Angelman syndrome

Summary

Angelman syndrome (MONDO:0007113) is a disease caused by UBE3A (GenCC Definitive), with 15 cohort genes and 49 clinical trials. Top therapeutic interventions include carbidopa anhydrous, levodopa, and levomefolic acid.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: UBE3A (GenCC Definitive)
• Cohort genes: 15
• ClinVar variants: 818
• Phenotypes (HPO): 71
• Clinical trials: 49

Clinical features

Epidemiology

Prevalence records

12 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	7.5	Worldwide	Validated
Point prevalence	1-9 / 100 000		Europe	Validated
Prevalence at birth	1-9 / 100 000	1.3	Europe	Validated
Point prevalence	1-9 / 100 000	8.3	Spain	Validated
Point prevalence	1-5 / 10 000	10	Denmark	Validated
Point prevalence	1-9 / 100 000	4	United Kingdom	Validated
Prevalence at birth	1-9 / 100 000	2.5	Australia	Validated
Prevalence at birth	1-9 / 100 000	5	Spain	Validated
Prevalence at birth	1-9 / 100 000	1.8	Estonia	Validated
Prevalence at birth	1-9 / 1 000 000	0.5	Denmark	Validated
Point prevalence	1-9 / 100 000		Australia	Not yet validated
Point prevalence	1-9 / 100 000		Estonia	Not yet validated

Signs & symptoms

Clinical features (HPO)

71 HPO clinical features (Orphanet curated; top 50 by frequency):

HPO ID	Term	Frequency
HP:0000252	Microcephaly	Very frequent (80-99%)
HP:0000708	Atypical behavior	Very frequent (80-99%)
HP:0000729	Autistic behavior	Very frequent (80-99%)
HP:0000748	Inappropriate laughter	Very frequent (80-99%)
HP:0000750	Delayed speech and language development	Very frequent (80-99%)
HP:0000752	Hyperactivity	Very frequent (80-99%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0001270	Motor delay	Very frequent (80-99%)
HP:0001337	Tremor	Very frequent (80-99%)
HP:0002120	Cerebral cortical atrophy	Very frequent (80-99%)
HP:0002136	Broad-based gait	Very frequent (80-99%)
HP:0002167	Abnormality of speech or vocalization	Very frequent (80-99%)
HP:0002353	EEG abnormality	Very frequent (80-99%)
HP:0002360	Sleep abnormality	Very frequent (80-99%)
HP:0002465	Poor speech	Very frequent (80-99%)
HP:0010864	Intellectual disability, severe	Very frequent (80-99%)
HP:0011344	Severe global developmental delay	Very frequent (80-99%)
HP:0100716	Self-injurious behavior	Very frequent (80-99%)
HP:0000154	Wide mouth	Frequent (30-79%)
HP:0000483	Astigmatism	Frequent (30-79%)
HP:0000486	Strabismus	Frequent (30-79%)
HP:0001010	Hypopigmentation of the skin	Frequent (30-79%)
HP:0001513	Obesity	Frequent (30-79%)
HP:0001999	Abnormal facial shape	Frequent (30-79%)
HP:0002019	Constipation	Frequent (30-79%)
HP:0002020	Gastroesophageal reflux	Frequent (30-79%)
HP:0002286	Fair hair	Frequent (30-79%)
HP:0002307	Drooling	Frequent (30-79%)
HP:0002591	Polyphagia	Frequent (30-79%)
HP:0002650	Scoliosis	Frequent (30-79%)
HP:0006979	Sleep-wake cycle disturbance	Frequent (30-79%)
HP:0007730	Iris hypopigmentation	Frequent (30-79%)
HP:0008947	Floppy infant	Frequent (30-79%)
HP:0010808	Protruding tongue	Frequent (30-79%)
HP:0011024	Abnormality of the gastrointestinal tract	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0100023	Recurrent hand flapping	Frequent (30-79%)
HP:0000303	Mandibular prognathia	Occasional (5-29%)
HP:0000508	Ptosis	Occasional (5-29%)
HP:0000540	Hypermetropia	Occasional (5-29%)
HP:0000543	Optic disc pallor	Occasional (5-29%)
HP:0000545	Myopia	Occasional (5-29%)
HP:0000563	Keratoconus	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0000646	Amblyopia	Occasional (5-29%)
HP:0000648	Optic atrophy	Occasional (5-29%)
HP:0000687	Widely spaced teeth	Occasional (5-29%)
HP:0000718	Aggressive behavior	Occasional (5-29%)
HP:0000739	Anxiety	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Angelman syndrome
Mondo ID	MONDO:0007113
MeSH	C531619, D017204
OMIM	105830
Orphanet	72
DOID	DOID:1932
ICD-10-CM	Q93.51
ICD-11	1106558408
NCIT	C75462
SNOMED CT	76880004
UMLS	C0162635
MedGen	58144
GARD	0005810
MedDRA	10049004
NORD	782
Is cancer (heuristic)	no

Also known as: Angelman syndrome · Angelman syndrome (Type 1) · Angelman syndrome (Type 2) · Angelman’s syndrome · AS · happy puppet syndrome (formerly) · happy puppet syndrome, formerly

Data availability: 818 ClinVar variants · 55 ClinGen variant curations · 4 GenCC gene-disease records · 52 cell lines.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Angelman syndrome

Related subtypes (1183): Neu-Laxova syndrome, inclusion body myopathy with Paget disease of bone and frontotemporal dementia, syndromic intellectual disability, abdominal obesity-metabolic syndrome, fibrogenesis imperfecta ossium, Fanconi renotubular syndrome, palindromic rheumatism, hepatorenal syndrome, Potter sequence, vertebral artery insufficiency, sick sinus syndrome, Tietze syndrome, toxic shock syndrome, capillary leak syndrome, dumping syndrome, FG syndrome, basilar artery insufficiency, long QT syndrome, Treacher-Collins syndrome, superior mesenteric artery syndrome, disappearing bone disease, Brown-Sequard syndrome, Froelich syndrome, diffuse infiltrative lymphocytosis syndrome, Capgras syndrome, compartment syndrome, central sleep apnea syndrome, irritable bowel syndrome, nephrotic syndrome, myalgic encephalomeyelitis/chronic fatigue syndrome, acute coronary syndrome, fibromyalgia, substance withdrawal syndrome, acute chest syndrome, Barre-Lieou syndrome, cauda equina syndrome, Kluver-Bucy syndrome, Miller Fisher syndrome, persian gulf syndrome, Reye syndrome, thoracic outlet syndrome, Waterhouse-Friderichsen syndrome, Wissler syndrome, acute respiratory distress syndrome, Achenbach syndrome, miliaria, anterior spinal artery syndrome, burning mouth syndrome, dry eye syndrome, empty sella syndrome, euthyroid sick syndrome, lateral medullary syndrome, subclavian steal syndrome, tarsal tunnel syndrome, tethered spinal cord syndrome, branchio-oto-renal syndrome, prune belly syndrome, Achard syndrome, alopecia-epilepsy-pyorrhea-intellectual disability syndrome, Finnish type amyloidosis, aniridia-absent patella syndrome, ankyloblepharon filiforme adnatum-cleft palate syndrome, Townes-Brocks syndrome, obstructive sleep apnea syndrome, Lown-Ganong-Levine syndrome, Behcet disease, brachydactyly-arterial hypertension syndrome, brachydactyly type A2, fibular aplasia-ectrodactyly syndrome, brachydactyly-nystagmus-cerebellar ataxia syndrome, Sillence syndrome, Brachymorphism-onychodysplasia-dysphalangism syndrome, brachytelephalangy-dysmorphism-Kallmann syndrome, dilated cardiomyopathy 1A, cat-eye syndrome, cerebrocostomandibular syndrome, Alagille syndrome, autosomal dominant chondrodysplasia punctata, cleidocranial dysplasia 1, cleidorhizomelic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Cri-du-chat syndrome, autosomal dominant deafness - onychodystrophy syndrome, cerebral arteriopathy with subcortical infarcts and leukoencephalopathy, Duane retraction syndrome, 3-M syndrome, dyschondrosteosis-nephritis syndrome, hereditary benign intraepithelial dyskeratosis, encephalopathy, recurrent, of childhood, Camurati-Engelmann disease, Felty syndrome, chromosome 16p12.1 deletion syndrome, 520kb, Frasier syndrome, Gamstorp-Wohlfart syndrome, Tourette syndrome, glaucoma-sleep apnea syndrome, renal cysts and diabetes syndrome, hypotrichosis-lymphedema-telangiectasia syndrome (grouping), GMS syndrome, gray platelet syndrome, hand-foot-genital syndrome, facial hemiatrophy, Bencze syndrome, alpha thalassemia-intellectual disability syndrome type 1, Gilbert syndrome, mullerian duct anomalies-limb anomalies syndrome, hypoparathyroidism-deafness-renal disease syndrome, chromosome 18p deletion syndrome, Pallister-Hall syndrome, ichthyosis-cheek-eyebrow syndrome, Jacobsen syndrome, palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome, palmoplantar keratoderma-esophageal carcinoma syndrome, Kleine-Levin syndrome, angioosteohypertrophic syndrome, congenital laryngeal web, Lenz-Majewski hyperostotic dwarfism, Noonan syndrome with multiple lentigines, lymphedema-cerebral arteriovenous anomaly syndrome, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, yellow nail syndrome, lymphedema-distichiasis syndrome, Nager acrofacial dysostosis, jaw-winking syndrome, Marfan syndrome, Melkersson-Rosenthal syndrome, metaphyseal chondrodysplasia, Jansen type, Schmid metaphyseal chondrodysplasia, metaphyseal dysplasia-maxillary hypoplasia-brachydacty syndrome, microgastria-limb reduction defect syndrome, Mobius syndrome, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, nail-patella syndrome, Schilbach-Rott syndrome, syndromic orbital border hypoplasia, Buschke-Ollendorff syndrome, nasopalpebral lipoma-coloboma syndrome, Perry syndrome, Poland syndrome, polydactyly-myopia syndrome, Greig cephalopolysyndactyly syndrome, Prader-Willi syndrome, Guttmacher syndrome, Currarino triad, Hutchinson-Gilford progeria syndrome, progeria-short stature-pigmented nevi syndrome, Liddle syndrome, exfoliation syndrome, ptosis-strabismus-ectopic pupils syndrome, radial hypoplasia-triphalangeal thumbs-hypospadias-maxillary diastema syndrome, radial ray hypoplasia-choanal atresia syndrome, Roussy-Levy syndrome, Silver-Russell syndrome, Ruvalcaba syndrome, oculodental syndrome, Rutherfurd type, aplasia of lacrimal and salivary glands, scalp defects-postaxial polydactyly syndrome, ulnar-mammary syndrome, septooptic dysplasia, Czeizel-Losonci syndrome, polycystic ovary syndrome, stiff-person syndrome, syndactyly-polydactyly-ear lobe syndrome, HELLP syndrome, double uterus-hemivagina-renal agenesis syndrome, VACTERL/vater association, posterior fusion of lumbosacral vertebrae-blepharoptosis syndrome, ptosis-vocal cord paralysis syndrome, Freeman-Sheldon syndrome, Williams syndrome, Denys-Drash syndrome, Wolf-Hirschhorn syndrome, ablepharon macrostomia syndrome, acrocallosal syndrome, PAGOD syndrome, alopecia - intellectual disability syndrome, mitochondrial DNA depletion syndrome 4a, Alstrom syndrome, aniridia-cerebellar ataxia-intellectual disability syndrome, aniridia-renal agenesis-psychomotor retardation syndrome, aplasia cutis congenita-intestinal lymphangiectasia syndrome, fetal akinesia deformation sequence, blepharophimosis-ptosis-esotropia-syndactyly-short stature syndrome, Bloom syndrome, Elsahy-Waters syndrome, campomelia, Cumming type, camptomelic syndrome, long-limb type, congenital cataract-ichthyosis syndrome, colobomatous optic disc-macular atrophy-chorioretinopathy syndrome, hepatic fibrosis-renal cysts-intellectual disability syndrome, Charcot-Marie-Tooth disease-hearing loss-intellectual disability syndrome, CHARGE syndrome, Aagenaes syndrome, infantile choroidocerebral calcification syndrome, Yunis-Varon syndrome, corneal dystrophy-perceptive deafness syndrome, cortical blindness-intellectual disability-polydactyly syndrome, Crigler-Najjar syndrome, cataract-nephropathy-encephalopathy syndrome, Fraser syndrome, cystic fibrosis-gastritis-megaloblastic anemia syndrome, cystinuria, DOORS syndrome, high myopia-sensorineural deafness syndrome, dermochondrocorneal dystrophy, nephrogenic diabetes insipidus-intracranial calcification syndrome, diverticulosis of bowel, hernia, and retinal detachment, Dyggve-Melchior-Clausen disease, cerebellar ataxia, intellectual disability, and dysequilibrium, ectrodactyly-polydactyly syndrome, Bonnemann-Meinecke-Reich syndrome, epidermolysis bullosa simplex 5B, with muscular dystrophy, Wolcott-Rallison syndrome, ermine phenotype, eyebrow duplication-syndactyly syndrome, Fanconi-like syndrome, gingival fibromatosis-facial dysmorphism syndrome, frontofacionasal dysplasia, Fryns syndrome, German syndrome, Bernard-Soulier syndrome, triple-A syndrome, Grubben-de Cock-Borghgraef syndrome, mullerian derivatives-lymphangiectasia-polydactyly syndrome, Hirschsprung disease-hearing loss-polydactyly syndrome, Hirschsprung disease-nail hypoplasia-dysmorphism syndrome, Holzgreve-Wagner-Rehder syndrome, multinucleated neurons-anhydramnios-renal dysplasia-cerebellar hypoplasia-hydranencephaly syndrome, growth delay-hydrocephaly-lung hypoplasia syndrome, Dubin-Johnson syndrome, ornithine translocase deficiency, acrofrontofacionasal dysostosis 2, hypertrichotic osteochondrodysplasia Cantu type, hypergonadotropic hypogonadism-cataract syndrome, primary hypergonadotropic hypogonadism-partial alopecia syndrome, hypoparathyroidism-retardation-dysmorphism syndrome, hypospadias-intellectual disability, Goldblatt type syndrome, Bamforth-Lazarus syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, ichthyosis-intellectual disability-dwarfism-renal impairment syndrome, Vici syndrome, channelopathy-associated congenital insensitivity to pain, autosomal recessive, Joubert syndrome with oculorenal defect, oculocerebrofacial syndrome, Kaufman type, Landau-Kleffner syndrome, laryngo-onycho-cutaneous syndrome, Laurence-Moon syndrome, Donohue syndrome, Miller-Dieker lissencephaly syndrome, Marinesco-Sjogren syndrome, Frank-Ter Haar syndrome, Mietens syndrome, mesomelic dwarfism-cleft palate-camptodactyly syndrome, metaphyseal chondrodysplasia-retinitis pigmentosa syndrome, metaphyseal dysostosis-intellectual disability-conductive deafness syndrome, microcephalic primordial dwarfism, Toriello type, Say-Barber-Miller syndrome, microcephaly and chorioretinopathy 1, Galloway-Mowat syndrome, microtia with meatal atresia and conductive deafness, mucopolysaccharidosis type 6, mulibrey nanism, lethal multiple pterygium syndrome, lethal congenital contracture syndrome 1, Schwartz-Jampel syndrome, Nathalie syndrome, nephronophthisis 1, nephropathy - deafness - hyperparathyroidism syndrome, nephrosis-deafness-urinary tract-digital malformations syndrome, Netherton syndrome, Norman-Roberts syndrome, cloacal exstrophy, ichthyosis-oral and digital anomalies syndrome, Primrose syndrome, familial osteodysplasia, Anderson type, multicentric osteolysis, nodulosis, and arthropathy, osteopenia-intellectual disability-sparse hair syndrome, osteoporosis-pseudoglioma syndrome, Shwachman-Diamond syndrome, Parana hard-skin syndrome, PEHO syndrome, Imerslund-Grasbeck syndrome, Peters plus syndrome, pili torti-developmental delay-neurological abnormalities syndrome, Rabson-Mendenhall syndrome, postaxial acrofacial dysostosis, Gitelman syndrome, Wiedemann-Rautenstrauch syndrome, Acrootoocular syndrome, holoprosencephaly-postaxial polydactyly syndrome, autosomal recessive multiple pterygium syndrome, Perlman syndrome, retinitis pigmentosa-intellectual disability-deafness-hypogenitalism syndrome, EEC syndrome, SHORT syndrome, Sjogren syndrome, spastic tetraplegia-retinitis pigmentosa-intellectual disability syndrome, corneal-cerebellar syndrome, spastic ataxia-corneal dystrophy syndrome, spondylocostal dysostosis-anal and genitourinary malformations syndrome, familial infantile bilateral striatal necrosis, subaortic stenosis-short stature syndrome, thrombocytopenia-absent radius syndrome, thyrocerebrorenal syndrome, Pendred syndrome, VACTERL with hydrocephalus, Weaver syndrome, Werner syndrome, Wernicke-Korsakoff syndrome, wooly hair-hypotrichosis-everted lower lip-outstanding ears syndrome, de Sanctis-Cacchione syndrome, corpus callosum agenesis-abnormal genitalia syndrome, Alport syndrome-intellectual disability-midface hypoplasia-elliptocytosis syndrome, X-linked lissencephaly with abnormal genitalia, X-linked myotubular myopathy-abnormal genitalia syndrome, Christianson syndrome, Armfield syndrome, Lesch-Nyhan syndrome, Atkin-Flaitz syndrome, alpha-thalassemia-myelodysplastic syndrome, deafness-intellectual disability, Martin-Probst type syndrome, fragile X-associated tremor/ataxia syndrome, fragile X syndrome, syndactyly-telecanthus-anogenital and renal malformations syndrome, X-linked dominant chondrodysplasia, Chassaing-Lacombe type, X-linked central congenital hypothyroidism with late-onset testicular enlargement, Meester-Loeys syndrome, Arts syndrome, X-linked mandibulofacial dysostosis, Abruzzo-Erickson syndrome, Aicardi syndrome, craniofrontonasal syndrome, deafness-hypogonadism syndrome, X-linked corneal dermoid, immune dysregulation-polyendocrinopathy-enteropathy-X-linked syndrome, hydrocephaly-cerebellar agenesis syndrome, keratosis follicularis-dwarfism-cerebral atrophy syndrome, laryngeal abductor paralysis-intellectual disability syndrome, oculocerebrorenal syndrome, Menkes disease, paraplegia-intellectual disability-hyperkeratosis syndrome, mucopolysaccharidosis type 2, orofaciodigital syndrome I, otopalatodigital syndrome type 1, Pallister-W syndrome, Rett syndrome, SCARF syndrome, Simpson-Golabi-Behmel syndrome, torticollis-keloids-cryptorchidism-renal dysplasia syndrome, trigonocephaly-short stature-developmental delay syndrome, ulnar hypoplasia-split foot syndrome, van den Bosch syndrome, Wildervanck syndrome, Kearns-Sayre syndrome, MELAS syndrome, MERRF syndrome, Pearson syndrome, proximal tubulopathy-diabetes mellitus-cerebellar ataxia syndrome, pancreatic hypoplasia-diabetes-congenital heart disease syndrome, chondrodysplasia-pseudohermaphroditism syndrome, Qazi Markouizos syndrome, familial developmental dysphasia, atrioventricular defect-blepharophimosis-radial and anal defect syndrome, CODAS syndrome, lethal hemolytic anemia-genital anomalies syndrome, HEC syndrome, anophthalmia plus syndrome, infundibulopelvic stenosis-multicystic kidney syndrome, Ayme-Gripp syndrome, dilated cardiomyopathy 1E, diaphragmatic defect-limb deficiency-skull defect syndrome, skeletal dysplasia-epilepsy-short stature syndrome, Potocki-Shaffer syndrome, amelia cleft lip palate hydrocephalus iris coloboma, human HOXA1 syndromes, dyssegmental dysplasia-glaucoma syndrome, lung agenesis-heart defect-thumb anomalies syndrome, tetrasomy 12p, chromosome 18q deletion syndrome, lymphedema-atrial septal defects-facial changes syndrome, infantile convulsions and choreoathetosis, RHYNS syndrome, Pierre Robin sequence with pectus excavatum and rib and scapular anomalies, colobomatous macrophthalmia-microcornea syndrome, Marshall-Smith syndrome, distal monosomy 13q, MPI-congenital disorder of glycosylation, camptodactyly, myopia, and fibrosis of the medial rectus muscle of eye, radioulnar synostosis-microcephaly-scoliosis syndrome, blepharophimosis - intellectual disability syndrome, SBBYS type, complex regional pain syndrome type 1, temtamy preaxial brachydactyly syndrome, Diamond-Blackfan anemia 2, genitopatellar syndrome, Phelan-McDermid syndrome, hypotonia-cystinuria syndrome, DNA ligase IV deficiency, Hurler syndrome, Hurler-Scheie syndrome, Scheie syndrome, Duane-radial ray syndrome, psoriatic arthritis, neonatal ichthyosis-sclerosing cholangitis syndrome, skin fragility-woolly hair-palmoplantar keratoderma syndrome, tubulointerstitial nephritis and uveitis syndrome, caudal duplication, sweet syndrome, ichthyosis prematurity syndrome, Meacham syndrome, BNAR syndrome, PCWH syndrome, foveal hypoplasia - optic nerve decussation defect - anterior segment dysgenesis syndrome, B-cell immunodeficiency, distal limb anomalies, and urogenital malformations, MEDNIK syndrome, Cerebrorenodigital syndrome, fetal valproate syndrome, Goldberg-Shprintzen syndrome, Al-Gazali syndrome, CEDNIK syndrome, osteosclerosis-ichthyosis-premature ovarian failure syndrome, cortical dysplasia-focal epilepsy syndrome, DK1-congenital disorder of glycosylation, Potocki-Lupski syndrome, Pitt-Hopkins syndrome, XFE progeroid syndrome, deafness-infertility syndrome, COG1-congenital disorder of glycosylation, autosomal dominant familial hematuria-retinal arteriolar tortuosity-contractures syndrome, microtia-eye coloboma-imperforation of the nasolacrimal duct syndrome, mitochondrial DNA depletion syndrome, encephalomyopathic form with methylmalonic aciduria, ANE syndrome, CLOVES syndrome, Hirschsprung disease-ganglioneuroblastoma syndrome, parkinsonism-dystonia, infantile, alpha 1-antitrypsin deficiency, COG5-congenital disorder of glycosylation, chromosome 13q14 deletion syndrome, deafness-lymphedema-leukemia syndrome, microcephaly-capillary malformation syndrome, EDICT syndrome, peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome, hypomyelinating leukodystrophy 8 with or without oligodontia and-or hypogonadotropic hypogonadism, IMAGe syndrome, short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome, microcephalic primordial dwarfism, Alazami type, intellectual disability-strabismus syndrome, estrogen resistance syndrome, Hartsfield-Bixler-Demyer syndrome, severe dermatitis-multiple allergies-metabolic wasting syndrome, alacrima, achalasia, and intellectual disability syndrome, familial episodic pain syndrome with predominantly lower limb involvement, congenital microcephaly - severe encephalopathy - progressive cerebral atrophy syndrome, diffuse cerebral and cerebellar atrophy - intractable seizures - progressive microcephaly syndrome, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, tall stature-scoliosis-macrodactyly of the great toes syndrome, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, congenital sideroblastic anemia-B-cell immunodeficiency-periodic fever-developmental delay syndrome, retinitis pigmentosa-juvenile cataract-short stature-intellectual disability syndrome, polyendocrine-polyneuropathy syndrome, chronic atrial and intestinal dysrhythmia, motor developmental delay due to 14q32.2 paternally expressed gene defect, peeling skin-leukonuchia-acral punctate keratoses-cheilitis-knuckle pads syndrome, mandibulofacial dysostosis with alopecia, epilepsy with myoclonic atonic seizures, short stature, microcephaly, and endocrine dysfunction, progressive microcephaly-seizures-cortical blindness-developmental delay syndrome, PMP22-RAI1 contiguous gene duplication syndrome, acute infantile liver failure-cerebellar ataxia-peripheral sensory motor neuropathy syndrome, familial progressive retinal dystrophy-iris coloboma-congenital cataract syndrome, macrothrombocytopenia-lymphedema-developmental delay-facial dysmorphism-camptodactyly syndrome, Luscan-Lumish syndrome, even-plus syndrome, MIRAGE syndrome, growth retardation, intellectual developmental disorder, hypotonia, and hepatopathy, intellectual disability-epilepsy-extrapyramidal syndrome, 48,XXYY syndrome, FRAXF syndrome, complex hereditary spastic paraplegia, aniridia-ptosis-intellectual disability-familial obesity syndrome, aniridia - intellectual disability syndrome, ankyloblepharon filiforme-imperforate anus syndrome, pentasomy X, Bardet-Biedl syndrome, anophthalmia-megalocornea-cardiopathy-skeletal anomalies syndrome, Bartter syndrome, arachnodactyly-intellectual disability-dysmorphism syndrome, ataxia-photosensitivity-short stature syndrome, Brugada syndrome, Feingold syndrome, cardiomyopathy-cataract-hip spine disease syndrome, cataract - microcornea syndrome, autism-facial port-wine stain syndrome, cataract-intellectual disability-anal atresia-urinary defects syndrome, cataract-deafness-hypogonadism syndrome, syndromic craniosynostosis, drug rash with eosinophilia and systemic symptoms, multicentric reticulohistiocytosis, hereditary sensory and autonomic neuropathy with deafness and global delay, craniofacial microsomia, ring chromosome 10, Coffin-Siris syndrome, corpus callosum agenesis-double urinary collecting system syndrome, short rib-polydactyly syndrome, oromandibular-limb anomalies syndrome, hemophagocytic syndrome, cataract-glaucoma syndrome, diencephalic syndrome, hypereosinophilic syndrome, distal trisomy 14q, intellectual disability-cataracts-kyphosis syndrome, progressive familial intrahepatic cholestasis, thoraco-abdominal enteric duplication, oculomaxillofacial dysostosis, growth hormone insensitivity syndrome, syndromic dyslipidemia, macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss, epiphyseal dysplasia-hearing loss-dysmorphism syndrome, eosinophilic granulomatosis with polyangiitis, axial mesodermal dysplasia spectrum, fetal hydantoin syndrome, vitamin K-antagonist embryofetopathy, fetal alcohol syndrome, methimazole embryofetopathy, Evans syndrome, Cornelia de Lange syndrome, cleft lip-retinopathy syndrome, cleft lip/palate-deafness-sacral lipoma syndrome, Crandall syndrome, syndromic microphthalmia, Cole-Carpenter syndrome, myotonic syndrome, Guillain-Barre syndrome, atypical hemolytic-uremic syndrome, Hennekam syndrome, Hernández-Aguirre Negrete syndrome, nodular neuronal heterotopia, Hirschsprung disease-type D brachydactyly syndrome, holoprosencephaly, hydrocephalus-obesity-hypogonadism syndrome, hydrocephalus-blue sclerae-nephropathy syndrome, xeroderma pigmentosum-Cockayne syndrome complex, Joubert syndrome with ocular defect, hypogonadism-mitral valve prolapse-intellectual disability syndrome, hypogonadotropic hypogonadism-retinitis pigmentosa syndrome, hypotrichosis-intellectual disability, Lopes type, congenital ichthyosis-microcephalus-tetraplegia syndrome, Hughes-Stovin syndrome, heart-hand syndrome, ptosis-upper ocular movement limitation-absence of lacrimal punctum syndrome, syndromic agammaglobulinemia, isotretinoin syndrome, microcornea-posterior megalolenticonus-persistent fetal vasculature-coloboma syndrome, Kabuki syndrome, Kenny-Caffey syndrome, muscular pseudohypertrophy-hypothyroidism syndrome, Kousseff syndrome, limb body wall complex, Lennox-Gastaut syndrome, Lowe-Kohn-Cohen syndrome, macrocephaly-short stature-paraplegia syndrome, primary ciliary dyskinesia, familial intestinal malrotation-facial anomalies syndrome, primary hypertrophic osteoarthropathy, Melhem-Fahl syndrome, lower limb deficiency-hypospadias syndrome, 8p23.1 microdeletion syndrome, sickle cell-beta-thalassemia disease syndrome, sickle cell-hemoglobin c disease syndrome, sickle cell-hemoglobin d disease syndrome, sickle cell-hemoglobin E disease syndrome, hereditary persistence of fetal hemoglobin-sickle cell disease syndrome, microcephaly-brain defect-spasticity-hypernatremia syndrome, microcephaly-microcornea syndrome, Seemanova type, Meier-Gorlin syndrome, Mikati-Najjar-Sahli syndrome, shoulder and girdle defects-familial intellectual disability syndrome, myopathy-growth delay-intellectual disability-hypospadias syndrome, Fuchs heterochromic iridocyclitis, microcephalic osteodysplastic primordial dwarfism types I and III, osteochondrodysplatic nanism-deafness-retinitis pigmentosa syndrome, arthrogryposis-renal dysfunction-cholestasis syndrome, oculo-skeletal-renal syndrome, olivopontocerebellar atrophy-deafness syndrome, Opitz G/BBB syndrome, imperforate oropharynx-costo vetebral anomalies syndrome, Bruck syndrome, osteoporosis-macrocephaly-blindness-joint hyperlaxity syndrome, calciphylaxis, recessive intellectual disability-motor dysfunction-multiple joint contractures syndrome, X-linked ichthyosis syndrome, autoimmune polyendocrinopathy, renal caliceal diverticuli-deafness syndrome, tempi syndrome, syndromic oculocutaneous albinism, short stature-deafness-neutrophil dysfunction-dysmorphism syndrome, congenital varicella syndrome, polyneuropathy-intellectual disability-acromicria-premature menopause syndrome, celiac trunk compression syndrome, hypoplastic pancreas-intestinal atresia-hypoplastic gallbalder syndrome, fetal cytomegalovirus syndrome, Reunion island Larsen syndrome, 46,XX disorder of sex development-anorectal anomalies syndrome, mitochondrial neurogastrointestinal encephalomyopathy, Baraitser-Winter cerebrofrontofacial syndrome, mirror polydactyly-vertebral segmentation-limbs defects syndrome, intellectual disability-hypotonia-skin hyperpigmentation syndrome, congenital hereditary facial paralysis-variable hearing loss syndrome, intellectual disability-microcephaly-phalangeal-facial abnormalities syndrome, Mayer-Rokitansky-Kuster-Hauser syndrome, developmental and speech delay due to SOX5 deficiency, Spigelian hernia-cryptorchidism syndrome, autosomal recessive leukoencephalopathy-ischemic stroke-retinitis pigmentosa syndrome, severe neonatal hypotonia-seizures-encephalopathy syndrome due to 5q31.3 microdeletion, multiple sclerosis-ichthyosis-factor VIII deficiency syndrome, X-linked spasticity-intellectual disability-epilepsy syndrome, spina bifida-hypospadias syndrome, hantavirus pulmonary syndrome, white matter hypoplasia-corpus callosum agenesis-intellectual disability syndrome, deafness-genital anomalies-metacarpal and metatarsal synostosis syndrome, hearing loss-familial salivary gland insensitivity to aldosterone syndrome, multiple synostoses syndrome, central nervous system calcification-deafness-tubular acidosis-anemia syndrome, multiple paragangliomas associated with polycythemia, syngnathia multiple anomalies, Takayasu arteritis, severe early-onset obesity-insulin resistance syndrome due to SH2B1 deficiency, spondylocostal dysostosis-hypospadias-intellectual disability syndrome, hypotrichosis-deafness syndrome, thalidomide embryopathy, trisomy X, trisomy 13, trisomy 18, umbilical cord ulceration-intestinal atresia syndrome, microcephaly-brachydactyly-kyphoscoliosis syndrome, Waardenburg syndrome, Weill-Marchesani syndrome, infantile spasms, Wolfram syndrome, epidermal nevus syndrome, digital anomalies-intellectual disability-short stature syndrome, intellectual disability-obesity-brain malformations-facial dysmorphism syndrome, Erdheim-Chester disease, Stevens-Johnson syndrome, CADDS, finger hyperphalangy - toe anomalies - severe pectus excavatum syndrome, ataxia - telangiectasia variant, growth retardation-mild developmental delay-chronic hepatitis syndrome, primary microcephaly-mild intellectual disability-young-onset diabetes syndrome, ferro-cerebro-cutaneous syndrome, dystonia-aphonia syndrome, microcephaly-complex motor and sensory axonal neuropathy syndrome, X-linked microcephaly-growth retardation-prognathism-cryptorchidism syndrome, severe intellectual disability-hypotonia-strabismus-coarse face-planovalgus syndrome, intrauterine growth restriction-short stature-early adult-onset diabetes syndrome, pseudoxanthoma elasticum-like skin manifestations with retinitis pigmentosa, familial chylomicronemia syndrome, caudal regression-sirenomelia spectrum, visceral heterotaxy, Holmes-Adie syndrome, microcephalic primordial dwarfism due to RTTN deficiency, Joubert syndrome, congenital generalized hypercontractile muscle stiffness syndrome, Kallmann syndrome, Caroli syndrome, X-linked female restricted facial dysmorphism-short stature-choanal atresia-intellectual disability, microlissencephaly-micromelia syndrome, branchiootic syndrome, Plummer-Vinson syndrome, Cushing syndrome, McCune-Albright syndrome, Meckel syndrome, SUNCT syndrome, mucopolysaccharidosis type 3, mucopolysaccharidosis type 4, congenital myasthenic syndrome, Loeys-Dietz syndrome, Alport syndrome, schisis association, Tolosa-Hunt syndrome, iridocorneal endothelial syndrome, Noonan syndrome, short fifth metacarpals-insulin resistance syndrome, progressive supranuclear palsy, benign exophthalmos syndrome, Sandifer syndrome, global developmental delay-osteopenia-ectodermal defect syndrome, tubular renal disease-cardiomyopathy syndrome, angioosteohypotrophic syndrome, 6q terminal deletion syndrome, Axenfeld-Rieger syndrome, peroxisome biogenesis disorder, ectodermal dysplasia syndrome, Seckel syndrome, Sotos syndrome, Stickler syndrome, pelvis syndrome, Susac syndrome, ischio-vertebral syndrome, BRESEK syndrome, Turner syndrome, Usher syndrome, obesity-colitis-hypothyroidism-cardiac hypertrophy-developmental delay syndrome, CREST syndrome, Sheehan syndrome, polymyalgia rheumatica, autoinflammatory syndrome, neuroleptic malignant syndrome, pituitary stalk interruption syndrome, monosomy 13q34, ring chromosome 13, 48,XXXY syndrome, 49,XXXXY syndrome, hereditary continuous muscle fiber activity, Eisenmenger syndrome, Robinow syndrome, Ehlers-Danlos syndrome, hypoplastic right heart syndrome, shone complex, 48,XYYY syndrome, subcortical band heterotopia, complex regional pain syndrome type 2, faciodigitogenital syndrome, neoplastic syndrome, paraneoplastic syndrome, post-infectious syndrome, Achard-Thiers syndrome, acral dysostosis dyserythropoiesis syndrome, agnathia-microstomia-synotia, Aksu von Stockhausen syndrome, Aloi Tomasini Isaia syndrome, temporomandibular joint dysfunction syndrome, Apert-like polydactyly syndrome, arakawa syndrome 2, arena syndrome, Arnold stickler bourne syndrome, baetz-greenwalt syndrome, bagatelle Cassidy syndrome, baker Vinters syndrome, bobble-head doll syndrome, Boerhaave syndrome, Cantu Sanchez-Corona Fragoso syndrome, Cantu Sanchez-Corona Hernandez syndrome, carbon baby syndrome, Carnevale hernandez castillo syndrome, Cartwright Nelson Fryns syndrome, Charles bonnet syndrome, Parinaud syndrome, corticobasal degeneration disorder, hair defect with photosensitivity and intellectual disability syndrome, AIDS dysmorphic syndrome, congenital acardia, acute lymphoblastic leukemia congenital sporadic aniridia, aglossia and situs inversus, agyria pachygyria polymicrogyria, agyria-pachygyria type 1, Ahumada Del Castillo syndrome, alopecia congenita keratosis palmoplantaris, alpha-mannosidosis type 1, aluminosis, Mauriac syndrome, ankle defects short stature, ankyloblepharon filiforme imperforate anus, annular constricting bands, anophthalmia cleft palate micrognathia, anophthalmia esophageal atresia cryptorchidism, anotia facial palsy cardiac defect, aortic dissection lentiginosis, childhood aortic valve stenosis, arthrogryposis IUGR thoracic dystrophy, arthrogryposis multiplex congenita CNS calcification, arthrogryposis spinal muscular atrophy, asternia, atlanto-axial fusion, atrophoderma of Pierini and Pasini, Barnicoat Baraitser syndrome, Basedow’s coma, BD syndrome, Beardwell syndrome, bhaskar jagannathan syndrome, bidirectional tachycardia, bilirubin induced brain injury in the newborn, blepharo naso facial syndrome van Maldergem type, bone dysplasia corpus callosum agenesis, brachydactyly absence of distal phalanges, brachydactyly anonychia, brachydactyly small stature face anomalies, brachydactyly tibial hypoplasia, brittle bone syndrome lethal type, bronchiectasis oligospermia, Brunsting-Perry syndrome, bruyn scheltens syndrome, burn goodship syndrome, camptodactyly joint contractures and facial skeletal dysplasia, camptodactyly vertebral fusion, Cantu Sanchez-Corona Garcia-Cruz syndrome, cardiac hydatid cysts with intracavitary expansion, cardioencephalomyopathy, cardiofacial syndrome short limbs, cardiomelic syndrome stratton Koehler type, cardiomyopathy and deafness due to tRNA lysine gene mutation, cardiomyopathy diabetes deafness, cardiomyopathy hypogonadism collagenoma syndrome, cardiomyopathy hypogonadism metabolic anomalies, cardiomyopathy spherocytosis, carpo tarsal osteolysis recessive, autosomal dominant cataract, cataract skeletal anomalies, cennamo gangemi syndrome, cerebellar agenesis, cerebello-olivary atrophy, cerebral calcification cerebellar hypoplasia, cerebral calcifications opalescent teeth phosphaturia, oculo digital syndrome, chondrodysplasia, choreoacanthocytosis amyotrophic, chorioretinopathy dominant form microcephaly, Christian Demyer Franken syndrome, Christian Johnson angenieta syndrome, chromosome 3 duplication syndrome, chronic demyelinizing neuropathy with IgM monoclonal, ciliary dyskinesia-bronchiectasis, circumscribed cutaneous aplasia of the vertex, circumscribed disseminated keratosis Jadassohn lew type, cleft lip and palate malrotation cardiopathy, cleft lip and/or palate with mucous cysts of lower, cleft lip palate dysmorphism kumar type, cleft lip palate intellectual disability corneal opacity, cleft lip palate oligodontia syndactyly pili torti, cleft lip palate pituitary deficiency, cleft lip palate-tetraphocomelia, cleft lower lip cleft lateral canthi chorioretinal, cleft palate cardiac defect ectrodactyly, cleft palate colobomata radial synostosis deafness, cleft palate heart disease polydactyly absent tibia, cleft tongue, coarse face hypotonia constipation, Cohen Lockood Wyborney syndrome, type 2 collagenopathy, Collins-Sakati syndrome, coloboma porencephaly hydronephrosis, colobomata unilobar lung heart defect, colonic malakoplakia, Colver Steer Godman syndrome, Combarros Calleja Leno syndrome, complement receptor deficiency, congenital absence of the sternocleidomastoid muscle, congenital amputation, congenital aneurysms of the great vessels, congenital articular rigidity, congenital benign spinal muscular atrophy dominant, congenital cardiovascular shunt, congenital contractures, congenital craniosynostosis maternal hyperthyroiditis, congenital cystic eye, congenital heart disease ptosis hypodontia craniostosis, congenital heart disease radio ulnar synostosis intellectual disability, congenital mumps, congenital stenosis of cervical medullary canal, Dennis-Fairhurst-Moore syndrome, congenital unilateral pulmonary hypoplasia, congenital vagal hyperreflexivity, Cormier Rustin Munnich syndrome, corneal crystals myopathy neuropathy, corneal dystrophy ichthyosis microcephaly intellectual disability, corneal dystrophy pigmentary anomaly malabsorption, corpus callosum agenesis of blepharophimosis robin type, corpus callosum dysgenesis X-linked recessive, corpus callosum dysgenesis cleft spasm, corpus callosum dysgenesis hypopituitarism, cortada Koussef Matsumoto syndrome, Cortes Lacassie syndrome, craniofacial and skeletal defects, craniofacial dysostosis arthrogryposis progeroid appearance, craniofrontonasal syndrome Teebi type, craniostenosis with congenital heart disease intellectual disability, crawfurd syndrome, cutis gyratum acanthosis nigricans craniosynostosis, cutis laxa osteoporosis, Davenport-Donlan syndrome, Davis Lafer syndrome, de Hauwere Leroy adriaenssens syndrome, deafness conductive stapedial ear malformation facial palsy, deafness goiter stippled epiphyses, deafness hypospadias metacarpal and metatarsal syndrome, deafness mesenteric diverticula of small bowel neuropathy, deafness peripheral neuropathy arterial disease, deafness progressive cataract autosomal dominant, dermatocardioskeletal syndrome boronne type, dextrocardia with situs inversus, diabetes persistent mullerian ducts, diaphragmatic agenesis radial aplasia omphalocele, diaphragmatic hernia exomphalos corpus callosum agenesis, diaphragmatic hernia upper limb defects, die Smulders droog van dijk syndrome, diomedi bernardi placidi syndrome, diphallus rachischisis imperforate anus, distichiasis heart congenital anomalies, double discordia, double uterus-hemivagina-renal agenesis, Drachtman Weinblatt Sitarz syndrome, Duker-Weiss-Siber syndrome, duodenal atresia tetralogy of fallot, duplication of leg mirror foot, duplication of the thumb unilateral biphalangeal, dupont sellier chochillon syndrome, dwarfism bluish sclerae, dwarfism deafness retinitis pigmentosa, dwarfism lethal type advanced bone age, dwarfism thin bones multiple fractures, dysmorphism cleft palate loose skin, Eagle syndrome, ectrodactyly cardiopathy dysmorphism, Elliott ludman Teebi syndrome, enamel hypoplasia cataract hydrocephaly, encephalocele anencephaly, enchondromatosis dwarfism deafness, Engelhard Yatziv syndrome, enlarged vestibular aqueduct syndrome, epidermal nevus vitamin D resistant rickets, epimetaphyseal dysplasia cataract, epiphyseal dysplasia dysmorphism camptodactyly, esophageal atresia coloboma talipes, extrasystoles short stature hyperpigmentation microcephaly, facial clefting corpus callosum agenesis, facio digito genital syndrome recessive form, facio skeletal genital syndrome rippberger type, familial capillaro-venous leptomeningeal angiomatosis, Dursun syndrome, Faye-Petersen-Ward-Carey syndrome, feigenbaum Bergeron syndrome, Feingold trainer syndrome, fetal brain disruption sequence, fetal enterovirus syndrome, fetal parainfluenza virus type 3 syndrome, fetal phenothiazine syndrome, fibromatosis multiple non ossifying, fibula aplasia complex brachydactyly, fibular hypoplasia scapulo pelvic dysplasia absent, Fitz-Hugh-Curtis syndrome, focal alopecia congenital megalencephaly, focal or multifocal malformations in neuronal migration, foix chavany Marie syndrome, Fontaine farriaux blanckaert syndrome, Fraser Jequier Chen syndrome, Freiberg disease, Friedman Goodman syndrome, frontonasal malformation cloacal exstrophy, frontonasal dysplasia Klippel feil syndrome, frontonasal dysplasia phocomelic upper limbs, Fryns Fabry Remans syndrome, Fryns Smeets Thiry syndrome, Fuchs atrophia gyrata chorioideae et retinae, Fukuda-Miyanomae-Nakata syndrome, Fuqua Berkovitz syndrome, Garret-Tripp syndrome, gas bloat syndrome, Gaucher ichthyosis restrictive dermopathy, gershinibaruch Leibo syndrome, Ghose-Sachdev-Kumar syndrome, gigantism advanced bone age hoarse cry, glossopalatine ankylosis micrognathia ear anomalies, goldstein hutt syndrome, goniodysgenesis intellectual disability short stature, green sandford davison syndrome, grix Blankenship Peterson syndrome, Ho-Kaufman-McAlister syndrome, Jaffer-Beighton syndrome, Judge Misch wright syndrome, Kashani-Strom-Utley syndrome, Kasznica-Carlson-Coppedge syndrome, Katsantoni-Papadakou-Lagoyanni syndrome, Kocher-debre-Semelaigne syndrome, Koone-Rizzo-Elias syndrome, Kozlowski Brown Hardwick syndrome, Kozlowski Ouvrier syndrome, Kozlowski Rafinski Klicharska syndrome, Kozlowski Warren Fisher syndrome, Krauss Herman Holmes syndrome, Krieble Bixler syndrome, Kuster Majewski Hammerstein syndrome, Kuster syndrome, Laugier-Hunziker syndrome, Laurence-Prosser-Rocker syndrome, le Marec-Bracq-Picaud syndrome, levator syndrome, Marinesco-Sjogren-like syndrome, Milner-Khallouf-Gibson syndrome, radio-digito-facial dysplasia, Seckel like syndrome majoor-krakauer type, neonatal aspiration syndrome, muscular fibrosis multifocal obstructed vessels, short stature contractures hypotonia, Alice in Wonderland syndrome, megacystis-microcolon-intestinal hypoperistalsis syndrome, Basilicata-Akhtar syndrome, Liberfarb syndrome, craniofacial dysmorphism, skeletal anomalies, and impaired intellectual development syndrome, cardiac, facial, and digital anomalies with developmental delay, fibrosis, neurodegeneration, and cerebral angiomatosis, Duane anomaly-myopathy-scoliosis syndrome, congenital cataract-severe neonatal hepatopathy-global developmental delay syndrome, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, acute radiation syndrome, monoclonal mast cell activation syndrome, oculocerebrodental syndrome, syndromic congenital sodium diarrhea, congenital brachyesophagus-intrathoracic stomach-vertebral anomalies syndrome, intellectual disability-cardiac anomalies-short stature-joint laxity syndrome, intrauterine growth restriction-congenital multiple café-au-lait macules-increased sister chromatid exchange syndrome, frontonasal dysplasia-bifid nose-upper limb anomalies syndrome, microcephaly-facial dysmorphism-ocular anomalies-multiple congenital anomalies syndrome, diaphragmatic hernia-short bowel-asplenia syndrome, warts-immunodeficiency-lymphedema-anogenital dysplasia syndrome, Cramp-fasciculation syndrome, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome, blepharophimosis-intellectual disability syndrome/genitopatellar overlap 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, KLHL7-related cold-induced sweating-like syndrome, KAT6B-related multiple congenital anomalies syndrome, oculogastrointestinal-neurodevelopmental syndrome, spastic paraparesis-cataracts-speech delay syndrome, Ruzicka-Goerz-Anton syndrome, Sammartino-Decreccio syndrome, Samson-Gardner syndrome, Samson-Viljoen syndrome, Sanderson-Fraser syndrome, Sandhaus-Ben-Ami syndrome, prostatic malacoplakia associated with prostatic abscess, Saul-Wilkes-Stevenson syndrome, macrogyria, pseudobulbar palsy and intellectual disability, Schwartz-Cohen-addad-Lambert syndrome, Schlegelberger-Grote syndrome, Schrander-stumpel-Theunissen-Hulsmans syndrome, Saal-Bulas syndrome, Sackey-Sakati-Aur syndrome, Slti-Salem syndrome, Zerres Rietschel Majewski syndrome, Zazam Sheriff Phillips syndrome, Zadik-Barak-Levin syndrome, weinstein kliman scully syndrome, thickened earlobes with conductive deafness from incus-stapes abnormalities, ichthyosis linearis circumflexa, infantile striato thalamic degeneration, Landy-Donnai syndrome, merlob grunebaum reisner syndrome, Pavone Fiumara Rizzo syndrome, pfeiffer rockelein syndrome, Pfeiffer Tietze Welte syndrome, phosphoribosylpyrophosphate synthetase deficiency, piepkorn karp hickok syndrome, podder-tolmie syndrome, pointer syndrome, richieri-costa guion-almeida cohen syndrome, Rubinstein Taybi like syndrome, ruvalcaba churesigaew myhre syndrome, short limb dwarf lethal colavita kozlowski type, Mallory-Weiss syndrome, superior vena cava syndrome, piriformis syndrome, engraftment syndrome, Adams-Stokes syndrome, Leriche syndrome, multiple organ dysfunction syndrome, posterior leukoencephalopathy syndrome, cardio-renal syndrome, Rahman syndrome, X-linked keloid scarring-reduced joint mobility-increased optic cup-to-disc ratio syndrome, retinitis pigmentosa-hearing loss-premature aging-short stature-facial dysmorphism syndrome, congenital labioscrotal agenesis-cerebellar malformation-corneal dystrophy-facial dysmorphism syndrome, Lopes-Maciel-Rodan syndrome, Stankiewicz-Isidor syndrome, Skraban-Deardorff syndrome, joint laxity, short stature, and myopia, Sweeney-Cox syndrome, Alkuraya-Kucinskas syndrome, Jaberi-Elahi syndrome, neurodevelopmental disorder with regression, abnormal movements, loss of speech, and seizures, hearing impairment and infertile male syndrome, cardiocutaneous syndrome, neonatal diabetes, congenital sensorineural hearing loss and congenital cataracts, cardioectodermal syndrome, cannabinoid hyperemesis syndrome, retrograde cricopharyngeus dysfunction, Zinner syndrome, retinal dystrophy-ataxia-pituitary hormone abnormality-hypogonadism syndrome, IFAP syndrome, DICER1-related tumor predisposition, Roberts-SC phocomelia syndrome, carcinoid syndrome, Bonnevie-Ullrich syndrome, NKX2-1 related choreoathetosis and congenital hypothyroidism with or without pulmonary dysfunction, RNU4ATAC spectrum disorder, syndromic congenital heart disease, hand-foot syndrome, central hypoventilation syndrome, congenital, 1, with or without Hirschsprung disease, gastrointestinal defects and immunodeficiency syndrome 1, achalasia-alacrima syndrome, black locks with albinism and deafness syndrome, Birt-Hogg-Dube syndrome, trigeminal trophic syndrome, developmental and/or epileptic encephalopathy with spike-wave activation in sleep, syndromic microspherophakia, painful legs and moving toes syndrome, congenital aphakia-iris hypoplasia-microphthalmia-microcornea syndrome, hereditary persistence of fetal hemoglobin-intellectual disability syndrome, developmental delay-immunodeficiency-leukoencephalopathy-hypohomocysteinemia syndrome, primary hypomagnesemia-generalized seizures-intellectual disability-obesity syndrome, post-cardiac arrest syndrome, early-onset obesity-hyperphagia-severe developmental delay syndrome, hereditary alpha tryptasemia syndrome, KINSSHIP syndrome, developmental delay, hypotrophy, and dysmorphic features without moebius syndrome, breast implant illness, cataracts, hearing impairment, nephrotic syndrome, and enterocolitis, craniosynostosis-facial dysmorphism-chiari-1 malformation-developmental and language delay syndrome, MYT1L-related developmental delay-intellectual disability-obesity syndrome, Houge-Janssens syndrome, xerosis and growth failure with immune and pulmonary dysfunction syndrome, Fliedner-Zweier syndrome, Lui-Jee-Baron syndrome, Long-Olsen-Distelmaier syndrome, Tan-Almurshedi syndrome, diabetes, deafness, developmental delay, and short stature syndrome, Alfadhel syndrome, Hoxha-Aliu syndrome, cleft palate-congenital heart defect-intellectual disability syndrome, congenital insensitivity to pain syndrome, Marsili type, Yuksel-Vogel-Bauer syndrome, polydactyly-macrocephaly syndrome, pyoderma gangrenosum-acne-hidradenitis suppurativa-ankylosing spondylitis syndrome, psoriatic arthritis-pyoderma gangrenosum-acne-hidradenitis suppurativa syndrome, megalencephaly-polydactyly syndrome, Leigh syndrome, mitochondrial, auroneurodental syndrome, orofacial clefting-cardiac anomalies-facial dysmorphism syndrome, Grisel syndrome, arterial tortuosity-bone fragility syndrome, dialysis disequilibrium syndrome, brain abnormalities-severe developmental delay-facial dysmorphism-intellectual disability syndrome due to MEF2C mutation, Kariminejad neurodevelopmental syndrome, myelofibrosis, congenital, with anemia, neutropenia, developmental delay, and ocular abnormalities, brain malformation renal syndrome, myopathy with myalgia, increased serum creatine kinase, and with or without episodic rhabdomyolysis 2, Karayol-Borroto-Haghshenas neurodevelopmental syndrome, neurodegeneration, infantile-onset, with optic atrophy and brain abnormalities, Morimoto-Ryu-Malicdan neuromuscular syndrome, neurodevelopmental disorder with dysmorphic facies, absent speech and ambulation, and brain abnormalities, neurodevelopmental disorder with variable familial hypercholanemia, Pan-Chung-Bellen syndrome, telangiectasia, impaired intellectual development, microcephaly, metaphyseal dysplasia, eye abnormalities, and short stature, Muggenthaler-Chowdhury-Chioza syndrome, Tayoun-Maawali syndrome, ragopathy, cardiovascular-kidney-metabolic syndrome, craniofaciocardiohepatic syndrome, FICUS syndrome, Li-Takada-Miyake syndrome, Guillouet-Gordon syndrome, ICHAD syndrome, cataract, alopecia, oral mucosal disorder, and psoriasis-like syndrome, RAC2-related combined immunodeficiency-bronchiectasis-cancer-predisposing syndrome, oculovertebral syndrome, Alsahan-Harris syndrome, Ververi-Brady syndrome, Dursun-Ozgul neurodevelopmental syndrome, immune dysregulation, neurodevelopmental defects, and colitis, Harel-Tora neurodevelopmental syndrome, Valence-Farazi cerebellar ataxia syndrome, dyschromatosis, ichthyosis, deafness, and atopic disease, Ramond-Elliott neurodevelopmental syndrome, STAD syndrome, craniosynostosis-scoliosis syndrome, loin pain hematuria syndrome, IRF6-related condition, linkeropathy, NDUFB11-related disorders, CRYAB-related myofibrillar myopathy-cataract-cardiomyopathy spectrum disorder, TSEN2-related neurodevelopmental disorder with or without thrombotic microangiopathy, antiphospholipid syndrome

Subtypes (4): Angelman syndrome due to a point mutation, Angelman syndrome due to imprinting defect in 15q11-q13, Angelman syndrome due to maternal 15q11q13 deletion, Angelman syndrome due to paternal uniparental disomy of chromosome 15

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

600 retrieved; paginated sample, class counts are floors:

209 uncertain significance, 164 likely benign, 152 pathogenic, 37 likely pathogenic, 13 conflicting classifications of pathogenicity, 13 benign, 9 pathogenic/likely pathogenic, 2 benign/likely benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
1703671	GRCh37/hg19 15q11.2-13.2(chr15:23285775-30386399)	APBA2	Pathogenic	no assertion criteria provided
1703669	GRCh37/hg19 15q11.2-13.1(chr15:23615768-28522838)	ATP10A	Pathogenic	no assertion criteria provided
1703670	GRCh37/hg19 15q11.2-13.1(chr15:23290862-28522838)	ATP10A	Pathogenic	no assertion criteria provided
1703673	GRCh37/hg19 15q11.2-13.1(chr15:23689315-28644578)	ATP10A	Pathogenic	no assertion criteria provided
209214	NC_000015.9:g.(?23730704)(28530182_?)del	ATP10A	Pathogenic	criteria provided, single submitter
2579285	GRCh38/hg38 15q11.2-12(chr15:20966971-25963714)x1	ATP10A	Pathogenic	criteria provided, single submitter
143838	NM_001323289.2(CDKL5):c.902_903dup (p.Leu302fs)	CDKL5	Pathogenic	criteria provided, single submitter
1703672	GRCh37/hg19 15q11.2-13.1(chr15:22770421-29855014)	ENTREP2	Pathogenic	no assertion criteria provided
2663786	NC_000015.10:g.(?23319714)(28314256_?)del	HERC2	Pathogenic	criteria provided, single submitter
11809	NM_001110792.2(MECP2):c.433C>T (p.Arg145Cys)	MECP2	Pathogenic	reviewed by expert panel
11811	NM_001110792.2(MECP2):c.509C>T (p.Thr170Met)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11818	NM_001110792.2(MECP2):c.203_204del (p.Pro68fs)	MECP2	Pathogenic	criteria provided, single submitter
11824	NM_001110792.2(MECP2):c.952C>T (p.Arg318Cys)	MECP2	Pathogenic	reviewed by expert panel
11833	NM_001110792.2(MECP2):c.459C>G (p.Tyr153Ter)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143328	NM_001110792.2(MECP2):c.144_147del (p.Glu49fs)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
143372	NM_001110792.2(MECP2):c.1193_1236del (p.Leu398fs)	MECP2	Pathogenic	criteria provided, multiple submitters, no conflicts
143526	NM_001110792.2(MECP2):c.338C>G (p.Pro113Arg)	MECP2	Pathogenic	reviewed by expert panel
189662	NM_001110792.2(MECP2):c.1195_1246del (p.Pro399fs)	MECP2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1032380	NM_130839.5(UBE3A):c.1402del (p.Thr468fs)	SNHG14	Pathogenic	criteria provided, single submitter
1064603	NM_130839.5(UBE3A):c.1960G>C (p.Val654Leu)	SNHG14	Pathogenic	criteria provided, single submitter
1067820	NM_130839.5(UBE3A):c.2423G>A (p.Gly808Asp)	SNHG14	Pathogenic	criteria provided, single submitter
1073548	NM_130839.5(UBE3A):c.2515_2531dup (p.Leu846fs)	SNHG14	Pathogenic	criteria provided, single submitter
1323732	NM_130839.5(UBE3A):c.2162_2166dup (p.Val723fs)	SNHG14	Pathogenic	criteria provided, single submitter
136187	NM_130839.5(UBE3A):c.159del (p.Cys54fs)	SNHG14	Pathogenic	no assertion criteria provided
136188	NM_130839.5(UBE3A):c.259_262dup (p.Gly88fs)	SNHG14	Pathogenic	no assertion criteria provided
136189	NM_130839.5(UBE3A):c.323_324del (p.Ile108fs)	SNHG14	Pathogenic	no assertion criteria provided
136190	NM_130839.5(UBE3A):c.335dup (p.Lys113fs)	SNHG14	Pathogenic	no assertion criteria provided
136191	NM_130839.5(UBE3A):c.337_340del (p.Lys113fs)	SNHG14	Pathogenic	no assertion criteria provided
136192	NM_130839.5(UBE3A):c.372_375del (p.Thr123_Tyr124insTer)	SNHG14	Pathogenic	criteria provided, multiple submitters, no conflicts
136193	NM_130839.5(UBE3A):c.422_423del (p.Glu141fs)	SNHG14	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 4 · Orphanet: 26 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

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
UBE3A	Definitive	Autosomal dominant	Angelman syndrome	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
UBE3A	Orphanet:238446	15q11q13 microduplication syndrome
UBE3A	Orphanet:411511	Angelman syndrome due to a point mutation
UBE3A	Orphanet:411515	Angelman syndrome due to imprinting defect in 15q11-q13
UBE3A	Orphanet:98794	Angelman syndrome due to maternal 15q11q13 deletion
UBE3A	Orphanet:98795	Angelman syndrome due to paternal uniparental disomy of chromosome 15
CDKL5	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
CDKL5	Orphanet:3095	Atypical Rett syndrome
CDKL5	Orphanet:505652	CDKL5-deficiency disorder
CDKL5	Orphanet:697160	Infantile epileptic spasms syndrome
ATP10A	Orphanet:411515	Angelman syndrome due to imprinting defect in 15q11-q13
TPP1	Orphanet:284324	Childhood-onset autosomal recessive slowly progressive spinocerebellar ataxia
TPP1	Orphanet:699751	Infantile CLN2 disease
TPP1	Orphanet:699761	Late infantile CLN2 disease
TPP1	Orphanet:699769	Juvenile CLN2 disease
ACD	Orphanet:3322	Hoyeraal-Hreidarsson syndrome
ACD	Orphanet:397692	Hereditary isolated aplastic anemia
ACD	Orphanet:618	Familial melanoma
GABRA5	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
HERC2	Orphanet:329195	Developmental delay with autism spectrum disorder and gait instability
MECP2	Orphanet:1762	Proximal Xq28 duplication syndrome
MECP2	Orphanet:209370	MECP2-related severe neonatal encephalopathy
MECP2	Orphanet:3077	X-linked intellectual disability-psychosis-macroorchidism syndrome
MECP2	Orphanet:3095	Atypical Rett syndrome
MECP2	Orphanet:536	Systemic lupus erythematosus
MECP2	Orphanet:777	X-linked non-syndromic intellectual disability
MECP2	Orphanet:778	Rett syndrome

Cohort genes → proteins

15 cohort genes, 11 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	15

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UBE3A	HGNC:12496	ENSG00000114062	Q05086	Ubiquitin-protein ligase E3A	gencc,clinvar
CDKL5	HGNC:11411	ENSG00000008086	O76039	Cyclin-dependent kinase-like 5	clinvar
ATP10A	HGNC:13542	ENSG00000206190	O60312	Phospholipid-transporting ATPase VA	clinvar
TPP1	HGNC:2073	ENSG00000166340	O14773	Tripeptidyl-peptidase 1	clinvar
ACD	HGNC:25070	ENSG00000102977	Q96AP0	Adrenocortical dysplasia protein homolog	clinvar
ENTREP2	HGNC:29075	ENSG00000104059	O60320	Protein ENTREP2	clinvar
SNORD115-16	HGNC:33035	ENSG00000200757		small nucleolar RNA, C/D box 115-16	clinvar
SNORD115-17	HGNC:33036	ENSG00000201482		small nucleolar RNA, C/D box 115-17	clinvar
SNHG14	HGNC:37462	ENSG00000224078		small nucleolar RNA host gene 14	clinvar
GABRA5	HGNC:4079	ENSG00000186297	P31644	Gamma-aminobutyric acid receptor subunit alpha-5	clinvar
GABRG3	HGNC:4088	ENSG00000182256	Q99928	Gamma-aminobutyric acid receptor subunit gamma-3	clinvar
HERC2	HGNC:4868	ENSG00000128731	O95714	E3 ubiquitin-protein ligase HERC2	clinvar
PWAR6	HGNC:49129	ENSG00000257151		Prader Willi/Angelman region RNA 6	clinvar
APBA2	HGNC:579	ENSG00000034053	Q99767	Amyloid-beta A4 precursor protein-binding family A member 2	clinvar
MECP2	HGNC:6990	ENSG00000169057	P51608	Methyl-CpG-binding protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBE3A	Ubiquitin-protein ligase E3A	E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and transfers it to its substrates.
CDKL5	Cyclin-dependent kinase-like 5	Mediates phosphorylation of MECP2.
ATP10A	Phospholipid-transporting ATPase VA	Catalytic component of P4-ATPase flippase complex, which catalyzes the hydrolysis of ATP coupled to the transport of phosphatidylcholine (PC) from the outer to the inner leaflet of the plasma membrane.
TPP1	Tripeptidyl-peptidase 1	Lysosomal serine protease with tripeptidyl-peptidase I activity.
ACD	Adrenocortical dysplasia protein homolog	Component of the shelterin complex (telosome) that is involved in the regulation of telomere length and protection.
GABRA5	Gamma-aminobutyric acid receptor subunit alpha-5	Alpha subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
GABRG3	Gamma-aminobutyric acid receptor subunit gamma-3	Gamma subunit of the heteropentameric ligand-gated chloride channel gated by gamma-aminobutyric acid (GABA), a major inhibitory neurotransmitter in the brain.
HERC2	E3 ubiquitin-protein ligase HERC2	E3 ubiquitin-protein ligase that regulates ubiquitin-dependent retention of repair proteins on damaged chromosomes.
APBA2	Amyloid-beta A4 precursor protein-binding family A member 2	Putative function in synaptic vesicle exocytosis by binding to STXBP1, an essential component of the synaptic vesicle exocytotic machinery.
MECP2	Methyl-CpG-binding protein 2	Chromosomal protein that binds to methylated DNA.

Protein-family classification

Druggable: 3 · Difficult: 3 · Unknown: 9 · Druggable fraction: 0.2

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
Protease	1	2.4×	0.709
Kinase	1	1.9×	0.709
Scaffold/PPI	1	1.1×	0.709
Transcription factor	2	1.1×	0.709
Other/Unknown	9	1.1×	0.709
Enzyme (other)	1	0.8×	0.729

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UBE3A	Enzyme (other)	yes	2.3.2.26	HECT_dom, UBE3A, AZUL
CDKL5	Kinase	yes	2.7.11.22	Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
ATP10A	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
TPP1	Protease	yes	3.4.14.9	Peptidase_S8/S53_dom, S53_propep, Sedolisin_dom
ACD	Other/Unknown	no		TPP1/Est3, ACD
ENTREP2	Other/Unknown	no		CD20-like_TM, ENTREP1-3
SNORD115-16	Other/Unknown	no
SNORD115-17	Other/Unknown	no
SNHG14	Other/Unknown	no
GABRA5	Other/Unknown	no		GABAAa_rcpt, GABBAa5_rcpt, GABAA/Glycine_rcpt
GABRG3	Other/Unknown	no		GABRG-1/4, GABBAg3_rcpt, GABAA/Glycine_rcpt
HERC2	Transcription factor	no		Reg_chr_condens, Znf_ZZ, HECT_dom
PWAR6	Other/Unknown	no
APBA2	Scaffold/PPI	no		PDZ, PTB/PI_dom, PH-like_dom_sf
MECP2	Other/Unknown	no		Methyl_CpG_DNA-bd, DNA-bd_dom_sf, Me_CpG-bd_MeCP2

Expression context

Cohort genes with no expression data: 0.

12 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)	0
broad (>20)	14
unknown	1

Top tissues across cohort

Tissue	Cohort genes
sural nerve	4
right hemisphere of cerebellum	3
Brodmann (1909) area 23	2
cortical plate	2
cerebellar cortex	2
Brodmann (1909) area 10	2
calcaneal tendon	1
skeletal muscle tissue of rectus abdominis	1
sperm	1
frontal pole	1
descending thoracic aorta	1
endothelial cell	1
thoracic aorta	1
dorsal motor nucleus of vagus nerve	1
pigmented layer of retina	1
retina	1
cerebellar hemisphere	1
Ammon’s horn	1
primary visual cortex	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBE3A	295	ubiquitous	marker	sperm, skeletal muscle tissue of rectus abdominis, calcaneal tendon
CDKL5	257	ubiquitous	marker	frontal pole, Brodmann (1909) area 23, cortical plate
ATP10A	229	broad	marker	endothelial cell, descending thoracic aorta, thoracic aorta
TPP1	298	ubiquitous	marker	pigmented layer of retina, retina, dorsal motor nucleus of vagus nerve
ACD	282	ubiquitous	marker	right hemisphere of cerebellum, cerebellar hemisphere, cerebellar cortex
ENTREP2	124	tissue_specific	marker	primordial germ cell in gonad, Ammon’s horn, primary visual cortex
SNORD115-16	36		yes	caudate nucleus, Brodmann (1909) area 9, sural nerve
SNORD115-17	67		yes	sural nerve, liver, skeletal muscle tissue
SNHG14	283	broad	marker	lateral nuclear group of thalamus, Brodmann (1909) area 23, pons
GABRA5	141	broad	marker	nucleus accumbens, prefrontal cortex, Brodmann (1909) area 10
GABRG3	115	broad	marker	male germ line stem cell (sensu Vertebrata) in testis, cortical plate, right testis
HERC2	146		marker	sural nerve, right hemisphere of cerebellum, cerebellar cortex
PWAR6		broad
APBA2	131	ubiquitous	marker	superior frontal gyrus, right hemisphere of cerebellum, cerebellum
MECP2	277	ubiquitous	marker	paraflocculus, Brodmann (1909) area 10, sural nerve

Protein interactions among cohort

Intra-cohort edges: 7.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MECP2	5,688
HERC2	2,843
APBA2	2,193
GABRA5	1,907
TPP1	1,739
CDKL5	1,357
UBE3A	1,197
GABRG3	1,126
ACD	1,044
ATP10A	1,016

Intra-cohort edges

A	B	Sources
APBA2	ENTREP2	string_interaction
APBA2	HERC2	biogrid_interaction, intact
ATP10A	GABRA5	string_interaction
ATP10A	GABRG3	string_interaction
CDKL5	MECP2	string_interaction
GABRA5	MECP2	string_interaction
GABRG3	MECP2	string_interaction

Structural data

PDB: 7 · AlphaFold-only: 4 · No structure: 4

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBE3A	Q05086	25
GABRA5	P31644	23
ACD	Q96AP0	19
HERC2	O95714	15
MECP2	P51608	9
CDKL5	O76039	3
TPP1	O14773	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
GABRG3	Q99928	75.44
ATP10A	O60312	71.30
APBA2	Q99767	59.74
ENTREP2	O60320	59.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 54. Enrichment computed across 15 evidence-associated genes (9 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 9 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
GABA receptor activation	2	70.5×	0.019	GABRA5, GABRG3
Loss of MECP2 binding ability to 5hmC-DNA	1	1268.9×	0.021	MECP2
MECP2 regulates transcription of genes involved in GABA signaling	1	423.0×	0.034	MECP2
Loss of phosphorylation of MECP2 at T308	1	317.2×	0.034	MECP2
Loss of MECP2 binding ability to 5mC-DNA	1	317.2×	0.034	MECP2
MECP2 regulates transcription factors	1	253.8×	0.035	MECP2
Depurination	1	181.3×	0.037	ACD
Loss of MECP2 binding ability to the NCoR/SMRT complex	1	181.3×	0.037	MECP2
MECP2 regulates transcription of neuronal ligands	1	158.6×	0.038	MECP2
Depyrimidination	1	105.7×	0.045	ACD
Base-Excision Repair, AP Site Formation	1	97.6×	0.045	ACD
Telomere C-strand synthesis initiation	1	90.6×	0.045	ACD
Processive synthesis on the C-strand of the telomere	1	84.6×	0.045	ACD
Telomere C-strand (Lagging Strand) Synthesis	1	84.6×	0.045	ACD
Base Excision Repair	1	79.3×	0.045	ACD
Removal of the Flap Intermediate from the C-strand	1	70.5×	0.045	ACD
Extension of Telomeres	1	66.8×	0.045	ACD
MECP2 regulates neuronal receptors and channels	1	66.8×	0.045	MECP2
Telomere Extension By Telomerase	1	50.8×	0.056	ACD
Polymerase switching on the C-strand of the telomere	1	47.0×	0.057	ACD
Telomere Maintenance	1	40.9×	0.057	ACD
Regulation of MECP2 expression and activity	1	40.9×	0.057	MECP2
Antigen processing: Ubiquitination & Proteasome degradation	2	8.3×	0.057	UBE3A, HERC2
Nuclear events stimulated by ALK signaling in cancer	1	36.2×	0.061	MECP2
Transcriptional Regulation by MECP2	1	35.2×	0.061	MECP2
Meiosis	1	31.7×	0.064	ACD
Signaling by ERBB4	1	30.2×	0.064	GABRG3
Protein-protein interactions at synapses	1	29.5×	0.064	APBA2
Packaging Of Telomere Ends	1	24.4×	0.068	ACD
XBP1(S) activates chaperone genes	1	23.9×	0.068	TPP1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 10 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
protein localization to chromosome, telomeric region	2	306.4×	0.002	TPP1, ACD
inhibitory synapse assembly	2	124.8×	0.006	GABRA5, GABRG3
gamma-aminobutyric acid signaling pathway	2	108.7×	0.006	GABRA5, GABRG3
synaptic transmission, GABAergic	2	99.1×	0.006	GABRA5, GABRG3
behavioral fear response	2	86.4×	0.006	GABRA5, MECP2
sperm entry	1	1685.2×	0.008	UBE3A
catecholamine secretion	1	1685.2×	0.008	MECP2
trans-synaptic signaling by BDNF	1	1685.2×	0.008	MECP2
obsolete positive regulation of Golgi lumen acidification	1	1685.2×	0.008	UBE3A
chloride transmembrane transport	2	47.5×	0.010	GABRA5, GABRG3
cardiolipin metabolic process	1	842.6×	0.013	MECP2
segmentation	1	842.6×	0.013	ACD
nervous system process involved in regulation of systemic arterial blood pressure	1	561.7×	0.013	MECP2
biogenic amine metabolic process	1	561.7×	0.013	MECP2
response to other organism	1	561.7×	0.013	MECP2
regulation of establishment of protein localization to telomere	1	561.7×	0.013	ACD
positive regulation of membrane tubulation	1	561.7×	0.013	ATP10A
proprioception	1	421.3×	0.016	MECP2
telomere assembly	1	421.3×	0.016	ACD
regulation of ubiquitin-dependent protein catabolic process	1	337.0×	0.019	UBE3A
glucocorticoid metabolic process	1	280.9×	0.022	MECP2
inositol metabolic process	1	240.7×	0.022	MECP2
protection from non-homologous end joining at telomere	1	240.7×	0.022	ACD
inner ear receptor cell development	1	240.7×	0.022	GABRA5
prostate gland growth	1	210.7×	0.022	UBE3A
establishment of protein localization to telomere	1	210.7×	0.022	ACD
positive regulation of microtubule nucleation	1	210.7×	0.022	MECP2
negative regulation of smooth muscle cell differentiation	1	187.2×	0.024	MECP2
regulation of respiratory gaseous exchange by nervous system process	1	129.6×	0.031	MECP2
L-glutamine metabolic process	1	129.6×	0.031	MECP2

Therapeutics

Drugs indicated for this disease

0 approved, 1 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Gaboxadol	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Levodopa, Minocycline.

Drug target analysis

Approved (phase 4): 3 · Phase ≥3: 3 · Phased (≥1): 3 · Undrugged: 12

Druggability breadth: 6 of 15 evidence-associated genes (40%) 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
CDKL5	FEDRATINIB
GABRA5	ENZALUTAMIDE
GABRG3	ENZALUTAMIDE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GABRA5	27	4
GABRG3	15	4
CDKL5	14	4
UBE3A	0	0
ATP10A	0	0
TPP1	0	0
ACD	0	0
ENTREP2	0	0
SNORD115-16	0	0
SNORD115-17	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
ENZALUTAMIDE	4	GABRA5, GABRG3
DIAZEPAM	4	GABRA5, GABRG3
LIOTHYRONINE	4	GABRA5, GABRG3
GANAXOLONE	4	GABRA5, GABRG3
BREXANOLONE	4	GABRA5, GABRG3
APALUTAMIDE	4	GABRA5, GABRG3
FLUMAZENIL	4	GABRA5, GABRG3
CLONAZEPAM	4	GABRA5, GABRG3
FLUNITRAZEPAM	4	GABRA5
CHLORDIAZEPOXIDE	4	GABRA5
TRIAZOLAM	4	GABRA5
PROPOFOL	4	GABRA5
ALPRAZOLAM	4	GABRA5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
DELORAZEPAM	2	GABRA5, GABRG3
FLAVONE	2	GABRA5, GABRG3
PROGABIDE	2	GABRA5, GABRG3
ABECARNIL	2	GABRA5, GABRG3
BAICALEIN	2	GABRA5, GABRG3
MK-0777	2	GABRA5
DARIGABAT	2	GABRA5

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 4.

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

Symbol	Assays	Type breakdown
GABRA5	413	Binding:352, Functional:57, Toxicity:3, ADMET:1
GABRG3	191	Binding:172, Functional:15, Toxicity:3, ADMET:1
CDKL5	74	Binding:74
UBE3A	1	Binding:1
TPP1	1	Binding:1
MECP2	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
UBE3A	2.3.2.26	HECT-type E3 ubiquitin transferase
CDKL5	2.7.11.22	cyclin-dependent kinase
ATP10A	7.6.2.1	P-type phospholipid transporter
TPP1	3.4.14.9	tripeptidyl-peptidase I

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GABRA5	413
GABRG3	191

Pharmacogenomics

Cohort genes with a PharmGKB record: 13; 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)
FEDRATINIB	4	CDKL5
CAPMATINIB	4	CDKL5
ENZALUTAMIDE	4	GABRA5, GABRG3
DIAZEPAM	4	GABRA5, GABRG3
LIOTHYRONINE	4	GABRA5, GABRG3
GANAXOLONE	4	GABRA5, GABRG3
BREXANOLONE	4	GABRA5, GABRG3
APALUTAMIDE	4	GABRA5, GABRG3
FLUMAZENIL	4	GABRA5, GABRG3
CLONAZEPAM	4	GABRA5, GABRG3
FLUNITRAZEPAM	4	GABRA5
CHLORDIAZEPOXIDE	4	GABRA5
TRIAZOLAM	4	GABRA5
PROPOFOL	4	GABRA5
ALPRAZOLAM	4	GABRA5
DEFACTINIB	3	CDKL5
ALVOCIDIB	3	CDKL5
LESTAURTINIB	3	CDKL5
RUBOXISTAURIN	3	CDKL5
FORETINIB	2	CDKL5
RG-547	2	CDKL5
AT-7519	2	CDKL5
TOZASERTIB	2	CDKL5
DELORAZEPAM	2	GABRA5, GABRG3
FLAVONE	2	GABRA5, GABRG3
PROGABIDE	2	GABRA5, GABRG3
ABECARNIL	2	GABRA5, GABRG3
BAICALEIN	2	GABRA5, GABRG3
MK-0777	2	GABRA5
DARIGABAT	2	GABRA5

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	CDKL5, GABRA5, GABRG3
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	2	UBE3A, TPP1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	10	ATP10A, ACD, ENTREP2, SNORD115-16, SNORD115-17, SNHG14, HERC2, PWAR6, APBA2, MECP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
UBE3A	1	—
ATP10A	0	—
TPP1	1	—
ACD	0	—
ENTREP2	0	—
SNORD115-16	0	—
SNORD115-17	0	—
SNHG14	0	—
HERC2	0	—
PWAR6	0	—
APBA2	0	—
MECP2	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 49.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	29
PHASE3	6
PHASE2	5
PHASE1	4
PHASE1/PHASE2	3
PHASE2/PHASE3	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06415344	PHASE3	ENROLLING_BY_INVITATION	Long-term Extension of GTX-102 in Angelman Syndrome
NCT06617429	PHASE3	ACTIVE_NOT_RECRUITING	Phase 3 Efficacy and Safety Study of GTX-102 in Pediatric Subjects With Angelman Syndrome (AS)
NCT06914609	PHASE3	RECRUITING	REVEAL: A Phase 3 Study of ION582 in Angelman Syndrome
NCT07605429	PHASE3	NOT_YET_RECRUITING	Phase III Clinical Study of Rugonersen in Angelman Syndrome.
NCT01281475	PHASE2/PHASE3	COMPLETED	A Trial of Levodopa in Angelman Syndrome
NCT02893254	PHASE3	COMPLETED	Efficacy and Safety of IBI303 in Adult Patients With Active Ankylosing Spondylitis
NCT03882918	PHASE3	TERMINATED	An Open-Label Study to Evaluate the Long-Term Safety, Tolerability, and Efficacy of OV101 in Individuals With Angelman Syndrome
NCT05127226	PHASE1/PHASE2	RECRUITING	HALOS: A Safety, Tolerability, Pharmacokinetics and Pharmacodynamics Study of Multiple Ascending Doses of ION582 in Participants With Angelman Syndrome
NCT07157254	PHASE2	RECRUITING	A Safety and Efficacy Study of GTX-102 in Subjects With Deletion- or Nondeletion-type Angelman Syndrome (AS)
NCT07181837	PHASE1/PHASE2	RECRUITING	A Phase 1/2 Study of the Safety and Efficacy of MVX-220 in Angelman Syndrome
NCT02056665	PHASE2	COMPLETED	Study to Evaluate the Efficacy and Safety of Minocycline in Angelman Syndrome
NCT02996305	PHASE2	COMPLETED	A Study in Adults and Adolescents With Angelman Syndrome (STARS)
NCT04259281	PHASE1/PHASE2	COMPLETED	A Study of the Safety and Tolerability of GTX-102 in Children With Angelman Syndrome
NCT05011851	PHASE2	COMPLETED	An Open-Label Study of the Safety, Tolerability, and Pharmacokinetics of Oral NNZ-2591 in Angelman Syndrome
NCT05630066	PHASE2	COMPLETED	A Study to Investigate the Pharmacokinetics (PK) and Safety and to Provide Proof of Mechanism of Alogabat in Children and Adolescents Aged 5-17 Years With Angelman Syndrome (AS) With Deletion Genotype.
NCT00829439	PHASE1	COMPLETED	Study on Tolerability of Levodopa/Carbidopa in Children With Angelman Syndrome
NCT03109756	PHASE1	COMPLETED	Single Dose Pharmacokinetic (PK) Study
NCT04428281	PHASE1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics (PK) and Pharmacodynamics (PD) of RO7248824 in Participants With Angelman Syndrome (AS)
NCT04863794	PHASE1	COMPLETED	A Study To Assess Distribution Of RO7248824 In The Central Nervous System Following Single Intrathecal Doses Of [89zr] Labeled RO7248824 In Healthy Male Participants
NCT04103333	EARLY_PHASE1	COMPLETED	Angelman Syndrome (AS) Biomarker Study
NCT03655223	Not specified	ENROLLING_BY_INVITATION	Early Check: Expanded Screening in Newborns
NCT03836300	Not specified	ENROLLING_BY_INVITATION	Parent and Infant Inter(X)Action Intervention (PIXI)
NCT04507997	Not specified	RECRUITING	Angelman Syndrome Natural History Study
NCT05293184	Not specified	RECRUITING	The Global Angelman Syndrome Registry
NCT05945576	Not specified	RECRUITING	IDMet (RaDiCo Cohort) (RaDiCo-IDMet)
NCT06139172	Not specified	RECRUITING	Web Intervention for Parents of Youth With Genetic Syndromes (WINGS)
NCT06229769	Not specified	RECRUITING	Natural History Study for Patients With Angelman Syndrome
NCT06353620	Not specified	RECRUITING	Structural-functional Connectome in Drug-resistant Epilepsies and Neurodevelopmental Syndromes With Epilepsy
NCT06737718	Not specified	RECRUITING	Use of Eye Tracking to Study Social Perception Abnormalities in Children With Angelman Syndrome
NCT07136454	Not specified	AVAILABLE	Expanded Access/Compassionate Use of Rugonersen in Patients With Angelman Syndrome
NCT07383805	Not specified	NOT_YET_RECRUITING	Expression of Tim-3 on Neutrophils in Ankylosing Spondylitis
NCT07417137	Not specified	RECRUITING	A Natural History Study of Angelman Syndrome
NCT00004351	Not specified	COMPLETED	Study of Phenotype and Genotype Correlations in Patients With Contiguous Gene Deletion Syndromes
NCT00296764	Not specified	COMPLETED	Characterization of Angelman Syndrome
NCT00348933	Not specified	COMPLETED	Dietary Supplements for the Treatment of Angelman Syndrome
NCT01531582	Not specified	COMPLETED	Minocycline in the Treatment of Angelman Syndrome
NCT02381457	Not specified	COMPLETED	SNP-based Microdeletion and Aneuploidy RegisTry (SMART)
NCT02670694	Not specified	COMPLETED	Sleep Abnormalities in Rare Genetic Disorders: AS, RTT, and PW
NCT03235037	Not specified	COMPLETED	Clinical Trial of Levodopa/Carbidopa ( Sinemet) Therapy in Angel Man Syndrome
NCT03358823	Not specified	COMPLETED	Study on the Brain Network of Angelman Syndrome

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CARBIDOPA ANHYDROUS	4	3
LEVODOPA	4	3
LEVOMEFOLIC ACID	4	2
BETAINE	4	1
CYANOCOBALAMIN	4	1
CREATINE	3	1
ALOGABAT	2	1
NNZ-2591	2	1
OBUDANERSEN SODIUM	1	2
RUGONERSEN	1	2
CHEMBL351042	0	2
CHEMBL4303681	0	1
GLYCINEBETAINE	0	1
VITAMIN B12	0	1