Ehlers-Danlos syndrome

Summary

Ehlers-Danlos syndrome (MONDO:0020066) is a disease (an umbrella term covering 25 Mondo subtypes) caused by variants in COL5A1, COL5A2, and TNXB, with 33 cohort genes and 49 clinical trials. The dominant Reactome pathway is Collagen biosynthesis and modifying enzymes (9 cohort genes). Top therapeutic interventions include dextrose and oxygen.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal genes: COL5A1 (GenCC Definitive), COL5A2 (GenCC Definitive), TNXB (GenCC Definitive)
• Umbrella term: 25 Mondo subtypes
• Cohort genes: 33
• ClinVar variants: 1,220
• Clinical trials: 49

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Prevalence at birth	1-9 / 1 000 000	0.9	Europe	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Ehlers-Danlos syndrome
Mondo ID	MONDO:0020066
MeSH	D004535
OMIM	130000
Orphanet	98249
DOID	DOID:13359
ICD-10-CM	Q79.6
ICD-11	1122707206
NCIT	C34568
SNOMED CT	398114001
UMLS	C0013720
MedGen	41720
GARD	0006322
MedDRA	10014316
NORD	1080
Is cancer (heuristic)	no

Also known as: Danlos disease · Danlos Disease, Ehlers · danlos ehlers syndrome · Disease, Ehlers Danlos · Disease, Ehlers-Danlos · Dystrophia mesodermalis congenita · ED syndrome · EDS · Ehler Danlos Syndrome · Ehlers Danlos Disease · Ehlers Danlos Syndrome · Ehlers Danlos syndrome · Ehlers-Danlos Disease · Ehlers-Danlos syndromes · elastic skin · Fibrodysplasia elastica generalisata · Hereditary collagen dysplasia · Meekeren-Ehlers-Danlos syndrome · skin elastic · Syndrome, Ehlers-Danlos

Data availability: 1,220 ClinVar variants · 5 GenCC gene-disease records · 56 cell lines.

Disease family

An umbrella term covering 25 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › Ehlers-Danlos 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, Angelman syndrome, 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, 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 (25): Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, hypermobility type, Ehlers-Danlos syndrome, arthrochalasia type, Ehlers-Danlos syndrome, spondylodysplastic type, Ehlers-Danlos syndrome, periodontitis type, Ehlers-Danlos syndrome, autosomal dominant, type unspecified, joint laxity, familial, Ehlers-Danlos syndrome, fibronectinemic type, Ehlers-Danlos syndrome, dermatosparaxis type, brittle cornea syndrome, X-linked Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, musculocontractural type, Ehlers-Danlos syndrome due to tenascin-X deficiency, Ehlers-Danlos syndrome, Beasley-Cohen type, Ehlers-Danlos syndrome, kyphoscoliotic type, 2, Ehlers-Danlos syndrome, kyphoscoliotic type 1, Ehlers-Danlos syndrome, vascular-like type, Ehlers-Danlos/osteogenesis imperfecta syndrome, Ehlers-Danlos syndrome, vascular type, spondylodysplastic Ehlers-Danlos syndrome, Bethlem myopathy 2, Ehlers-Danlos syndrome, classic-like, 2, COL1A1-related Ehlers-Danlos syndrome, COL1A2-related Ehlers-Danlos syndrome, Ehlers-Danlos syndrome, classic-like, 3

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:

212 conflicting classifications of pathogenicity, 190 uncertain significance, 128 benign/likely benign, 25 benign, 23 likely pathogenic, 9 likely benign, 7 pathogenic, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
17343	NM_000088.4(COL1A1):c.934C>T (p.Arg312Cys)	COL1A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343353	NM_000089.4(COL1A2):c.2701G>A (p.Gly901Ser)	COL1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17251	NM_000089.4(COL1A2):c.279+1G>A	COL1A2	Pathogenic	criteria provided, single submitter
17270	NM_000089.4(COL1A2):c.226-2A>G	COL1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17275	NM_000089.4(COL1A2):c.1404+1G>A	COL1A2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072145	NM_000090.4(COL3A1):c.2044G>A (p.Glu682Lys)	COL3A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702219	NM_000093.5(COL5A1):c.5031del (p.Ser1678fs)	COL5A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
17191	NM_000093.5(COL5A1):c.2374C>T (p.Arg792Ter)	COL5A1	Pathogenic	criteria provided, multiple submitters, no conflicts
14364	NM_000302.4(PLOD1):c.955C>T (p.Arg319Ter)	PLOD1	Pathogenic	criteria provided, multiple submitters, no conflicts
14370	NM_000302.4(PLOD1):c.1533C>G (p.Tyr511Ter)	PLOD1	Pathogenic	criteria provided, multiple submitters, no conflicts
1702256	NM_000302.4(PLOD1):c.1362del (p.Tyr455fs)	PLOD1	Pathogenic	criteria provided, single submitter
1702284	NM_003238.6(TGFB2):c.1041del (p.Gly348fs)	TGFB2	Pathogenic	criteria provided, single submitter
1702327	NM_001365276.2(TNXB):c.3942dup (p.Thr1315fs)	TNXB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1701998	NM_000089.4(COL1A2):c.486+2T>G	COL1A2	Likely pathogenic	criteria provided, single submitter
1702191	NM_000089.4(COL1A2):c.2737G>A (p.Gly913Ser)	COL1A2	Likely pathogenic	criteria provided, multiple submitters, no conflicts
101206	NM_000090.4(COL3A1):c.582+1G>C	COL3A1	Likely pathogenic	criteria provided, single submitter
101346	NM_000090.4(COL3A1):c.2113G>A (p.Gly705Arg)	COL3A1	Likely pathogenic	criteria provided, single submitter
1702196	NM_000090.4(COL3A1):c.2122G>A (p.Gly708Ser)	COL3A1	Likely pathogenic	criteria provided, single submitter
1702197	NM_000090.4(COL3A1):c.2815G>C (p.Gly939Arg)	COL3A1	Likely pathogenic	criteria provided, single submitter
1702202	NM_000090.4(COL3A1):c.971G>T (p.Gly324Val)	COL3A1	Likely pathogenic	criteria provided, single submitter
1702209	NM_000093.5(COL5A1):c.3259G>T (p.Gly1087Ter)	COL5A1	Likely pathogenic	criteria provided, single submitter
1702212	NM_000093.5(COL5A1):c.3809_3810dup (p.Pro1271fs)	COL5A1	Likely pathogenic	criteria provided, single submitter
1702213	NM_000093.5(COL5A1):c.4014+1G>A	COL5A1	Likely pathogenic	criteria provided, single submitter
1702218	NM_000093.4(COL5A1):c.4646dupG	COL5A1	Likely pathogenic	criteria provided, single submitter
1702222	NM_000093.5(COL5A1):c.655-2A>T	COL5A1	Likely pathogenic	criteria provided, multiple submitters, no conflicts
1702240	NM_001999.4(FBN2):c.1723+1G>T	FBN2	Likely pathogenic	criteria provided, single submitter
1702263	NM_000302.4(PLOD1):c.979dup (p.Gln327fs)	PLOD1	Likely pathogenic	criteria provided, single submitter
1702283	NM_005902.4(SMAD3):c.594del (p.His198fs)	SMAD3	Likely pathogenic	criteria provided, single submitter
1702293	NM_003242.6(TGFBR2):c.1582C>G (p.Arg528Gly)	TGFBR2	Likely pathogenic	criteria provided, single submitter
1702298	NM_001365276.2(TNXB):c.10623_10624del (p.Pro3542fs)	TNXB	Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 26 · Orphanet: 85 · 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
COL5A1	Definitive	Autosomal dominant	Ehlers-Danlos syndrome, classic type	7
COL5A2	Definitive	Autosomal dominant	Ehlers-Danlos syndrome	4
TNXB	Definitive	Autosomal recessive	Ehlers-Danlos syndrome due to tenascin-X deficiency	8
ADAMTSL2	Moderate	Autosomal dominant	Ehlers-Danlos syndrome, dermatosparaxis type	6
ATP6V0D2	Limited	Autosomal recessive	Ehlers-Danlos syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TNXB	Orphanet:230839	Classical-like Ehlers-Danlos syndrome type 1
TNXB	Orphanet:289365	Familial vesicoureteral reflux
COL5A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL5A2	Orphanet:287	Classical Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
ADAMTSL2	Orphanet:2623	Geleophysic dysplasia
SMARCA2	Orphanet:3051	Nicolaides-Baraitser syndrome
SMARCA2	Orphanet:637013	SMARCA2-related blepharophimosis-intellectual disability syndrome
TCOF1	Orphanet:861	Treacher-Collins syndrome
TGFB2	Orphanet:60030	Loeys-Dietz syndrome
TGFB2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR1	Orphanet:284973	Marfan syndrome type 2
TGFBR1	Orphanet:60030	Loeys-Dietz syndrome
TGFBR1	Orphanet:65748	Multiple self-healing squamous epithelioma
TGFBR1	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:144	Lynch syndrome
TGFBR2	Orphanet:284973	Marfan syndrome type 2
TGFBR2	Orphanet:60030	Loeys-Dietz syndrome
TGFBR2	Orphanet:91387	Familial thoracic aortic aneurysm and aortic dissection
TGFBR2	Orphanet:99977	Squamous cell carcinoma of the esophagus
C1R	Orphanet:169147	Immunodeficiency due to a classical component pathway complement deficiency
C1R	Orphanet:300345	Autosomal systemic lupus erythematosus
C1R	Orphanet:75392	Periodontal Ehlers-Danlos syndrome
FKBP14	Orphanet:300179	Kyphoscoliotic Ehlers-Danlos syndrome due to FKBP22 deficiency
SLC39A13	Orphanet:157965	SLC39A13-related spondylodysplastic Ehlers-Danlos syndrome
DSE	Orphanet:2953	Musculocontractural Ehlers-Danlos syndrome
ADAMTS2	Orphanet:1901	Dermatosparaxis Ehlers-Danlos syndrome
COL12A1	Orphanet:536516	Myopathic Ehlers-Danlos syndrome
COL12A1	Orphanet:610	Bethlem muscular dystrophy
COL12A1	Orphanet:75840	Ullrich congenital muscular dystrophy
COL1A1	Orphanet:1310	Caffey disease
COL1A1	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A1	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A1	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A1	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A1	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A1	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A1	Orphanet:287	Classical Ehlers-Danlos syndrome
COL1A1	Orphanet:31112	Dermatofibrosarcoma protuberans
COL1A1	Orphanet:314029	High bone mass osteogenesis imperfecta
COL1A2	Orphanet:1899	Arthrochalasia Ehlers-Danlos syndrome
COL1A2	Orphanet:216796	Osteogenesis imperfecta type 1
COL1A2	Orphanet:216804	Osteogenesis imperfecta type 2
COL1A2	Orphanet:216812	Osteogenesis imperfecta type 3
COL1A2	Orphanet:216820	Osteogenesis imperfecta type 4
COL1A2	Orphanet:230851	Cardiac-valvular Ehlers-Danlos syndrome
COL1A2	Orphanet:230857	Ehlers-Danlos/osteogenesis imperfecta syndrome
COL1A2	Orphanet:314029	High bone mass osteogenesis imperfecta
COL3A1	Orphanet:231160	Familial cerebral saccular aneurysm
COL3A1	Orphanet:2500	Acrogeria

Cohort genes → proteins

33 cohort genes, 32 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	33

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TNXB	HGNC:11976	ENSG00000168477	P22105	Tenascin-X	gencc,clinvar
COL5A1	HGNC:2209	ENSG00000130635	P20908	Collagen alpha-1(V) chain	gencc,clinvar
COL5A2	HGNC:2210	ENSG00000204262	P05997	Collagen alpha-2(V) chain	gencc,clinvar
ADAMTSL2	HGNC:14631	ENSG00000197859	Q86TH1	ADAMTS-like protein 2	gencc
ATP6V0D2	HGNC:18266	ENSG00000147614	Q8N8Y2	V-type proton ATPase subunit d 2	gencc
SMARCA2	HGNC:11098	ENSG00000080503	P51531	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	clinvar
TCOF1	HGNC:11654	ENSG00000070814	Q13428	Treacle protein	clinvar
TGFB2	HGNC:11768	ENSG00000092969	P61812	Transforming growth factor beta-2 proprotein	clinvar
TGFBR1	HGNC:11772	ENSG00000106799	P36897	TGF-beta receptor type-1	clinvar
TGFBR2	HGNC:11773	ENSG00000163513	P37173	TGF-beta receptor type-2	clinvar
THBS2	HGNC:11786	ENSG00000186340	P35442	Thrombospondin-2	clinvar
C1R	HGNC:1246	ENSG00000159403	P00736	Complement C1r subcomponent	clinvar
FKBP14	HGNC:18625	ENSG00000106080	Q9NWM8	Peptidyl-prolyl cis-trans isomerase FKBP14	clinvar
SLC39A13	HGNC:20859	ENSG00000165915	Q96H72	Zinc transporter ZIP13	clinvar
DSE	HGNC:21144	ENSG00000111817	Q9UL01	Dermatan-sulfate epimerase	clinvar
ADAMTS2	HGNC:218	ENSG00000087116	O95450	A disintegrin and metalloproteinase with thrombospondin motifs 2	clinvar
COL12A1	HGNC:2188	ENSG00000111799	Q99715	Collagen alpha-1(XII) chain	clinvar
COL1A1	HGNC:2197	ENSG00000108821	P02452	Collagen alpha-1(I) chain	clinvar
COL1A2	HGNC:2198	ENSG00000164692	P08123	Collagen alpha-2(I) chain	clinvar
COL3A1	HGNC:2201	ENSG00000168542	P02461	Collagen alpha-1(III) chain	clinvar
COL6A1	HGNC:2211	ENSG00000142156	P12109	Collagen alpha-1(VI) chain	clinvar
ZNF469	HGNC:23216	ENSG00000225614	Q96JG9	Zinc finger protein 469	clinvar
CHST14	HGNC:24464	ENSG00000169105	Q8NCH0	Carbohydrate sulfotransferase 14	clinvar
CYP21A2	HGNC:2600	ENSG00000231852	P08686	Steroid 21-hydroxylase	clinvar
FBN2	HGNC:3604	ENSG00000138829	P35556	Fibrillin-2	clinvar
FLNA	HGNC:3754	ENSG00000196924	P21333	Filamin-A	clinvar
FKBP14-AS1	HGNC:40990	ENSG00000227014		FKBP14 antisense RNA 1	clinvar
SMAD3	HGNC:6769	ENSG00000166949	P84022	SMAD family member 3	clinvar
ATP7A	HGNC:869	ENSG00000165240	Q04656	Copper-transporting ATPase 1	clinvar
PLOD1	HGNC:9081	ENSG00000083444	Q02809	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1	clinvar
B4GALT7	HGNC:930	ENSG00000027847	Q9UBV7	Beta-1,4-galactosyltransferase 7	clinvar
PRDM5	HGNC:9349	ENSG00000138738	Q9NQX1	PR domain zinc finger protein 5	clinvar
RECQL4	HGNC:9949	ENSG00000160957	O94761	ATP-dependent DNA helicase Q4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TNXB	Tenascin-X	Appears to mediate interactions between cells and the extracellular matrix.
COL5A1	Collagen alpha-1(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
COL5A2	Collagen alpha-2(V) chain	Type V collagen is a member of group I collagen (fibrillar forming collagen).
ATP6V0D2	V-type proton ATPase subunit d 2	Subunit of the V0 complex of vacuolar(H+)-ATPase (V-ATPase), a multisubunit enzyme composed of a peripheral complex (V1) that hydrolyzes ATP and a membrane integral complex (V0) that translocates protons.
SMARCA2	SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2	ATPase involved in transcriptional activation and repression of select genes by chromatin remodeling (alteration of DNA-nucleosome topology).
TCOF1	Treacle protein	Nucleolar protein that acts as a regulator of RNA polymerase I by connecting RNA polymerase I with enzymes responsible for ribosomal processing and modification.
TGFB2	Transforming growth factor beta-2 proprotein	Precursor of the Latency-associated peptide (LAP) and Transforming growth factor beta-2 (TGF-beta-2) chains, which constitute the regulatory and active subunit of TGF-beta-2, respectively.
TGFBR1	TGF-beta receptor type-1	Transmembrane serine/threonine kinase forming with the TGF-beta type II serine/threonine kinase receptor, TGFBR2, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
TGFBR2	TGF-beta receptor type-2	Transmembrane serine/threonine kinase forming with the TGF-beta type I serine/threonine kinase receptor, TGFBR1, the non-promiscuous receptor for the TGF-beta cytokines TGFB1, TGFB2 and TGFB3.
THBS2	Thrombospondin-2	Adhesive glycoprotein that mediates cell-to-cell and cell-to-matrix interactions.
C1R	Complement C1r subcomponent	Serine protease component of the complement C1 complex, a multiprotein complex that initiates the classical pathway of the complement system, a cascade of proteins that leads to phagocytosis and breakdown of pathogens and signaling that st…
FKBP14	Peptidyl-prolyl cis-trans isomerase FKBP14	PPIase which accelerates the folding of proteins during protein synthesis.
SLC39A13	Zinc transporter ZIP13	Functions as a zinc transporter transporting Zn(2+) from the Golgi apparatus to the cytosol and thus influences the zinc level at least in areas of the cytosol.
DSE	Dermatan-sulfate epimerase	Converts D-glucuronic acid to L-iduronic acid (IdoUA) residues.
ADAMTS2	A disintegrin and metalloproteinase with thrombospondin motifs 2	Cleaves the propeptides of type I and II collagen prior to fibril assembly.
COL12A1	Collagen alpha-1(XII) chain	Type XII collagen interacts with type I collagen-containing fibrils, the COL1 domain could be associated with the surface of the fibrils, and the COL2 and NC3 domains may be localized in the perifibrillar matrix.
COL1A1	Collagen alpha-1(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
COL1A2	Collagen alpha-2(I) chain	Type I collagen is a member of group I collagen (fibrillar forming collagen).
COL3A1	Collagen alpha-1(III) chain	Collagen type III occurs in most soft connective tissues along with type I collagen.
COL6A1	Collagen alpha-1(VI) chain	Collagen VI acts as a cell-binding protein.
ZNF469	Zinc finger protein 469	May be involved in transcriptional regulation.
CHST14	Carbohydrate sulfotransferase 14	Catalyzes the transfer of sulfate to position 4 of the N-acetylgalactosamine (GalNAc) residue of dermatan sulfate.
CYP21A2	Steroid 21-hydroxylase	A cytochrome P450 monooxygenase that plays a major role in adrenal steroidogenesis.
FBN2	Fibrillin-2	Fibrillins are structural components of 10-12 nm extracellular calcium-binding microfibrils, which occur either in association with elastin or in elastin-free bundles.
FLNA	Filamin-A	Promotes orthogonal branching of actin filaments and links actin filaments to membrane glycoproteins.
SMAD3	SMAD family member 3	Receptor-regulated SMAD (R-SMAD) that is an intracellular signal transducer and transcriptional modulator activated by TGF-beta (transforming growth factor) and activin type 1 receptor kinases.
ATP7A	Copper-transporting ATPase 1	ATP-driven copper (Cu(+)) ion pump that plays an important role in intracellular copper ion homeostasis.
PLOD1	Procollagen-lysine,2-oxoglutarate 5-dioxygenase 1	Part of a complex composed of PLOD1, P3H3 and P3H4 that catalyzes hydroxylation of lysine residues in collagen alpha chains and is required for normal assembly and cross-linkling of collagen fibrils.
B4GALT7	Beta-1,4-galactosyltransferase 7	Required for the biosynthesis of the tetrasaccharide linkage region of proteoglycans, especially for small proteoglycans in skin fibroblasts.
PRDM5	PR domain zinc finger protein 5	Sequence-specific DNA-binding transcription factor.
RECQL4	ATP-dependent DNA helicase Q4	An ATP-dependent DNA helicase which unwinds dsDNA with a 3’-overhang in a 3’-5’ direction.

Protein-family classification

Druggable: 13 · Difficult: 3 · Unknown: 17 · Druggable fraction: 0.39

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
Antibody/Immunoglobulin	3	2.6×	0.307
Enzyme (other)	6	2.2×	0.307
Protease	2	2.2×	0.455
Kinase	2	1.7×	0.503
Other/Unknown	17	0.9×	0.780
Transcription factor	3	0.8×	0.780

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TNXB	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
COL5A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
COL5A2	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
ADAMTSL2	Other/Unknown	no		TSP1_rpt, ADAMTS_spacer1, PLAC
ATP6V0D2	Other/Unknown	no		ATPase_V0-cplx_csu/dsu, ATPase_V0-cplx_dsu, V-type_ATPase_csu/dsu
SMARCA2	Other/Unknown	no		SNF2_N, Bromodomain, Helicase_C-like
TCOF1	Other/Unknown	no		Treacle_dom, LisH, Treacle
TGFB2	Other/Unknown	no		TGF-b_propeptide, TGF-b_C, TGFb2
TGFBR1	Kinase	yes	2.7.10.2	TGFB_receptor, Activin_recp, Prot_kinase_dom
TGFBR2	Kinase	yes	2.7.10.2	TGFB_receptor, Prot_kinase_dom, Ser-Thr/Tyr_kinase_cat_dom
THBS2	Other/Unknown	no		EGF, TSP1_rpt, VWF_dom
C1R	Protease	yes	3.4.21.41	Sushi_SCR_CCP_dom, EGF, CUB_dom
FKBP14	Enzyme (other)	yes	5.2.1.8	PPIase_FKBP_dom, EF_hand_dom, EF-hand-dom_pair
SLC39A13	Other/Unknown	no		ZIP
DSE	Enzyme (other)	yes	5.1.3.19	Chondroitin_lyas, Dermatan-Sulfate_Isomerase
ADAMTS2	Protease	yes	3.4.24.14	TSP1_rpt, Peptidase_M12B, Peptidase_M12B_N
COL12A1	Antibody/Immunoglobulin	yes		VWF_A, FN3_dom, Collagen
COL1A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL1A2	Other/Unknown	no		Fib_collagen_C, Collagen, Collagen_superfamily
COL3A1	Other/Unknown	no		Fib_collagen_C, VWF_dom, Collagen
COL6A1	Other/Unknown	no		VWF_A, Collagen, vWFA_dom_sf
ZNF469	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf, ZNF469
CHST14	Enzyme (other)	yes	2.8.2.35	Sulfotransferase, Carb_sulfotrans_8-10
CYP21A2	Enzyme (other)	yes	1.14.14.16	Cyt_P450, Cyt_P450_E_grp-I, Cyt_P450_CS
FBN2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
FLNA	Antibody/Immunoglobulin	yes		Filamin/ABP280_rpt, Actinin_actin-bd_CS, CH_dom
FKBP14-AS1	Other/Unknown	no
SMAD3	Other/Unknown	no		SMAD_dom, MAD_homology1_Dwarfin-type, SMAD_FHA_dom_sf
ATP7A	Transcription factor	no	7.2.2.8	P_typ_ATPase, HMA_dom, HMA_Cu_ion-bd
PLOD1	Other/Unknown	no		Procol_lys_dOase, Oxoglu/Fe-dep_dioxygenase_dom, Pro_4_hyd_alph
B4GALT7	Enzyme (other)	yes	2.4.1.133	Galactosyl_T, Galactosyl_T_C, Galactosyl_T_N
PRDM5	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_PRDM5-like
RECQL4	Enzyme (other)	yes	3.6.4.12	Helicase_C-like, DNA_helicase_ATP-dep_RecQ, DEAD/DEAH_box_helicase_dom

Expression context

Cohort genes with no expression data: 0.

30 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)	33
unknown	0

Top tissues across cohort

Tissue	Cohort genes
stromal cell of endometrium	9
cartilage tissue	6
tendon of biceps brachii	5
calcaneal tendon	5
tibia	5
periodontal ligament	4
right adrenal gland	3
metanephros cortex	3
parietal pleura	3
skin of hip	3
apex of heart	2
right adrenal gland cortex	2
buccal mucosa cell	2
sural nerve	2
visceral pleura	2
pericardium	2
right coronary artery	2
ventricular zone	2
left adrenal gland	2
male germ line stem cell (sensu Vertebrata) in testis	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TNXB	134	ubiquitous	marker	apex of heart, right adrenal gland cortex, right adrenal gland
COL5A1	248	ubiquitous	marker	stromal cell of endometrium, periodontal ligament, tendon of biceps brachii
COL5A2	266	ubiquitous	marker	tendon of biceps brachii, periodontal ligament, stromal cell of endometrium
ADAMTSL2	159	broad	marker	right atrium auricular region, metanephros cortex, cardiac atrium
ATP6V0D2	144	broad	marker	adult mammalian kidney, buccal mucosa cell, metanephros cortex
SMARCA2	301	ubiquitous	marker	calcaneal tendon, colonic epithelium, cortical plate
TCOF1	265	ubiquitous	marker	sural nerve, oocyte, dorsal motor nucleus of vagus nerve
TGFB2	206	ubiquitous	marker	calcaneal tendon, tendon, cartilage tissue
TGFBR1	269	ubiquitous	marker	saphenous vein, tibia, visceral pleura
TGFBR2	289	ubiquitous	marker	pericardium, tibia, parietal pleura
THBS2	272	ubiquitous	marker	pericardium, right coronary artery, stromal cell of endometrium
C1R	134	ubiquitous	marker	right lobe of liver, liver, right ovary
FKBP14	260	ubiquitous	marker	tibia, corpus epididymis, cartilage tissue
SLC39A13	248	ubiquitous	marker	metanephros cortex, ascending aorta, thoracic aorta
DSE	275	ubiquitous	marker	parietal pleura, calcaneal tendon, germinal epithelium of ovary
ADAMTS2	139	ubiquitous	marker	stromal cell of endometrium, subcutaneous adipose tissue, adipose tissue
COL12A1	240	ubiquitous	marker	tibia, calcaneal tendon, cartilage tissue
COL1A1	298	ubiquitous	marker	stromal cell of endometrium, skin of hip, periodontal ligament
COL1A2	295	ubiquitous	marker	periodontal ligament, stromal cell of endometrium, skin of hip
COL3A1	281	ubiquitous	marker	skin of hip, parietal pleura, visceral pleura
COL6A1	291	ubiquitous	marker	stromal cell of endometrium, tendon of biceps brachii, lower esophagus muscularis layer
ZNF469	211	broad	yes	tibia, upper arm skin, cartilage tissue
CHST14	201	ubiquitous	marker	stromal cell of endometrium, ventricular zone, ileal mucosa
CYP21A2	130	tissue_specific	marker	right adrenal gland, left adrenal gland, right adrenal gland cortex
FBN2	194	ubiquitous	marker	cartilage tissue, placenta, adrenal tissue
FLNA	285	ubiquitous	marker	right coronary artery, popliteal artery, tibial artery
FKBP14-AS1	129		yes	male germ line stem cell (sensu Vertebrata) in testis, bone marrow cell, bone marrow
SMAD3	288	ubiquitous	marker	tendon of biceps brachii, cartilage tissue, hindlimb stylopod muscle
ATP7A	275	ubiquitous	marker	buccal mucosa cell, trabecular bone tissue, upper leg skin
PLOD1	279	ubiquitous	marker	stromal cell of endometrium, smooth muscle tissue, apex of heart

Protein interactions among cohort

Intra-cohort edges: 68.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SMAD3	6,440
RECQL4	6,330
TGFBR2	5,777
COL1A1	5,341
FLNA	5,321
TGFBR1	4,828
SMARCA2	4,237
ATP7A	3,901
COL3A1	3,629
THBS2	3,405

Intra-cohort edges

A	B	Sources
ADAMTS2	ADAMTSL2	string_interaction
ADAMTS2	COL1A1	string_interaction
ADAMTS2	COL3A1	string_interaction
ADAMTS2	COL5A1	string_interaction
ADAMTS2	FKBP14	string_interaction
ADAMTS2	PLOD1	string_interaction
ADAMTSL2	COL6A1	string_interaction
ADAMTSL2	FBN2	string_interaction
B4GALT7	CHST14	string_interaction
B4GALT7	FKBP14	string_interaction
B4GALT7	PRDM5	string_interaction
B4GALT7	SLC39A13	string_interaction
B4GALT7	ZNF469	string_interaction
CHST14	DSE	string_interaction
CHST14	FKBP14	string_interaction
CHST14	PLOD1	string_interaction
CHST14	PRDM5	string_interaction
CHST14	SLC39A13	string_interaction
CHST14	ZNF469	string_interaction
COL12A1	COL1A1	string_interaction
COL12A1	COL5A2	string_interaction
COL12A1	COL6A1	string_interaction
COL12A1	PLOD1	intact
COL12A1	THBS2	string_interaction
COL1A1	COL1A2	intact
COL1A1	COL3A1	string_interaction
COL1A1	COL5A1	intact, string_interaction
COL1A1	COL5A2	string_interaction
COL1A1	COL6A1	string_interaction
COL1A1	FKBP14	string_interaction
COL1A1	PLOD1	intact
COL1A1	THBS2	string_interaction
COL1A2	COL5A1	intact
COL3A1	COL5A1	string_interaction
COL3A1	COL5A2	string_interaction
COL3A1	FBN2	string_interaction
COL3A1	FKBP14	string_interaction
COL3A1	THBS2	string_interaction
COL3A1	TNXB	string_interaction
COL5A1	COL5A2	string_interaction
COL5A1	COL6A1	intact
COL5A1	FKBP14	string_interaction
COL5A1	PLOD1	biogrid_interaction, string_interaction
COL5A1	TNXB	string_interaction
COL5A1	ZNF469	string_interaction
COL5A2	COL6A1	string_interaction
COL5A2	FKBP14	string_interaction
COL5A2	PLOD1	string_interaction
COL5A2	THBS2	string_interaction
COL5A2	TNXB	string_interaction

Structural data

PDB: 22 · AlphaFold-only: 10 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TGFBR1	P36897	44
SMARCA2	P51531	32
FLNA	P21333	26
TGFBR2	P37173	22
ATP7A	Q04656	22
COL1A1	P02452	14
C1R	P00736	12
SMAD3	P84022	12
TGFB2	P61812	11
COL3A1	P02461	11
COL1A2	P08123	5
TNXB	P22105	3
THBS2	P35442	2
FKBP14	Q9NWM8	2
CYP21A2	P08686	2
B4GALT7	Q9UBV7	2
RECQL4	O94761	2
COL5A1	P20908	1
DSE	Q9UL01	1
COL12A1	Q99715	1
COL6A1	P12109	1
PRDM5	Q9NQX1	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PLOD1	Q02809	93.04
ATP6V0D2	Q8N8Y2	85.88
CHST14	Q8NCH0	84.17
SLC39A13	Q96H72	76.33
ADAMTS2	O95450	71.59
ADAMTSL2	Q86TH1	67.10
COL5A2	P05997	53.15
TCOF1	Q13428	41.78
ZNF469	Q96JG9
FBN2	P35556

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 156. Enrichment computed across 33 evidence-associated genes (27 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 27 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Collagen biosynthesis and modifying enzymes	9	56.8×	3e-12	COL5A1, COL5A2, ADAMTS2, COL12A1, COL1A1, COL1A2, COL3A1, COL6A1 (+1 more)
Collagen chain trimerization	7	67.3×	3e-10	COL5A1, COL5A2, COL12A1, COL1A1, COL1A2, COL3A1, COL6A1
ECM proteoglycans	8	44.5×	3e-10	TNXB, COL5A1, COL5A2, TGFB2, COL1A1, COL1A2, COL3A1, COL6A1
Assembly of collagen fibrils and other multimeric structures	7	51.9×	2e-09	COL5A1, COL5A2, COL12A1, COL1A1, COL1A2, COL3A1, COL6A1
Collagen degradation	7	45.5×	4e-09	COL5A1, COL5A2, COL12A1, COL1A1, COL1A2, COL3A1, COL6A1
Fibronectin matrix formation	5	105.7×	2e-08	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1
Syndecan interactions	5	78.3×	9e-08	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1
MET activates PTK2 signaling	5	70.5×	1e-07	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1
Integrin cell surface interactions	6	29.9×	6e-07	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1, COL6A1
Signaling by PDGF	5	47.0×	9e-07	COL5A1, COL5A2, THBS2, COL3A1, COL6A1
Developmental Lineage of Pancreatic Ductal Cells	5	42.3×	1e-06	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1
Loss of Function of TGFBR1 in Cancer	3	253.8×	2e-06	TGFBR1, TGFBR2, SMAD3
Loss of Function of SMAD2/3 in Cancer	3	211.5×	2e-06	TGFBR1, TGFBR2, SMAD3
Signaling by TGF-beta Receptor Complex in Cancer	3	211.5×	2e-06	TGFBR1, TGFBR2, SMAD3
SMAD2/3 Phosphorylation Motif Mutants in Cancer	3	211.5×	2e-06	TGFBR1, TGFBR2, SMAD3
TGFBR1 KD Mutants in Cancer	3	211.5×	2e-06	TGFBR1, TGFBR2, SMAD3
TGFBR3 regulates TGF-beta signaling	3	158.6×	6e-06	TGFB2, TGFBR1, TGFBR2
Signaling by TGFBR3	4	54.6×	6e-06	TGFB2, TGFBR1, TGFBR2, SMAD3
Non-integrin membrane-ECM interactions	5	28.6×	6e-06	COL5A1, COL5A2, COL1A1, COL1A2, COL3A1
TGF-beta receptor signaling activates SMADs	4	48.3×	1e-05	TGFB2, TGFBR1, TGFBR2, SMAD3
GP1b-IX-V activation signalling	3	105.7×	2e-05	COL1A1, COL1A2, FLNA
NCAM1 interactions	4	36.8×	3e-05	COL5A1, COL5A2, COL3A1, COL6A1
Signaling by TGF-beta Receptor Complex	4	29.7×	6e-05	TGFB2, TGFBR1, TGFBR2, SMAD3
Scavenging by Class A Receptors	3	66.8×	7e-05	COL1A1, COL1A2, COL3A1
Loss of Function of TGFBR2 in Cancer	2	282.0×	9e-05	TGFBR1, TGFBR2
TGFBR2 Kinase Domain Mutants in Cancer	2	282.0×	9e-05	TGFBR1, TGFBR2
Defective VWF binding to collagen type I	2	282.0×	9e-05	COL1A1, COL1A2
TGFBR1 LBD Mutants in Cancer	2	211.5×	2e-04	TGFBR1, TGFBR2
Enhanced cleavage of VWF variant by ADAMTS13	2	211.5×	2e-04	COL1A1, COL1A2
Defective VWF cleavage by ADAMTS13 variant	2	211.5×	2e-04	COL1A1, COL1A2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 31 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
collagen fibril organization	13	94.2×	9e-21	TNXB, COL5A1, COL5A2, TGFB2, TGFBR1, ADAMTS2, COL12A1, COL1A1 (+5 more)
positive regulation of epithelial to mesenchymal transition	6	61.5×	1e-07	TNXB, TGFB2, TGFBR1, TGFBR2, COL1A1, SMAD3
skin development	5	71.5×	1e-06	COL5A1, COL5A2, ADAMTS2, COL3A1, ATP7A
blood vessel development	5	60.4×	2e-06	COL5A1, TGFBR2, COL1A1, COL1A2, ATP7A
positive regulation of epithelial to mesenchymal transition involved in endocardial cushion formation	3	407.7×	2e-06	TGFB2, TGFBR1, TGFBR2
transforming growth factor beta receptor signaling pathway	6	30.8×	3e-06	TGFB2, TGFBR1, TGFBR2, COL1A2, COL3A1, SMAD3
cellular response to amino acid stimulus	5	49.4×	4e-06	COL5A2, COL1A1, COL1A2, COL3A1, COL6A1
skeletal system development	6	24.3×	9e-06	COL5A2, TCOF1, TGFB2, TGFBR1, COL1A1, COL1A2
elastic fiber assembly	3	148.3×	5e-05	TNXB, COL3A1, ATP7A
positive regulation of SMAD protein signal transduction	4	49.4×	6e-05	TGFB2, TGFBR1, TGFBR2, SMAD3
negative regulation of endodermal cell differentiation	2	543.6×	1e-04	COL5A1, COL5A2
collagen metabolic process	3	101.9×	1e-04	TNXB, COL1A2, COL6A1
collagen biosynthetic process	3	101.9×	1e-04	COL5A1, COL1A1, PLOD1
supramolecular fiber organization	3	101.9×	1e-04	COL5A1, COL3A1, B4GALT7
activin receptor signaling pathway	3	85.8×	2e-04	TGFBR1, TGFBR2, SMAD3
limb joint morphogenesis	2	362.4×	3e-04	COL3A1, COL6A1
dermatan sulfate proteoglycan metabolic process	2	362.4×	3e-04	DSE, CHST14
wound healing	4	29.4×	3e-04	TGFB2, TGFBR1, COL3A1, SMAD3
regulation of transforming growth factor beta2 production	2	271.8×	5e-04	TGFB2, SMAD3
eye morphogenesis	2	271.8×	5e-04	COL5A1, COL5A2
embryonic cranial skeleton morphogenesis	3	56.2×	5e-04	TGFBR1, TGFBR2, SMAD3
endocardial cushion fusion	2	217.4×	8e-04	TGFB2, TGFBR2
heart development	5	12.7×	9e-04	TGFB2, TGFBR1, TGFBR2, COL3A1, COL6A1
ventricular septum morphogenesis	3	41.8×	0.001	TGFB2, TGFBR1, TGFBR2
trophoblast cell migration	2	155.3×	0.001	TGFBR1, SMAD3
bone trabecula formation	2	135.9×	0.002	COL1A1, FBN2
positive regulation of extracellular matrix assembly	2	120.8×	0.002	TGFBR1, SMAD3
regulation of extracellular matrix organization	2	120.8×	0.002	ZNF469, PRDM5
response to angiotensin	2	120.8×	0.002	COL3A1, SMAD3
epithelial to mesenchymal transition	3	30.2×	0.002	TGFB2, TGFBR1, TGFBR2

Therapeutics

Drugs indicated for this disease

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

Drug	Development status
Celiprolol	Phase 3 (in late-stage trials)
Enzastaurin	Phase 3 (in late-stage trials)
Irbesartan	Phase 3 (in late-stage trials)

Drug target analysis

Approved (phase 4): 4 · Phase ≥3: 5 · Phased (≥1): 10 · Undrugged: 23

Druggability breadth: 18 of 33 evidence-associated genes (55%) 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
TGFBR1	MOMELOTINIB
TGFBR2	PONATINIB
CYP21A2	KETOCONAZOLE
SMAD3	FLUORESCEIN

Top cohort targets by molecule count

Symbol	Molecules	Max phase
TGFBR1	28	4
TGFBR2	22	4
CYP21A2	4	4
SMARCA2	2	2
SMAD3	2	4
TCOF1	1	2
TGFB2	1	2
C1R	1	3
FKBP14	1	2
FLNA	1	2

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
FLUORESCEIN	4	SMAD3
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
NAFAMOSTAT	3	C1R
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2
MOLIBRESIB	2	FLNA, SMARCA2, TCOF1
CAMIBIRSTAT	2	SMARCA2
GALUNISERTIB	2	TGFB2, TGFBR1, TGFBR2
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 11.

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

Symbol	Assays	Type breakdown
TGFBR1	541	Binding:516, Functional:13, ADMET:12
SMARCA2	311	Binding:274, Functional:25, ADMET:12
TGFBR2	188	Binding:188
C1R	29	Binding:29
SMAD3	24	Binding:18, Functional:6
CYP21A2	15	Binding:10, ADMET:5
ATP7A	11	Binding:11
TCOF1	8	Binding:8
COL1A1	8	Binding:8
FLNA	7	Binding:7
COL1A2	4	Functional:4
TGFB2	3	Binding:3
FKBP14	1	Binding:1
CHST14	1	Binding:1
PLOD1	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
TGFBR1	2.7.10.2, 2.7.11.30	non-specific protein-tyrosine kinase, receptor protein serine/threonine kinase
TGFBR2	2.7.10.2	non-specific protein-tyrosine kinase
C1R	3.4.21.41	complement subcomponent C1r
FKBP14	5.2.1.8	peptidylprolyl isomerase
DSE	5.1.3.19	chondroitin-glucuronate 5-epimerase
ADAMTS2	3.4.24.14	procollagen N-endopeptidase
CHST14	2.8.2.35	dermatan 4-sulfotransferase
CYP21A2	1.14.14.16	steroid 21-monooxygenase
ATP7A	7.2.2.8, 7.2.2.9	P-type Cu+ transporter, P-type Cu2+ transporter
B4GALT7	2.4.1.133, 2.4.1.38	xylosylprotein 4-beta-galactosyltransferase, beta-N-acetylglucosaminylglycopeptide beta-1,4-galactosyltransferase
RECQL4	3.6.4.12	DNA helicase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SMARCA2	311
TGFBR1	541
TGFBR2	188

Pharmacogenomics

Cohort genes with a PharmGKB record: 32; 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)
MOMELOTINIB	4	TGFBR1
DABRAFENIB	4	TGFBR1, TGFBR2
NINTEDANIB	4	TGFBR1
DASATINIB	4	TGFBR1, TGFBR2
CRIZOTINIB	4	TGFBR1
PONATINIB	4	TGFBR2
VEMURAFENIB	4	TGFBR2
FEDRATINIB	4	TGFBR2
SORAFENIB	4	TGFBR2
TOVORAFENIB	4	TGFBR2
PAZOPANIB	4	TGFBR2
KETOCONAZOLE	4	CYP21A2
ABIRATERONE	4	CYP21A2
FLUORESCEIN	4	SMAD3
SARACATINIB	3	TGFBR1
CANERTINIB	3	TGFBR1, TGFBR2
TESEVATINIB	3	TGFBR1
CEDIRANIB	3	TGFBR1
LESTAURTINIB	3	TGFBR1, TGFBR2
ALVOCIDIB	3	TGFBR2
NAFAMOSTAT	3	C1R
ORTERONEL	3	CYP21A2
GALETERONE	3	CYP21A2
MOLIBRESIB	2	FLNA, SMARCA2, TCOF1
CAMIBIRSTAT	2	SMARCA2
GALUNISERTIB	2	TGFB2, TGFBR1, TGFBR2
OSI-632	2	TGFBR1
OSI-027	2	TGFBR1
VACTOSERTIB	2	TGFBR1
BMS-690514	2	TGFBR1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	4	TGFBR1, TGFBR2, CYP21A2, SMAD3
B	Phased (≥1) drug, not yet approved	6	SMARCA2, TCOF1, TGFB2, C1R, FKBP14, FLNA
C	Druggable family + PDB, no drug	5	TNXB, DSE, COL12A1, B4GALT7, RECQL4
D	Druggable family + AlphaFold only, no drug	2	ADAMTS2, CHST14
E	Difficult family or no structure, no drug	16	COL5A1, COL5A2, ADAMTSL2, ATP6V0D2, THBS2, SLC39A13, COL1A1, COL1A2, COL3A1, COL6A1 (+6 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PRDM5	0	FKBP14
TNXB	0	—
COL5A1	0	—
COL5A2	0	—
ADAMTSL2	0	—
ATP6V0D2	0	—
THBS2	0	—
SLC39A13	0	—
DSE	0	—
ADAMTS2	0	—
COL12A1	0	—
COL1A1	8	—
COL1A2	4	—
COL3A1	0	—
COL6A1	0	—
ZNF469	0	—
CHST14	1	—
FBN2	0	—
FKBP14-AS1	0	—
ATP7A	11	—
PLOD1	1	—
B4GALT7	0	—
RECQL4	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 49.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	44
PHASE4	2
PHASE3	1
PHASE2	1
EARLY_PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05603741	PHASE4	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04890431	PHASE4	UNKNOWN	Impact of Oxygen Therapy on Fatigue in Patients With Hypermobile-type Ehlers-Danlos Syndrome
NCT05279937	PHASE3	NOT_YET_RECRUITING	The Ultrasound-Guided Dextrose Prolotherapy in Ehlers-Danlos Syndrome Patients
NCT00001966	PHASE2	COMPLETED	Mind-Body Therapy for Pain in Ehlers-Danlos Syndrome
NCT03686748	EARLY_PHASE1	ACTIVE_NOT_RECRUITING	Two Point Discrimination
NCT02050113	Not specified	RECRUITING	Complex Aortic Aneurysm Repair Using Physician Modified Endografts and Custom Made Devices
NCT04036305	Not specified	ACTIVE_NOT_RECRUITING	Local Anesthetic Response in Ehlers-Danlos Syndrome (EDS) and Healthy Volunteers
NCT04133272	Not specified	RECRUITING	Registry of Ehlers-Danlos Syndrome
NCT04806620	Not specified	RECRUITING	Unhide® Project: A Digital Health Platform to Collect Lifestyle Data for Brain Inflammation Research
NCT05389865	Not specified	ACTIVE_NOT_RECRUITING	Proximal Aortopathy in Scotland - Epidemiology and Surgical Outcomes
NCT05561270	Not specified	RECRUITING	Light Exposure on Pain in Hypermobile Ehlers-Danlos Syndrome
NCT05720923	Not specified	ACTIVE_NOT_RECRUITING	Analysis of Muscular Properties in Patients With MFS and EDS
NCT05871216	Not specified	RECRUITING	Functional Instability in Patients Suffering From Collagen Disease and Joint Hypermobility
NCT06074276	Not specified	RECRUITING	The Effects of Almond on Facial Skin Collagen and Wrinkles
NCT06336473	Not specified	NOT_YET_RECRUITING	Evaluation of the Effects of Cross Linking on the Biomechanical Characteristics of Skin Samples From Patients With Classic or Hypermobile Ehlers-Danlos Syndrome
NCT06539169	Not specified	RECRUITING	FLOWER: Following Longitudinal Outcomes With Epidemiology for Rare Diseases
NCT06571721	Not specified	RECRUITING	The Effects of Topical Almond Oil and Tretinoin on Facial Wrinkles
NCT06967727	Not specified	RECRUITING	Registry and Natural History of Epilepsy-Dyskinesia Syndromes
NCT07083713	Not specified	ENROLLING_BY_INVITATION	Group Coaching Study for Life Goals
NCT07151274	Not specified	NOT_YET_RECRUITING	Impact of Ehlers-Danlos Syndrome on Gynaecological Health
NCT07169669	Not specified	NOT_YET_RECRUITING	Multicentre Longitudinal Study of Bone Mineralisation Characteristics in Marfan Syndrome and Ehlers-Danlos Syndrome
NCT07464093	Not specified	NOT_YET_RECRUITING	STABLE Pilates for Hypermobility
NCT00001641	Not specified	COMPLETED	Study of Heritable Connective Tissue Disorders
NCT00270686	Not specified	COMPLETED	Studies of Heritable Disorders of Connective Tissue
NCT01322165	Not specified	COMPLETED	National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions
NCT01356134	Not specified	COMPLETED	Vascular Fundus Changes in Patients With High Probability of Chronic Cerebrospinal Venous Insufficiency (CCSVI)
NCT01367977	Not specified	COMPLETED	Head Circumference Growth in Children With Ehlers-Danlos Syndrome Who Develop Dysautonomia Later in Life
NCT02435745	Not specified	COMPLETED	Obstructive Sleep Apnoea in Ehlers-Danlos Syndrome
NCT02721797	Not specified	UNKNOWN	Origins and Impact of EDS in Connective Tissues and Skin
NCT02985710	Not specified	COMPLETED	Assessment of Small Fiber Neuropathy in Rare Diseases Using Sudoscan
NCT03093493	Not specified	COMPLETED	Genetics of Ehlers-Danlos Syndrome
NCT03330977	Not specified	UNKNOWN	Efficiency Clinical Study of NOVATEX MEDICAL Compression Garments in Patients With Ehlers-Danlos Syndrome
NCT03575182	Not specified	UNKNOWN	Gait Retraining in Patients With Joint Hypermobility Syndrome/Hypermobile Ehlers Danlos Syndrome
NCT03596437	Not specified	UNKNOWN	Study of Arterial Properties by Ultra-high Frequency Ultrasound in Fibromuscular Dysplasia and Vascular Ehlers-Danlos Syndrome
NCT03602482	Not specified	COMPLETED	Standing Cognition and Co-morbidities of POTS Evaluation
NCT03681080	Not specified	COMPLETED	Concentration and Attentional Deficits in POTS and Other Autonomic Neuropathies
NCT03986229	Not specified	COMPLETED	Evaluation of the Effect of Custom Compression Garments on Standing Static Balance in Ehlers Danlos Syndrome
NCT04437589	Not specified	COMPLETED	Opioid-Free Anesthesia for Patients With Joint Hypermobility Syndrome Undergoing Craneo-Cervical Fixation: A Case-series
NCT04680793	Not specified	COMPLETED	Effects of a Multidisciplinary Outpatient Rehabilitation Program in Patients With Ehlers-Danlos Syndrome.
NCT04734041	Not specified	COMPLETED	Integrative Medicine for Hypermobility Spectrum Disorder and Ehlers-Danlos Syndromes (IMforHSDandEDS)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DEXTROSE	4	1
OXYGEN	4	1
CHEMBL423707	0	1