectasis and nasal polyposis, neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, spastic paraplegia, mitochondrial, Pan-Chung-Bellen syndrome, autoinflammation, panniculitis, and dermatosis syndrome, telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature, Muggenthaler-Chowdhury-Chioza syndrome, ocular pterygium-digital keloid dysplasia syndrome, Tayoun-Maawali syndrome, craniofaciocardiohepatic syndrome, FICUS syndrome, Guillouet-Gordon syndrome, immunodysregulation with variable immunodeficiency and autoimmunity, ICHAD syndrome, cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, immune dysregulation with immunodeficiency due to AIOLOS haploinsufficiency, ADNP-related blepharophimosis-intellectual disability syndrome, oculovertebral syndrome, Ververi-Brady syndrome, immune dysregulation, neurodevelopmental defects, and colitis, dyschromatosis, ichthyosis, deafness, and atopic disease, developmental delay with variable cardiac and renal congenital anomalies and dysmorphic facies, developmental delay with sleep apnea, Pitt-Hopkins or Pitt-Hopkins-like syndrome, intellectual developmental disorder, autosomal recessive 84, intellectual developmental disorder, autosomal dominant 77, periodontitis, aggressive, dental radicular dysplasia, intellectual developmental disorder with seizures and dysmorphic facies, STAD syndrome, craniosynostosis-scoliosis syndrome, COL4A1/A2-related disorder, TP63-related ectodermal dysplasia spectrum with limb and orofacial malformations, PI4KA-related disorder, NDUFB11-related disorders, EN1-related dorsoventral syndrome, DHDDS-CDG, PLEC-related muscular dystrophy-epidermolysis bullosa simplex spectrum disorder, FDXR-related optic atrophy mitochondrial dysfunction syndrome, PIK3R1-related immunodeficiency and SHORT syndrome, ACAN-related short stature spectrum, ELANE-related neutropenia, NR5A1-related sex development disorder, CRYAB-related myofibrillar myopathy-cataract-cardiomyopathy spectrum disorder, SYCE1-related gametogenic failure, RNU12-related minor spliceopathy disorder, MCM9-related gametogenic failure, CFTR-related disorder

Genetics & variants

GWAS landscape

25 GWAS associations across 7 studies. Top hits map to 8 distinct genes (as reported by GWAS).

Top associations by p-value

rsID	p-value	Gene	Risk allele	Odds ratio
rs2505994	2e-101	LINC01264 - RET	T	5.3
rs2505998	4e-43	LINC01264 - RET	A	3.57
rs2435357	3e-21	RET	?	23.12
rs1864400	6e-19	RET	?
rs2742234	4e-18	RET	T
rs117617821	7e-16	LINC03017 - HMGN2P11	C	2.71
rs4519046	3e-15	FXYD4 - HNRNPF	A	1.85
rs9282834	4e-14	RET	A	20.3
rs7005606	1e-11	NRG1	G	2.12
rs62472985	3e-11	LINC03017	G	1.74
rs12428625	4e-11	MOB1AP1 - DDX6P2	T	3.63
rs80227144	5e-10	LINC03017 - HMGN2P11	A	5.2
rs17653445	5e-10	TACC1P1 - MTND1P18	G	1.67
rs16879552	2e-08	NRG1	G	1.68
rs4672229	3e-08	VRK2	A	2.48
rs144432435	6e-07	LINC01264 - RET	T	3.73
rs11725593	2e-06	STIM2 - LINC02261	?
rs4299518	3e-06	SLC6A20	?	20
rs6074578	4e-06	DEFB128 - DEFB129	?
rs78871841	4e-06	DDX51	A
rs12639288	5e-06	LRRC77P - CYCSP56	?
rs6826373	6e-06	PHOX2B	C	1.75
rs11652075	8e-06	CARD14	C

Top studies (by case count)

Study	Lead author	Year	Cases	Controls	Title
GCST003764	Tang CS	2016	212	0	Trans-ethnic meta-analysis of genome-wide association studies for Hirschsprung disease.
GCST000334	Garcia-Barcelo MM	2009	181	0	Genome-wide association study identifies NRG1 as a susceptibility locus for Hirschsprung’s disease.
GCST005289	Fadista J	2018	170	0	Genome-wide association study of Hirschsprung disease detects a novel low-frequency variant at the RET locus.
GCST008016	Tang W	2016	167	0	Exome-Wide Association Study Identified New Risk Loci for Hirschsprung’s Disease.
GCST002658	Kim JH	2014	123	0	A genome-wide association study identifies potential susceptibility loci for Hirschsprung disease.
GCST006272	Virtanen VB	2018	105	0	Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant.
GCST006271	Virtanen VB	2018	68	0	Noncoding RET variants explain the strong association with Hirschsprung disease in patients without rare coding sequence variant.

Variant details and genetic-evidence tiers

Tier distribution (top 50 variants)

Tier	Variants
Tier 1: coding	3
Tier 2: splice/UTR	1
Tier 3: regulatory	0
Tier 4: intronic/intergenic	19

MAF distribution

Bucket	Variants
common (>=0.05)	18
low_freq (0.01-0.05)	5
rare (<0.01)	0
unknown	0

Functional consequences

Consequence	Count
intron_variant	15
intergenic_variant	4
missense_variant	3
3_prime_UTR_variant	1

Top variants

rsID	Chr	Pos	Alleles	MAF	Consequence	Gene	p-value	Tier
rs2505994	10	43073439	T>A,C	0.23	intron_variant	LINC01264 - RET	2e-101	Tier 4: intronic/intergenic
rs2505998	10	43075477	A>G,T	0.48	intron_variant	LINC01264 - RET	4e-43	Tier 4: intronic/intergenic
rs2435357	10	43086608	T>A,C,G	0.05	intron_variant	RET	3e-21	Tier 4: intronic/intergenic
rs1864400	10	43114918	G>A,C,T	0.05	intron_variant	RET	6e-19	Tier 4: intronic/intergenic
rs2742234	10	43117161	C>T	0.05	intron_variant	RET	4e-18	Tier 4: intronic/intergenic
rs117617821	7	84692873	T>C	0.04	intron_variant	LINC03017 - HMGN2P11	7e-16	Tier 4: intronic/intergenic
rs4519046	10	43379369	A>C,G,T	0.18	intergenic_variant	FXYD4 - HNRNPF	3e-15	Tier 4: intronic/intergenic
rs9282834	10	43111408	G>A,C,T	0.03	missense_variant	RET	4e-14	Tier 1: coding
rs7005606	8	32543983	T>G	0.21	intron_variant	NRG1	1e-11	Tier 4: intronic/intergenic
rs62472985	7	84567995	C>G	0.16	intron_variant	LINC03017	3e-11	Tier 4: intronic/intergenic
rs12428625	13	86134644	A>G,T	0.01	intron_variant	MOB1AP1 - DDX6P2	4e-11	Tier 4: intronic/intergenic
rs80227144	7	84720526	C>A	0.03	intron_variant	LINC03017 - HMGN2P11	5e-10	Tier 4: intronic/intergenic
rs17653445	10	37546726	A>G	0.16	intergenic_variant	TACC1P1 - MTND1P18	5e-10	Tier 4: intronic/intergenic
rs16879552	8	32553698	C>G,T	0.39	intron_variant	NRG1	2e-08	Tier 4: intronic/intergenic
rs4672229	2	58049145	C>A,T	0.05	intron_variant	VRK2	3e-08	Tier 4: intronic/intergenic
rs144432435	10	43063942	C>A,T	0.01	intron_variant	LINC01264 - RET	6e-07	Tier 4: intronic/intergenic
rs11725593	4	27064416	G>A,T	0.05	intergenic_variant	STIM2 - LINC02261	2e-06	Tier 4: intronic/intergenic
rs4299518	3	45767781	T>C	0.05	intron_variant	SLC6A20	3e-06	Tier 4: intronic/intergenic
rs6074578	20	211156	G>A,C,T	0.05	intergenic_variant	DEFB128 - DEFB129	4e-06	Tier 4: intronic/intergenic
rs78871841	12	132143736	C>A,G,T	0.051	missense_variant	DDX51	4e-06	Tier 1: coding
rs12639288	3	167943348	G>A	0.05	intron_variant	LRRC77P - CYCSP56	5e-06	Tier 4: intronic/intergenic
rs6826373	4	41744443	C>T	0.05	3_prime_UTR_variant	PHOX2B	6e-06	Tier 2: splice/UTR
rs11652075	17	80205094	C>A,G,T	0.353	missense_variant	CARD14	8e-06	Tier 1: coding

ClinVar germline variants

81 retrieved; paginated sample, class counts are floors:

40 uncertain significance, 13 conflicting classifications of pathogenicity, 10 likely pathogenic, 9 pathogenic, 3 benign/likely benign, 3 benign, 1 benign; risk factor, 1 pathogenic/likely pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
13915	NM_020975.6(RET):c.1858T>C (p.Cys620Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13916	NM_020975.6(RET):c.1859G>A (p.Cys620Tyr)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
13944	NM_020975.6(RET):c.1825T>C (p.Cys609Arg)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
24896	NM_020975.6(RET):c.1831T>C (p.Cys611Arg)	RET	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
24905	NM_020975.6(RET):c.1858T>G (p.Cys620Gly)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
3076011	NM_020975.6(RET):c.1860C>A (p.Cys620Ter)	RET	Pathogenic	criteria provided, single submitter
560625	NM_020975.6(RET):c.860G>A (p.Arg287Gln)	RET	Pathogenic	no assertion criteria provided
599630	NM_020975.6(RET):c.111G>A (p.Trp37Ter)	RET	Pathogenic	no assertion criteria provided
599634	NM_020975.6(RET):c.2865dup (p.Pro956fs)	RET	Pathogenic	criteria provided, multiple submitters, no conflicts
599635	NM_020975.6(RET):c.3143del (p.Leu1048fs)	RET	Pathogenic	no assertion criteria provided
599423	NM_001389.5(DSCAM):c.2363C>T (p.Ala788Val)	DSCAM	Likely pathogenic	no assertion criteria provided
599418	NM_001397.3(ECE1):c.1067T>G (p.Phe356Cys)	ECE1	Likely pathogenic	no assertion criteria provided
599419	NM_001397.3(ECE1):c.1879C>T (p.Arg627Trp)	ECE1	Likely pathogenic	no assertion criteria provided
599417	NM_003924.4(PHOX2B):c.445C>G (p.Arg149Gly)	PHOX2B	Likely pathogenic	no assertion criteria provided
599421	NM_006941.4(SOX10):c.832A>G (p.Ile278Val)	POLR2F	Likely pathogenic	no assertion criteria provided
13923	NM_020975.6(RET):c.95C>T (p.Ser32Leu)	RET	Likely pathogenic	criteria provided, multiple submitters, no conflicts
599631	NM_020975.6(RET):c.440T>C (p.Phe147Ser)	RET	Likely pathogenic	no assertion criteria provided
599632	NM_020975.6(RET):c.604G>C (p.Val202Leu)	RET	Likely pathogenic	no assertion criteria provided
692071	NM_020975.6(RET):c.860G>T (p.Arg287Leu)	RET	Likely pathogenic	criteria provided, single submitter
695031	NM_020975.6(RET):c.1753T>C (p.Cys585Arg)	RET	Likely pathogenic	criteria provided, single submitter
13952	NM_020975.6(RET):c.73+9277T>C	LOC110121502	Benign; risk factor	criteria provided, multiple submitters, no conflicts
127941	NM_004655.4(AXIN2):c.2051C>T (p.Ala684Val)	AXIN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
691474	NM_020066.5(FMN2):c.162del (p.Gly55fs)	FMN2	Conflicting classifications of pathogenicity	no assertion criteria provided
135188	NM_020975.6(RET):c.1424G>A (p.Arg475Gln)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13936	NM_020975.6(RET):c.2372A>T (p.Tyr791Phe)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13938	NM_020975.6(RET):c.2944C>T (p.Arg982Cys)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
13948	NM_020975.6(RET):c.3116C>T (p.Pro1039Leu)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161358	NM_020975.6(RET):c.2081G>A (p.Arg694Gln)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
161360	NM_020975.6(RET):c.539G>A (p.Arg180Gln)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1980323	NM_020975.6(RET):c.2906G>A (p.Arg969Gln)	RET	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 81 · Orphanet: 83 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 3

Dual-evidence genes (GWAS + Mendelian — highest-confidence targets)

Gene	HGNC	Evidence routes
RET	RET	GWAS, GenCC, Orphanet
NRG1	NRG1	GWAS, GenCC
PHOX2B	PHOX2B	GWAS, Orphanet

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
RET	Strong	Autosomal dominant	Hirschsprung disease, susceptibility to, 1	16
NRG1	Moderate	Autosomal dominant	Hirschsprung disease	3
ABCD1	Supportive	Autosomal dominant	Hirschsprung disease	11
ATP7A	Supportive	Autosomal dominant	Hirschsprung disease	15
ERBB2	Supportive	Autosomal dominant	Hirschsprung disease	4
ERBB3	Supportive	Autosomal dominant	Hirschsprung disease	7
SMO	Supportive	Autosomal dominant	Hirschsprung disease	9
SMOX	Supportive	Autosomal dominant	Hirschsprung disease	9
SREBF1	Supportive	Autosomal dominant	Hirschsprung disease	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
RET	Orphanet:146	Differentiated thyroid carcinoma
RET	Orphanet:1848	Renal agenesis, bilateral
RET	Orphanet:247698	Multiple endocrine neoplasia type 2A
RET	Orphanet:247709	Multiple endocrine neoplasia type 2B
RET	Orphanet:276621	Sporadic pheochromocytoma/secreting paraganglioma
RET	Orphanet:29072	Hereditary pheochromocytoma-paraganglioma
RET	Orphanet:388	Hirschsprung disease
RET	Orphanet:93100	Renal agenesis, unilateral
RET	Orphanet:99361	Isolated familial medullary thyroid carcinoma
RET	Orphanet:99803	Haddad syndrome
PHOX2B	Orphanet:2151	Hirschsprung disease-ganglioneuroblastoma syndrome
PHOX2B	Orphanet:635	Neuroblastoma
PHOX2B	Orphanet:661	Congenital central hypoventilation syndrome
PHOX2B	Orphanet:99803	Haddad syndrome
SMO	Orphanet:1553	Curry-Jones syndrome
SMO	Orphanet:2495	Meningioma
SMO	Orphanet:388	Hirschsprung disease
SREBF1	Orphanet:388	Hirschsprung disease
ERBB2	Orphanet:213726	Serous carcinoma of the corpus uteri
ERBB2	Orphanet:2800	Extramammary Paget disease
ERBB2	Orphanet:388	Hirschsprung disease
ERBB2	Orphanet:99976	Adenocarcinoma of the oesophagus and oesophagogastric junction
ERBB3	Orphanet:137776	Lethal congenital contracture syndrome type 2
ERBB3	Orphanet:388	Hirschsprung disease
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:139557	X-linked distal spinal muscular atrophy type 3
ATP7A	Orphanet:198	Occipital horn syndrome
ATP7A	Orphanet:388	Hirschsprung disease
ATP7A	Orphanet:565	Menkes disease
SEMA3D	Orphanet:388	Hirschsprung disease
VCL	Orphanet:154	Familial isolated dilated cardiomyopathy
YWHAE	Orphanet:213711	Endometrial stromal sarcoma
YWHAE	Orphanet:217385	17p13.3 microduplication syndrome
YWHAE	Orphanet:261257	Distal 17p13.3 microdeletion syndrome
YWHAE	Orphanet:457246	Clear cell sarcoma of kidney
YWHAE	Orphanet:531	Miller-Dieker syndrome
FMN2	Orphanet:88616	Autosomal recessive non-syndromic intellectual disability
ZEB2	Orphanet:261537	Mowat-Wilson syndrome due to monosomy 2q22
ZEB2	Orphanet:261552	Mowat-Wilson syndrome due to a ZEB2 point mutation
ZEB2	Orphanet:626	Large/giant congenital melanocytic nevus
CARD14	Orphanet:2897	Pityriasis rubra pilaris
PORCN	Orphanet:2092	Focal dermal hypoplasia
PORCN	Orphanet:98938	Colobomatous microphthalmia
FANCL	Orphanet:84	Fanconi anemia
PIGO	Orphanet:247262	Hyperphosphatasia-intellectual disability syndrome
ZNF592	Orphanet:83472	CAMOS syndrome
PACS1	Orphanet:329224	Schuurs-Hoeijmakers syndrome

Cohort genes → proteins

61 cohort genes, 61 distinct canonical proteins.

Evidence partition

Subset	Genes
gwas_only	9
gwas_and_gencc	1
gwas_and_clinvar	1
multi_evidence	50

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
RET	HGNC:9967	ENSG00000165731	P07949	Proto-oncogene tyrosine-protein kinase receptor Ret	gwas,gencc,clinvar
NRG1	HGNC:7997	ENSG00000157168	Q02297	Pro-neuregulin-1, membrane-bound isoform	gwas,gencc
PHOX2B	HGNC:9143	ENSG00000109132	Q99453	Paired mesoderm homeobox protein 2B	gwas,clinvar
SMO	HGNC:11119	ENSG00000128602	Q99835	Protein smoothened	gencc
SREBF1	HGNC:11289	ENSG00000072310	P36956	Sterol regulatory element-binding protein 1	gencc
SMOX	HGNC:15862	ENSG00000088826	Q9NWM0	Spermine oxidase	gencc
ERBB2	HGNC:3430	ENSG00000141736	P04626	Receptor tyrosine-protein kinase erbB-2	gencc
ERBB3	HGNC:3431	ENSG00000065361	P21860	Receptor tyrosine-protein kinase erbB-3	gencc
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	gencc
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	gencc
PHAX	HGNC:10241	ENSG00000164902	Q9H814	Phosphorylated adapter RNA export protein	clinvar
SEMA3D	HGNC:10726	ENSG00000153993	O95025	Semaphorin-3D	clinvar
SLC22A1	HGNC:10963	ENSG00000175003	O15245	Solute carrier family 22 member 1	clinvar
VCL	HGNC:12665	ENSG00000035403	P18206	Vinculin	clinvar
VRK2	HGNC:12719	ENSG00000028116	Q86Y07	Serine/threonine-protein kinase VRK2	gwas
YWHAE	HGNC:12851	ENSG00000108953	P62258	14-3-3 protein epsilon	clinvar
FMN2	HGNC:14074	ENSG00000155816	Q9NZ56	Formin-2	clinvar
MED15	HGNC:14248	ENSG00000099917	Q96RN5	Mediator of RNA polymerase II transcription subunit 15	clinvar
ZEB2	HGNC:14881	ENSG00000169554	O60315	Zinc finger E-box-binding homeobox 2	clinvar
DEFB129	HGNC:16218	ENSG00000125903	Q9H1M3	Beta-defensin 129	gwas
CARD14	HGNC:16446	ENSG00000141527	Q9BXL6	Caspase recruitment domain-containing protein 14	gwas
SNF8	HGNC:17028	ENSG00000159210	Q96H20	Vacuolar-sorting protein SNF8	clinvar
PORCN	HGNC:17652	ENSG00000102312	Q9H237	Protein-serine O-palmitoleoyltransferase porcupine	clinvar
DPPA5	HGNC:19201	ENSG00000203909	A6NC42	Developmental pluripotency-associated 5 protein	clinvar
STIM2	HGNC:19205	ENSG00000109689	Q9P246	Stromal interaction molecule 2	gwas
FANCL	HGNC:20748	ENSG00000115392	Q9NW38	E3 ubiquitin-protein ligase FANCL	gwas
DEPDC1	HGNC:22949	ENSG00000024526	Q5TB30	DEP domain-containing protein 1A	clinvar
PIGO	HGNC:23215	ENSG00000165282	Q8TEQ8	GPI ethanolamine phosphate transferase 3, catalytic subunit	clinvar
TBATA	HGNC:23511	ENSG00000166220	Q96M53	Protein TBATA	clinvar
RASGEF1A	HGNC:24246	ENSG00000198915	Q8N9B8	Ras-GEF domain-containing family member 1A	gwas
CSGALNACT2	HGNC:24292	ENSG00000169826	Q8N6G5	Chondroitin sulfate N-acetylgalactosaminyltransferase 2	gwas
PHRF1	HGNC:24351	ENSG00000070047	Q9P1Y6	PHD and RING finger domain-containing protein 1	clinvar
MGAM2	HGNC:28101	ENSG00000257743	Q2M2H8	Probable maltase-glucoamylase 2	clinvar
NOC4L	HGNC:28461	ENSG00000184967	Q9BVI4	Nucleolar complex protein 4 homolog	gwas
ZNF592	HGNC:28986	ENSG00000166716	Q92610	Zinc finger protein 592	clinvar
DENND3	HGNC:29134	ENSG00000105339	A2RUS2	DENN domain-containing protein 3	clinvar
PACS1	HGNC:30032	ENSG00000175115	Q6VY07	Phosphofurin acidic cluster sorting protein 1	clinvar
DSCAM	HGNC:3039	ENSG00000171587	O60469	Cell adhesion molecule DSCAM	clinvar
TMEM165	HGNC:30760	ENSG00000134851	Q9HC07	Putative divalent cation/proton antiporter TMEM165	clinvar
SLC6A20	HGNC:30927	ENSG00000163817	Q9NP91	Sodium- and chloride-dependent transporter XTRP3	gwas
ECE1	HGNC:3146	ENSG00000117298	P42892	Endothelin-converting enzyme 1	clinvar
EDN3	HGNC:3178	ENSG00000124205	P14138	Endothelin-3	clinvar
EDNRB	HGNC:3180	ENSG00000136160	P24530	Endothelin receptor type B	clinvar
IQCF5	HGNC:35159	ENSG00000214681	A8MTL0	IQ domain-containing protein F5	clinvar
F5	HGNC:3542	ENSG00000198734	P12259	Coagulation factor V	clinvar
GDNF	HGNC:4232	ENSG00000168621	P39905	Glial cell line-derived neurotrophic factor	clinvar
GFRA1	HGNC:4243	ENSG00000151892	P56159	GDNF family receptor alpha-1	clinvar
PROKR1	HGNC:4524	ENSG00000169618	Q8TCW9	Prokineticin receptor 1	clinvar
IKBKB	HGNC:5960	ENSG00000104365	O14920	Inhibitor of nuclear factor kappa-B kinase subunit beta	clinvar
L1CAM	HGNC:6470	ENSG00000198910	P32004	Neural cell adhesion molecule L1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
RET	Proto-oncogene tyrosine-protein kinase receptor Ret	Receptor tyrosine-protein kinase involved in numerous cellular mechanisms including cell proliferation, neuronal navigation, cell migration, and cell differentiation in response to glia cell line-derived growth family factors (GDNF, NRTN,…
NRG1	Pro-neuregulin-1, membrane-bound isoform	Direct ligand for ERBB3 and ERBB4 tyrosine kinase receptors.
PHOX2B	Paired mesoderm homeobox protein 2B	Involved in the development of several major noradrenergic neuron populations, including the locus coeruleus.
SMO	Protein smoothened	G protein-coupled receptor which associates with the patched protein (PTCH) to transduce hedgehog protein signaling.
SREBF1	Sterol regulatory element-binding protein 1	Precursor of the transcription factor form (Processed sterol regulatory element-binding protein 1), which is embedded in the endoplasmic reticulum membrane.
SMOX	Spermine oxidase	Flavoenzyme which catalyzes the oxidation of spermine to spermidine.
ERBB2	Receptor tyrosine-protein kinase erbB-2	Protein tyrosine kinase that is part of several cell surface receptor complexes, but that apparently needs a coreceptor for ligand binding.
ERBB3	Receptor tyrosine-protein kinase erbB-3	Tyrosine-protein kinase that plays an essential role as cell surface receptor for neuregulins.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.
PHAX	Phosphorylated adapter RNA export protein	A phosphoprotein adapter involved in the XPO1-mediated U snRNA export from the nucleus.
SEMA3D	Semaphorin-3D	Induces the collapse and paralysis of neuronal growth cones.
SLC22A1	Solute carrier family 22 member 1	Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics.
VCL	Vinculin	Actin filament (F-actin)-binding protein involved in cell-matrix adhesion and cell-cell adhesion.
VRK2	Serine/threonine-protein kinase VRK2	Serine/threonine kinase that regulates several signal transduction pathways.
YWHAE	14-3-3 protein epsilon	Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways.
FMN2	Formin-2	Actin-binding protein that is involved in actin cytoskeleton assembly and reorganization.
MED15	Mediator of RNA polymerase II transcription subunit 15	Component of the Mediator complex, a coactivator involved in the regulated transcription of nearly all RNA polymerase II-dependent genes.
ZEB2	Zinc finger E-box-binding homeobox 2	Transcriptional inhibitor that binds to DNA sequence 5’-CACCT-3’ in different promoters.
DEFB129	Beta-defensin 129	Has antibacterial activity.
CARD14	Caspase recruitment domain-containing protein 14	Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.
SNF8	Vacuolar-sorting protein SNF8	Component of the endosomal sorting complex required for transport II (ESCRT-II), which is required for multivesicular body (MVB) formation and sorting of endosomal cargo proteins into MVBs, and plays a role in autophagy.
PORCN	Protein-serine O-palmitoleoyltransferase porcupine	Protein-serine O-palmitoleoyltransferase that acts as a key regulator of the Wnt signaling pathway by mediating the attachment of palmitoleate, a 16-carbon monounsaturated fatty acid (C16:1(9Z)), to Wnt proteins.
DPPA5	Developmental pluripotency-associated 5 protein	Involved in the maintenance of embryonic stem (ES) cell pluripotency.
STIM2	Stromal interaction molecule 2	Plays a role in mediating store-operated Ca(2+) entry (SOCE), a Ca(2+) influx following depletion of intracellular Ca(2+) stores.
FANCL	E3 ubiquitin-protein ligase FANCL	Ubiquitin ligase protein that mediates monoubiquitination of FANCD2 in the presence of UBE2T, a key step in the DNA damage pathway.
DEPDC1	DEP domain-containing protein 1A	May be involved in transcriptional regulation as a transcriptional corepressor.
PIGO	GPI ethanolamine phosphate transferase 3, catalytic subunit	Catalytic subunit of the ethanolamine phosphate transferase 3 complex that transfers an ethanolamine phosphate (EtNP) from a phosphatidylethanolamine (PE) to the 6-OH position of the third alpha-1,2-linked mannose of the a 2-acyl-6-[alpha-…
TBATA	Protein TBATA	May play a role in spermatid differentiation.
RASGEF1A	Ras-GEF domain-containing family member 1A	Guanine nucleotide exchange factor (GEF) with specificity for RAP2A, KRAS, HRAS, and NRAS (in vitro).
CSGALNACT2	Chondroitin sulfate N-acetylgalactosaminyltransferase 2	Transfers 1,4-N-acetylgalactosamine (GalNAc) from UDP-GalNAc to the non-reducing end of glucuronic acid (GlcUA).
ZNF592	Zinc finger protein 592	May be involved in transcriptional regulation.
DENND3	DENN domain-containing protein 3	Guanine nucleotide exchange factor (GEF) activating RAB12.
PACS1	Phosphofurin acidic cluster sorting protein 1	Coat protein that is involved in the localization of trans-Golgi network (TGN) membrane proteins that contain acidic cluster sorting motifs.
DSCAM	Cell adhesion molecule DSCAM	Cell adhesion molecule that plays a role in neuronal self-avoidance.
TMEM165	Putative divalent cation/proton antiporter TMEM165	Putative divalent cation:proton antiporter that exchanges calcium or manganese ions for protons across the Golgi membrane.
SLC6A20	Sodium- and chloride-dependent transporter XTRP3	Mediates the Na(+)- and Cl(-)-dependent uptake of imino acids such as L-proline, N-methyl-L-proline and pipecolate as well as N-methylated amino acids.
ECE1	Endothelin-converting enzyme 1	Converts big endothelin-1 to endothelin-1.
EDN3	Endothelin-3	Endothelins are endothelium-derived vasoconstrictor peptides.
EDNRB	Endothelin receptor type B	Non-specific receptor for endothelin 1, 2, and 3.
F5	Coagulation factor V	Central regulator of hemostasis.
GDNF	Glial cell line-derived neurotrophic factor	Neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
GFRA1	GDNF family receptor alpha-1	Coreceptor for GDNF, a neurotrophic factor that enhances survival and morphological differentiation of dopaminergic neurons and increases their high-affinity dopamine uptake.
PROKR1	Prokineticin receptor 1	Receptor for prokineticin 1.
IKBKB	Inhibitor of nuclear factor kappa-B kinase subunit beta	Serine kinase that plays an essential role in the NF-kappa-B signaling pathway which is activated by multiple stimuli such as inflammatory cytokines, bacterial or viral products, DNA damages or other cellular stresses.
L1CAM	Neural cell adhesion molecule L1	Neural cell adhesion molecule involved in the dynamics of cell adhesion and in the generation of transmembrane signals at tyrosine kinase receptors.
MAN2A2	Alpha-mannosidase 2x	Catalyzes the first committed step in the biosynthesis of complex N-glycans.
MYBPC3	Myosin-binding protein C, cardiac-type	Thick filament-associated protein located in the crossbridge region of vertebrate striated muscle a bands.
NOTCH4	Neurogenic locus notch homolog protein 4	Functions as a receptor for membrane-bound ligands Jagged1, Jagged2 and Delta1 to regulate cell-fate determination.
NRG3	Pro-neuregulin-3, membrane-bound isoform	Direct ligand for the ERBB4 tyrosine kinase receptor.

Protein-family classification

Druggable: 23 · Difficult: 10 · Unknown: 28 · Druggable fraction: 0.38

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Kinase	6	2.7×	0.223
Antibody/Immunoglobulin	5	2.4×	0.288
Transporter	2	2.5×	0.616
Phosphatase	1	1.4×	0.866
GPCR	3	1.2×	0.866
Enzyme (other)	5	1.0×	0.866
Transcription factor	7	0.9×	0.866
Scaffold/PPI	3	0.8×	0.866
Protease	1	0.6×	0.906
Other/Unknown	28	0.8×	0.954

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
RET	Kinase	yes	2.7.10.1	Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom, Cadherin-like_dom
NRG1	Antibody/Immunoglobulin	yes		EGF, Neuregulin_C, Ig_sub2
PHOX2B	Transcription factor	no		HD, Homeodomain-like_sf, Homeobox_CS
SMO	GPCR	yes		Frizzled/Smoothened_7TM, Frizzled/SFRP, GPCR_2-like_7TM
SREBF1	Transcription factor	no		bHLH_dom, HLH_DNA-bd_sf
SMOX	Enzyme (other)	yes	1.5.3.16	Amino_oxidase, FAD/NAD-bd_sf, Flavin_monoamine_oxidase
ERBB2	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ERBB3	Kinase	yes	2.7.10.1	Rcpt_L-dom, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd
PHAX	Other/Unknown	no		PHAX_RNA-binding_domain, PHAX_RNA-binding_sf, PHAX
SEMA3D	Antibody/Immunoglobulin	yes		Semap_dom, Ig_sub, Ig-like_dom
SLC22A1	Transporter	yes		Orgcat_transp/SVOP, MFS_sugar_transport-like, Sugar_transporter_CS
VCL	Other/Unknown	no		Vinculin_CS, Vinculin/catenin, Vinculin
VRK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
YWHAE	Other/Unknown	no		14-3-3, 14-3-3_CS, 14-3-3_domain
FMN2	Other/Unknown	no		DEP_dom, FH2_Formin, FH2_Formin_sf
MED15	Other/Unknown	no		Med15_N, KIX_dom_sf, Med15_central
ZEB2	Transcription factor	no		HD, Di19_Zn-bd, Homeodomain-like_sf
DEFB129	Other/Unknown	no
CARD14	Scaffold/PPI	no		CARD, PDZ, Guanylate_kin-like_dom
SNF8	Other/Unknown	no		ESCRT-2_cplx_Snf8, WH-like_DNA-bd_sf, WH_DNA-bd_sf
PORCN	Enzyme (other)	yes	2.3.1.250	MBOAT_fam, LPLAT_7/PORCN-like
DPPA5	Other/Unknown	no		MOEP19_KH-like, KH_dom_type_1_sf
STIM2	Other/Unknown	no		SAM, SAM/pointed_sf, SOAR_STIM1/2
FANCL	Transcription factor	no	2.3.2.27	Znf_RING/FYVE/PHD, UBQ-conjugating_enzyme/RWD, FancL_WD-rpt_cont_dom
DEPDC1	Other/Unknown	no		DEP_dom, Rho_GTPase_activation_prot, WH-like_DNA-bd_sf
PIGO	Phosphatase	yes		Phosphodiest/P_Trfase, Alkaline_phosphatase_core_sf, PIG-O_N
TBATA	Other/Unknown	no		TBATA-like
RASGEF1A	Other/Unknown	no		Ras-like_Gua-exchang_fac_N, RASGEF_cat_dom, Ras-like_GEF
CSGALNACT2	Enzyme (other)	yes	2.4.1.174	Chond_GalNAc, Nucleotide-diphossugar_trans, CS_glycosyltransferase
PHRF1	Transcription factor	no		Znf_RING, Znf_PHD, Znf_FYVE_PHD
MGAM2	Other/Unknown	no		Glyco_hydro_31_TIM, P_trefoil_dom, Gal_mutarotase_sf_dom
NOC4L	Other/Unknown	no		CCAAT-binding_factor, ARM-type_fold, NOC4-like
ZNF592	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, Znf-C2H2_11
DENND3	Scaffold/PPI	no		cDENN_dom, WD40_rpt, dDENN_dom
PACS1	Other/Unknown	no		PACS1/2_C, PACS1/2_N
DSCAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom
TMEM165	Other/Unknown	no		GDT1-like, GDT1-like_CS
SLC6A20	Other/Unknown	no		Na/ntran_symport, Neutral_aa_SLC6, SNS_sf
ECE1	Protease	yes	3.4.24.71	Peptidase_M13, Peptidase_M13_N, Peptidase_M13_C
EDN3	Other/Unknown	no		Endothln-like_toxin, Endothelin_toxin_CS, Endothelin
EDNRB	GPCR	yes		GPCR_Rhodpsn, Endthln_rcpt, ETB_rcpt
IQCF5	Other/Unknown	no		IQ_motif_EF-hand-BS, IQCF
F5	Other/Unknown	no		FA58C, Cupredoxin, Galactose-bd-like_sf
GDNF	Other/Unknown	no		TGF-b_C, GDNF, Cystine-knot_cytokine
GFRA1	Other/Unknown	no		GDNF_rcpt, GDNF_rcpt_A1, GDNF/GAS1
PROKR1	GPCR	yes		GPCR_Rhodpsn, NPY_rcpt, GPCR_Rhodpsn_7TM
IKBKB	Kinase	yes	2.7.11.10	Ubiquitin-like_dom, Prot_kinase_dom, Ser/Thr_kinase_AS
L1CAM	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, FN3_dom

Expression context

Cohort genes with no expression data: 0.

52 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	60
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	7
lower esophagus mucosa	5
sural nerve	5
male germ line stem cell (sensu Vertebrata) in testis	5
dorsal root ganglion	4
ventricular zone	4
buccal mucosa cell	4
right lobe of liver	4
granulocyte	4
apex of heart	4
primordial germ cell in gonad	4
left testis	4
left adrenal gland cortex	3
right adrenal gland	3
C1 segment of cervical spinal cord	3
calcaneal tendon	3
endothelial cell	3
monocyte	3
right testis	3
ganglionic eminence	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
RET	193	broad	marker	substantia nigra pars reticulata, dorsal root ganglion, substantia nigra pars compacta
NRG1	209	ubiquitous	marker	ventricular zone, ganglionic eminence, oocyte
PHOX2B	53	tissue_specific	marker	muscle layer of sigmoid colon, buccal mucosa cell, dorsal motor nucleus of vagus nerve
SMO	225	ubiquitous	marker	ventricular zone, left ovary, right ovary
SREBF1	172	ubiquitous	marker	left adrenal gland, right adrenal gland, left adrenal gland cortex
SMOX	258	ubiquitous	marker	amygdala, lower esophagus mucosa, C1 segment of cervical spinal cord
ERBB2	276	ubiquitous	marker	lower esophagus mucosa, right uterine tube, sural nerve
ERBB3	274	broad	marker	trigeminal ganglion, jejunal mucosa, dorsal root ganglion
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin
PHAX	262	ubiquitous	marker	buccal mucosa cell, calcaneal tendon, endothelial cell
SEMA3D	183	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, spleen
SLC22A1	163	tissue_specific	marker	right lobe of liver, liver, cartilage tissue
VCL	300	ubiquitous	marker	saphenous vein, blood vessel layer, urethra
VRK2	280	ubiquitous	marker	monocyte, mononuclear cell, calcaneal tendon
YWHAE	155	ubiquitous	marker	superior frontal gyrus, ventricular zone, cortical plate
FMN2	187	broad	marker	cortical plate, prefrontal cortex, Brodmann (1909) area 9
MED15	274	ubiquitous	marker	sural nerve, granulocyte, peripheral nervous system
ZEB2	290	ubiquitous	marker	cortical plate, sural nerve, monocyte
DEFB129	13	tissue_specific	yes	corpus epididymis, cauda epididymis, sperm
CARD14	179	tissue_specific	yes	lower esophagus mucosa, skin of leg, skin of abdomen
SNF8	287	ubiquitous	marker	apex of heart, mucosa of transverse colon, lower esophagus muscularis layer
PORCN	184	ubiquitous	marker	lower esophagus mucosa, right adrenal gland cortex, right adrenal gland
DPPA5	37	tissue_specific	marker	secondary oocyte, oocyte, primordial germ cell in gonad
STIM2	246	ubiquitous	marker	olfactory segment of nasal mucosa, adenohypophysis, right uterine tube
FANCL	293	ubiquitous	marker	pituitary gland, adenohypophysis, calcaneal tendon
DEPDC1	173	ubiquitous	marker	ventricular zone, primordial germ cell in gonad, male germ line stem cell (sensu Vertebrata) in testis
PIGO	264	ubiquitous	yes	mucosa of transverse colon, diaphragm, vena cava
TBATA	67	tissue_specific	marker	right testis, thymus, left testis
RASGEF1A	209	broad	yes	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 35.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ERBB2	9,659
NTRK1	9,181
IKBKB	5,421
ERBB3	4,511
VCL	4,495
RET	4,203
NUP98	4,108
SREBF1	4,089
ATP7A	3,901
ZEB2	3,193

Intra-cohort edges

A	B	Sources
AXIN2	PORCN	string_interaction
DENND3	TBATA	string_interaction
ECE1	EDN3	string_interaction
ECE1	EDNRB	string_interaction
ECE1	GFRA1	string_interaction
EDN3	EDNRB	string_interaction
EDN3	GDNF	string_interaction
EDN3	GFRA1	string_interaction
EDN3	PHOX2B	string_interaction
EDN3	RET	string_interaction
EDNRB	GDNF	string_interaction
EDNRB	GFRA1	string_interaction
EDNRB	PHOX2B	string_interaction
EDNRB	RET	string_interaction
ERBB2	ERBB3	biogrid_interaction, intact, string_interaction
ERBB2	L1CAM	biogrid_interaction
ERBB2	NRG3	string_interaction
ERBB2	SEMA3D	string_interaction
ERBB3	L1CAM	biogrid_interaction
ERBB3	NRG1	intact
ERBB3	NRG3	string_interaction
FANCL	VRK2	string_interaction
GDNF	GFRA1	biogrid_interaction, string_interaction
GDNF	NTF3	string_interaction
GDNF	NTRK1	string_interaction
GDNF	PHOX2B	string_interaction
GDNF	RET	biogrid_interaction, string_interaction
GFRA1	NTRK1	string_interaction
GFRA1	RET	string_interaction
IQCF5	PHOX2B	string_interaction
NTF3	NTRK1	biogrid_interaction, string_interaction
NUP98	TBATA	string_interaction
PHOX2B	RET	string_interaction
PIGO	TMEM165	string_interaction
STIM2	YWHAE	intact

Structural data

PDB: 44 · AlphaFold-only: 17 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NTRK1	P04629	65
ERBB2	P04626	63
POLR2F	P61218	60
VCL	P18206	37
RET	P07949	34
ERBB3	P21860	23
ATP7A	Q04656	22
NUP98	P52948	22
EDNRB	P24530	18
F5	P12259	18
MYBPC3	Q14896	17
SLC22A1	O15245	16
SMO	Q99835	15
ABCD1	P33897	14
MED15	Q96RN5	12
NRG1	Q02297	11
YWHAE	P62258	11
SLC6A20	Q9NP91	10
POR	P16435	9
FANCL	Q9NW38	8
PORCN	Q9H237	7
PHOX2B	Q99453	5
VRK2	Q86Y07	5
IKBKB	O14920	5
NTF3	P20783	5
GDNF	P39905	4
PHAX	Q9H814	3
NOC4L	Q9BVI4	3
NOTCH4	Q99466	3
SMOX	Q9NWM0	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
IQCF5	A8MTL0	93.19
MAN2A2	P49641	91.27
DPPA5	A6NC42	88.63
CSGALNACT2	Q8N6G5	87.16
RASGEF1A	Q8N9B8	85.79
SEMA3D	O95025	84.10
PIGO	Q8TEQ8	82.57
DENND3	A2RUS2	81.23
PROKR1	Q8TCW9	77.64
MGAM2	Q2M2H8	76.60
TMEM165	Q9HC07	76.36
CARD14	Q9BXL6	75.89
TBATA	Q96M53	60.70
DEFB129	Q9H1M3	60.57
ZNF592	Q92610	54.79
NRG3	P56975	50.59
PHRF1	Q9P1Y6	46.11

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 438. Enrichment computed across 61 evidence-associated genes (49 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 49 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ERBB2 Activates PTK6 Signaling	4	66.6×	1e-04	NRG1, ERBB2, ERBB3, NRG3
ERBB2 Regulates Cell Motility	4	58.3×	1e-04	NRG1, ERBB2, ERBB3, NRG3
PI3K events in ERBB2 signaling	4	54.8×	1e-04	NRG1, ERBB2, ERBB3, NRG3
RAF/MAP kinase cascade	8	10.0×	1e-04	RET, NRG1, RASGEF1A, ERBB2, ERBB3, GDNF, GFRA1, NRG3
GRB7 events in ERBB2 signaling	3	116.5×	1e-04	NRG1, ERBB2, ERBB3
SHC1 events in ERBB2 signaling	4	38.8×	2e-04	NRG1, ERBB2, ERBB3, NRG3
Signaling by ERBB2 TMD/JMD mutants	4	38.8×	2e-04	NRG1, ERBB2, ERBB3, NRG3
Signaling by ERBB2 KD Mutants	4	34.5×	3e-04	NRG1, ERBB2, ERBB3, NRG3
Downregulation of ERBB2 signaling	4	31.1×	4e-04	NRG1, ERBB2, ERBB3, NRG3
Signaling by ERBB2	4	28.2×	5e-04	NRG1, ERBB2, ERBB3, NRG3
Downregulation of ERBB2:ERBB3 signaling	3	49.9×	0.001	NRG1, ERBB2, ERBB3
Constitutive Signaling by Aberrant PI3K in Cancer	5	12.9×	0.001	NRG1, ERBB2, ERBB3, NRG3, NTF3
GRB2 events in ERBB2 signaling	3	38.8×	0.002	NRG1, ERBB2, NRG3
Formation of the ureteric bud	3	30.4×	0.004	RET, GDNF, GFRA1
PI5P, PP2A and IER3 Regulate PI3K/AKT Signaling	5	9.9×	0.004	NRG1, ERBB2, ERBB3, NRG3, NTF3
Signaling by ERBB4	3	16.6×	0.020	NRG1, ERBB3, NRG3
PIP3 activates AKT signaling	5	6.8×	0.020	NRG1, ERBB2, ERBB3, NRG3, NTF3
RET signaling	3	15.9×	0.021	RET, GDNF, GFRA1
PI3K events in ERBB4 signaling	2	42.4×	0.022	NRG1, NRG3
SHC1 events in ERBB4 signaling	2	29.1×	0.046	NRG1, NRG3
Transcriptional and post-translational regulation of MITF-M expression and activity	3	10.9×	0.054	YWHAE, EDN3, EDNRB
Peptide ligand-binding receptors	4	6.0×	0.084	ECE1, EDN3, EDNRB, PROKR1
TRKA activation by NGF	1	116.5×	0.120	NTRK1
LGK974 inhibits PORCN	1	116.5×	0.120	PORCN
Variant SLC6A20 affecting neurotransmitter transport contributes towards hyperglycinuria (HG) and iminoglycinuria (IG)	1	116.5×	0.120	SLC6A20
Variant SLC6A20 affecting amino acid transport contributes towards hyperglycinuria (HG) and iminoglycinuria (IG)	1	116.5×	0.120	SLC6A20
Defective ABCD1 causes ALD	1	116.5×	0.120	ABCD1
NTF3 activates NTRK2 (TRKB) signaling	1	116.5×	0.120	NTF3
NTF3 activates NTRK3 signaling	1	116.5×	0.120	NTF3
SLC-mediated transport of neurotransmitters	2	16.6×	0.120	SLC22A1, SLC6A20

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 60 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
neural crest cell migration	7	39.3×	3e-07	RET, SEMA3D, SMO, ZEB2, EDN3, EDNRB, GDNF
enteric nervous system development	4	66.1×	1e-04	RET, PHOX2B, EDNRB, GDNF
cell surface receptor protein tyrosine kinase signaling pathway	6	17.4×	3e-04	RET, NRG1, ERBB2, ERBB3, NTF3, NTRK1
peripheral nervous system development	4	38.7×	6e-04	NRG1, EDNRB, ERBB3, GDNF
ERBB2-ERBB3 signaling pathway	3	84.3×	8e-04	NRG1, ERBB2, ERBB3
posterior midgut development	2	280.9×	0.002	RET, EDNRB
glial cell-derived neurotrophic factor receptor signaling pathway	3	60.2×	0.002	RET, GDNF, GFRA1
sympathetic nervous system development	3	46.8×	0.003	PHOX2B, GDNF, NTRK1
axon guidance	6	9.1×	0.003	RET, SEMA3D, DSCAM, EDN3, L1CAM, NTRK1
nervous system development	8	6.1×	0.003	NRG1, ZEB2, DSCAM, EDNRB, GDNF, GFRA1, L1CAM, NTF3
negative regulation of apoptotic process	9	5.2×	0.003	SMO, FMN2, CARD14, EDNRB, ERBB2, ERBB3, GDNF, NTRK1 (+1 more)
vein smooth muscle contraction	2	140.4×	0.005	EDN3, EDNRB
negative regulation of secretion	2	112.3×	0.007	NRG1, ERBB3
regulation of systemic arterial blood pressure by endothelin	2	93.6×	0.009	ECE1, EDN3
ERBB4 signaling pathway	2	93.6×	0.009	NRG1, NRG3
ERBB2-ERBB4 signaling pathway	2	93.6×	0.009	NRG1, ERBB2
negative regulation of neuron apoptotic process	5	9.2×	0.009	ERBB3, GDNF, NTF3, NTRK1, ATP7A
ERBB4-ERBB4 signaling pathway	2	80.2×	0.011	NRG1, NRG3
developmental pigmentation	2	70.2×	0.013	ZEB2, EDNRB
neural crest cell migration involved in autonomic nervous system development	2	62.4×	0.016	PHOX2B, GDNF
regulation of establishment of endothelial barrier	2	62.4×	0.016	VCL, IKBKB
axonogenesis involved in innervation	2	56.2×	0.019	ECE1, NTRK1
regulation of gene expression	5	7.0×	0.024	PHOX2B, DPPA5, EDN3, GDNF, ATP7A
positive regulation of melanin biosynthetic process	2	46.8×	0.025	ZEB2, ATP7A
positive regulation of MAPK cascade	5	6.7×	0.026	RET, EDN3, ERBB2, ERBB3, NTF3
nerve growth factor signaling pathway	2	43.2×	0.027	NTF3, NTRK1
regulation of oxidative phosphorylation	2	40.1×	0.030	ABCD1, ATP7A
Schwann cell development	2	35.1×	0.038	ERBB2, ERBB3
neuron projection development	4	8.1×	0.038	GDNF, GFRA1, L1CAM, NTRK1
astrocyte activation	2	33.0×	0.039	SMO, ZEB2

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

1 drug in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Lactobacillus Acidophilus	Phase 2

Drug target analysis

Approved (phase 4): 13 · Phase ≥3: 13 · Phased (≥1): 15 · Undrugged: 46

Druggability breadth: 29 of 61 evidence-associated genes (48%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
RET	PONATINIB
SMO	INFIGRATINIB
SREBF1	CALCIFEDIOL ANHYDROUS
ERBB2	CLOTRIMAZOLE
ERBB3	MOBOCERTINIB
SLC22A1	PROGESTERONE
VRK2	RUXOLITINIB
MGAM2	ACARBOSE
ECE1	IDARUBICIN HYDROCHLORIDE
EDNRB	AMBRISENTAN
F5	EDOXABAN
IKBKB	FEDRATINIB
NTRK1	PONATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
RET	135	4
SLC22A1	86	4
ERBB2	83	4
NTRK1	66	4
ERBB3	23	4
EDNRB	16	4
IKBKB	16	4
SMO	11	4
VRK2	4	4
MGAM2	4	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PONATINIB	4	ERBB2, NTRK1, RET
AFATINIB	4	ERBB2, ERBB3, RET
VEMURAFENIB	4	RET
FEDRATINIB	4	IKBKB, NTRK1, RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	NTRK1, RET
SORAFENIB	4	ERBB2, NTRK1, RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	IKBKB, NTRK1, RET, VRK2
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET, SMO
IBRUTINIB	4	ERBB2, RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	NTRK1, RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	ERBB2, NTRK1, RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	NTRK1, RET
VANDETANIB	4	ERBB2, ERBB3, RET
NILOTINIB	4	RET
BOSUTINIB	4	ERBB2, ERBB3, NTRK1, RET, VRK2
GILTERITINIB	4	RET
BRIGATINIB	4	ERBB2, RET
UPADACITINIB	4	RET

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 14.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
RET	1,586	Binding:1573, Functional:10, ADMET:3
ERBB2	1,221	Binding:1136, Functional:79, ADMET:6
NTRK1	1,194	Binding:1182, ADMET:7, Functional:5
IKBKB	855	Binding:839, Functional:11, ADMET:5
EDNRB	270	Binding:229, Functional:41
ERBB3	169	Binding:169
VRK2	146	Binding:146
MGAM2	136	Binding:136
SMO	131	Binding:111, Functional:20
SLC22A1	97	Functional:41, Binding:35, ADMET:21
ECE1	80	Binding:78, ADMET:1, Functional:1
PORCN	31	Binding:31
POR	21	ADMET:14, Binding:7
PROKR1	19	Binding:11, Functional:8
SMOX	18	Binding:15, ADMET:3
SREBF1	17	Binding:17
AXIN2	14	Binding:14
ATP7A	11	Binding:11
F5	10	Binding:10
NOC4L	6	Binding:6
YWHAE	4	Binding:4
VCL	2	Binding:2
STIM2	2	Binding:2
GFRA1	2	Binding:2
L1CAM	2	Binding:2
NOTCH4	2	Binding:2
PHAX	1	Binding:1
PIGO	1	Binding:1
TMEM165	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
RET	2.7.10.1	receptor protein-tyrosine kinase
SMOX	1.5.3.16	spermine oxidase
ERBB2	2.7.10.1	receptor protein-tyrosine kinase
ERBB3	2.7.10.1	receptor protein-tyrosine kinase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter
PORCN	2.3.1.250	[Wnt protein] O-palmitoleoyl transferase
FANCL	2.3.2.27	RING-type E3 ubiquitin transferase
CSGALNACT2	2.4.1.174, 2.4.1.175	glucuronylgalactosylproteoglycan 4-beta-N-acetylgalactosaminyltransferase, glucuronosyl-N-acetylgalactosaminyl-proteoglycan 4-beta-N-acetylgalactosaminyltransferase
ECE1	3.4.24.71	endothelin-converting enzyme 1
IKBKB	2.7.11.10	IkappaB kinase
NTRK1	2.7.10.1	receptor protein-tyrosine kinase
OAS3	2.7.7.84	2’-5’ oligoadenylate synthase
POR	1.6.2.4	NADPH-hemoprotein reductase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
RET	1,586
SMO	131
ERBB2	1,221
ERBB3	169
VRK2	146
MGAM2	136
EDNRB	270
IKBKB	855
NTRK1	1,194

Pharmacogenomics

Cohort genes with a PharmGKB record: 61; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PONATINIB	4	ERBB2, NTRK1, RET
AFATINIB	4	ERBB2, ERBB3, RET
VEMURAFENIB	4	RET
FEDRATINIB	4	IKBKB, NTRK1, RET
TIVOZANIB	4	RET
LENVATINIB	4	RET
AXITINIB	4	NTRK1, RET
SORAFENIB	4	ERBB2, NTRK1, RET
DASATINIB ANHYDROUS	4	RET
ALECTINIB	4	RET
RUXOLITINIB	4	IKBKB, NTRK1, RET, VRK2
INFIGRATINIB PHOSPHATE	4	RET
INFIGRATINIB	4	RET, SMO
IBRUTINIB	4	ERBB2, RET
PALBOCICLIB	4	RET
REGORAFENIB	4	RET
ENTRECTINIB	4	NTRK1, RET
TOFACITINIB CITRATE	4	RET
FOSTAMATINIB	4	RET
CABOZANTINIB	4	ERBB2, NTRK1, RET
BARICITINIB	4	RET
TOFACITINIB	4	RET
CAPIVASERTIB	4	RET
CERITINIB	4	NTRK1, RET
VANDETANIB	4	ERBB2, ERBB3, RET
NILOTINIB	4	RET
BOSUTINIB	4	ERBB2, ERBB3, NTRK1, RET, VRK2
GILTERITINIB	4	RET
BRIGATINIB	4	ERBB2, RET
UPADACITINIB	4	RET

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	13	RET, SMO, SREBF1, ERBB2, ERBB3, SLC22A1, VRK2, MGAM2, ECE1, EDNRB (+3 more)
B	Phased (≥1) drug, not yet approved	2	PORCN, POR
C	Druggable family + PDB, no drug	7	NRG1, SMOX, ABCD1, DSCAM, L1CAM, MYBPC3, OAS3
D	Druggable family + AlphaFold only, no drug	4	SEMA3D, PIGO, CSGALNACT2, PROKR1
E	Difficult family or no structure, no drug	35	PHOX2B, ATP7A, PHAX, VCL, YWHAE, FMN2, MED15, ZEB2, DEFB129, CARD14 (+25 more)

Undrugged target profiles

46 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NRG1	0	ERBB3
PHOX2B	0	RET
EDN3	0	EDNRB, ECE1
GDNF	0	RET, NTRK1
GFRA1	2	RET
NRG3	0	ERBB3
NTF3	0	NTRK1
SMOX	18	—
ABCD1	0	—
ATP7A	11	—
PHAX	1	—
SEMA3D	0	—
VCL	2	—
YWHAE	4	—
FMN2	0	—
MED15	0	—
ZEB2	0	—
DEFB129	0	—
CARD14	0	—
SNF8	0	—
DPPA5	0	—
STIM2	2	—
FANCL	0	—
DEPDC1	0	—
PIGO	1	—
TBATA	0	—
RASGEF1A	0	—
CSGALNACT2	0	—
PHRF1	0	—
NOC4L	6	—

Clinical trials & evidence

Clinical trials

Clinical trials: 53.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	46
PHASE4	2
PHASE3	2
PHASE2	1
PHASE1/PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02343562	PHASE4	UNKNOWN	Probiotics for Prophylaxis of Postoperative Hirschsprungs Associated Enterocolitis
NCT07186647	PHASE4	COMPLETED	Laparoscopic-Assisted Transanal Pull-Through for Hirschsprung Disease in Pediatric:Short and Intermediate Outcomes of Two Different Techniques
NCT03660176	PHASE3	UNKNOWN	Effects of Butyrate Enemas on Postoperative Intestinal Mobility Disorders in Hirschsprung’s Disease
NCT04904081	PHASE3	UNKNOWN	Feasibility of Use of Indocyanine Green in Pediatric Colorectal Surgery
NCT00630838	PHASE2	COMPLETED	Probiotic Prophylaxis of Hirschprung’s Disease Associated Enterocolitis (HAEC)
NCT00671684	PHASE1/PHASE2	UNKNOWN	Endoscopic Mucosal Resection (EMR) for Diagnosis of Hirschsprung’s Disease
NCT01985646	EARLY_PHASE1	COMPLETED	A Trial on Conservative Treatment for Infants’ Hirschsprung Disease
NCT00478712	Not specified	RECRUITING	Hirschsprung Disease Genetic Study
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT03626350	Not specified	ACTIVE_NOT_RECRUITING	Prospective Evaluation of the Efficacy and Safety of Submucosal Endoscopy
NCT04622410	Not specified	RECRUITING	Registry for Hirschsprung Disease of the BELAPS
NCT05450991	Not specified	RECRUITING	Long-term Qualitative and Quantitative Outcomes of Children With Hirschsprung’s Disease and Anorectal Malformations
NCT06072976	Not specified	RECRUITING	The Influence of Feeding Source on the Gut Microbiome and Time to Full Feeds in Neonates With Congenital Gastrointestinal Pathologies
NCT06573723	Not specified	RECRUITING	Institutional Registry of Rare Diseases
NCT06590142	Not specified	RECRUITING	Hirschsprung’s Advances; Working Towards Autologous tIssue therapIes
NCT06592534	Not specified	NOT_YET_RECRUITING	Babies With Enterocolitis - A Study of Faecal Calprotectin in Hirschsprung Disease (The BEACH Study)
NCT06650683	Not specified	RECRUITING	Impact of Providing Nursing Support on Parental Stress Related to Preoperative Care of a Newborn with Hirschsprung’s Disease
NCT07156981	Not specified	NOT_YET_RECRUITING	Effects of Physiotherapy in Children With Hirschsprung’s Disease
NCT07343622	Not specified	NOT_YET_RECRUITING	Robot/Laparoscopic-Assisted Transanal Transection Duhamel Versus Modified Soave Pull-Through for TCA
NCT07468565	Not specified	NOT_YET_RECRUITING	Surgical Approach for the Treatment of Hirschsprung Disease Using the Swenson Technique (SMILES)
NCT07519915	Not specified	RECRUITING	Improvement of Understanding of Pediatric Sacral Neuromodulation: Therapeutic Strategies and Outcome Variables
NCT07526636	Not specified	NOT_YET_RECRUITING	Pattern And Outcome Of Neonatal Gastrointestinal Emergencies In Assiut University Children Hospital
NCT01515501	Not specified	COMPLETED	Endoscopic Mucosal Resection for the Diagnosis of a-Ganglionosis, a Controlled Prospective Trial (EDGE Trial)
NCT01927809	Not specified	UNKNOWN	Genetic Mosaicism in Hirschsprung’s Disease
NCT02193685	Not specified	UNKNOWN	Identification Genetic, Immunologic and Microbial Markers of Hirschsprung Associated Enterocolitis in Children With Hirschsprung Disease
NCT02216994	Not specified	UNKNOWN	A New Scoring System Improves Diagnostic Accuracy of Intestinal Dysganglionosis –a Prospective Study
NCT02296008	Not specified	COMPLETED	3D High Resolution Anorectal Manometry in Children After Surgery for Anorectal Disorders
NCT02776176	Not specified	UNKNOWN	Enhanced Recovery After Surgery In Hirschsprung Disease
NCT02857205	Not specified	COMPLETED	MICROPRUNG : Intestinal Microbiota Analysis in Patients With or Without Hirschsprung’s Associated EnteroColitis
NCT03269812	Not specified	UNKNOWN	Laparoscopic Assisted Pull-through Versus Other Surgical Procedures for Treatment of Hirschsprung Disease
NCT03406741	Not specified	COMPLETED	Neuropsychological Development and Functional Outcome Sin Children With Hirschsprung Disease at School Age
NCT03666767	Not specified	COMPLETED	Management and Outcomes of Congenital Anomalies in Low-, Middle- and High-Income Countries
NCT04020939	Not specified	COMPLETED	The Role of Indocyanine Green Angiography Fluorescence on Intestinal Resections in Pediatric Surgery.
NCT04106947	Not specified	UNKNOWN	Transition of Care for Patients With Hirschsprung Disease and Anorectal Malformations
NCT04149093	Not specified	UNKNOWN	The Association Between Calretinin and the Function of Ganglion Cells in Hirschsprung Disease
NCT04150120	Not specified	COMPLETED	eHealth as an Aid for Facilitating and Supporting Self-management in Families With Long-term Childhood Illness
NCT04213976	Not specified	UNKNOWN	Ostomy in Continuity or Conventional Ileostomy: a Retrospective Multicentric Analysis
NCT04476225	Not specified	COMPLETED	Induced Pluripotent Stem Cells for Disease Research
NCT04598841	Not specified	COMPLETED	Nutrition Support for Hirschsprung Disease
NCT04624334	Not specified	TERMINATED	Non-invasive Assessment of Colonic Motility

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
INDOCYANINE GREEN ACID FORM	4	3