Progressive familial intrahepatic cholestasis

Summary

Progressive familial intrahepatic cholestasis (MONDO:0015762) is a disease (an umbrella term covering 16 Mondo subtypes) caused by variants in ABCB11 and ATP8B1, with 6 cohort genes and 23 clinical trials. Top therapeutic interventions include maralixibat, odevixibat, and cholestyramine.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: ABCB11 (GenCC Strong), ATP8B1 (GenCC Strong)
• Umbrella term: 16 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 69
• Phenotypes (HPO): 14
• Clinical trials: 23

Clinical features

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000952	Jaundice	Very frequent (80-99%)
HP:0001396	Cholestasis	Very frequent (80-99%)
HP:0001508	Failure to thrive	Very frequent (80-99%)
HP:0001744	Splenomegaly	Very frequent (80-99%)
HP:0001928	Abnormality of coagulation	Very frequent (80-99%)
HP:0002024	Malabsorption	Very frequent (80-99%)
HP:0002240	Hepatomegaly	Very frequent (80-99%)
HP:0004322	Short stature	Very frequent (80-99%)
HP:0100543	Cognitive impairment	Very frequent (80-99%)
HP:0001872	Abnormality of thrombocytes	Frequent (30-79%)
HP:0002750	Delayed skeletal maturation	Frequent (30-79%)
HP:0002901	Hypocalcemia	Frequent (30-79%)
HP:0004349	Reduced bone mineral density	Frequent (30-79%)
HP:0002664	Neoplasm	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	progressive familial intrahepatic cholestasis
Mondo ID	MONDO:0015762
OMIM	211600
Orphanet	172
DOID	DOID:0070221
ICD-11	1457142642
NCIT	C84453
UMLS	C0268312
MedGen	75668
GARD	0015255
Is cancer (heuristic)	no

Also known as: cholestasis, progressive familial intrahepatic · PFIC

Data availability: 69 ClinVar variants · 3 GenCC gene-disease records · 15 cell lines.

Disease family

An umbrella term covering 16 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › progressive familial intrahepatic cholestasis

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, 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 (16): progressive familial intrahepatic cholestasis type 1, benign recurrent intrahepatic cholestasis type 1, progressive familial intrahepatic cholestasis type 2, progressive familial intrahepatic cholestasis type 3, hereditary North American Indian childhood cirrhosis, cholestasis, progressive familial intrahepatic, 4, cholestasis, progressive familial intrahepatic, 5, MYO5B-related progressive familial intrahepatic cholestasis, cholestasis, progressive familial intrahepatic, 6, cholestasis, progressive familial intrahepatic, 7, with or without hearing loss, cholestasis, progressive familial intrahepatic, 8, cholestasis, progressive familial intrahepatic, 9, cholestasis, progressive familial intrahepatic, 10, cholestasis, progressive familial intrahepatic, 11, cholestasis, progressive familial intrahepatic, 12, cholestasis, progressive familial intrahepatic, 13

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

69 retrieved; paginated sample, class counts are floors:

25 pathogenic/likely pathogenic, 22 conflicting classifications of pathogenicity, 10 likely pathogenic, 6 pathogenic, 6 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
1446335	NM_003742.4(ABCB11):c.499G>A (p.Ala167Thr)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1456442	NM_003742.4(ABCB11):c.959_960del (p.Ile320fs)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1803125	NM_003742.4(ABCB11):c.99-2A>G	ABCB11	Pathogenic	criteria provided, single submitter
2504002	NM_003742.4(ABCB11):c.3803G>A (p.Arg1268Gln)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
284637	NM_003742.4(ABCB11):c.2012-8T>G	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290081	NM_003742.4(ABCB11):c.1460G>A (p.Arg487His)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
290133	NM_003742.4(ABCB11):c.2296G>A (p.Gly766Arg)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
501603	NM_003742.4(ABCB11):c.2494C>T (p.Arg832Cys)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
594531	NM_003742.4(ABCB11):c.1763C>T (p.Ala588Val)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
598092	NM_003742.4(ABCB11):c.2842C>T (p.Arg948Cys)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
598701	NM_003742.4(ABCB11):c.1550G>A (p.Arg517His)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
639640	NM_003742.4(ABCB11):c.3382C>T (p.Arg1128Cys)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
6590	NM_003742.4(ABCB11):c.890A>G (p.Glu297Gly)	ABCB11	Pathogenic	criteria provided, multiple submitters, no conflicts
951369	NM_003742.4(ABCB11):c.1493T>C (p.Ile498Thr)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
956883	NM_003742.4(ABCB11):c.1409G>A (p.Arg470Gln)	ABCB11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13690	NM_000443.4(ABCB4):c.959C>T (p.Ser320Phe)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2687809	NM_000443.4(ABCB4):c.1436C>T (p.Pro479Leu)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372802	NM_000443.4(ABCB4):c.526C>T (p.Arg176Trp)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
501724	NM_000443.4(ABCB4):c.3486+1G>A	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812754	NM_000443.4(ABCB4):c.449G>A (p.Arg150Lys)	ABCB4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
126382	NM_001374385.1(ATP8B1):c.1993G>T (p.Glu665Ter)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
1878254	NM_001374385.1(ATP8B1):c.922G>A (p.Gly308Ser)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2504019	NM_001374385.1(ATP8B1):c.1210_1213del (p.Leu404fs)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2679858	NM_001374385.1(ATP8B1):c.2418+5G>A	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736747	NM_001374385.1(ATP8B1):c.1336G>A (p.Gly446Arg)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2736748	NM_001374385.1(ATP8B1):c.886C>T (p.Arg296Cys)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
631804	NM_001374385.1(ATP8B1):c.2844del (p.Met947_Cys948insTer)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
7262	NM_001374385.1(ATP8B1):c.923G>T (p.Gly308Val)	ATP8B1	Pathogenic	criteria provided, multiple submitters, no conflicts
7267	NM_001374385.1(ATP8B1):c.1982T>C (p.Ile661Thr)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
918158	NM_001374385.1(ATP8B1):c.1581CTT[2] (p.Phe529del)	ATP8B1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 30 · Orphanet: 18 · 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
ABCB11	Definitive	Autosomal recessive	progressive familial intrahepatic cholestasis type 2	5
ATP8B1	Definitive	Autosomal recessive	progressive familial intrahepatic cholestasis type 1	7
PLEC	Moderate	Autosomal recessive	progressive familial intrahepatic cholestasis	18

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ATP8B1	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ATP8B1	Orphanet:79306	Progressive familial intrahepatic cholestasis type 1
ATP8B1	Orphanet:99960	Benign recurrent intrahepatic cholestasis type 1
ABCB11	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB11	Orphanet:79304	Progressive familial intrahepatic cholestasis type 2
ABCB11	Orphanet:99961	Benign recurrent intrahepatic cholestasis type 2
PLEC	Orphanet:1114	Aplasia cutis congenita
PLEC	Orphanet:158684	Epidermolysis bullosa simplex with pyloric atresia
PLEC	Orphanet:254361	Plectin-related limb-girdle muscular dystrophy R17
PLEC	Orphanet:257	Epidermolysis bullosa simplex with muscular dystrophy
PLEC	Orphanet:79401	PLEC-related intermediate epidermolysis bullosa simplex without extracutaneous involvement
GLB1	Orphanet:309310	Mucopolysaccharidosis type 4B
GLB1	Orphanet:79255	GM1 gangliosidosis type 1
GLB1	Orphanet:79256	GM1 gangliosidosis type 2
GLB1	Orphanet:79257	GM1 gangliosidosis type 3
ABCB4	Orphanet:69663	Low phospholipid-associated cholelithiasis
ABCB4	Orphanet:69665	Intrahepatic cholestasis of pregnancy
ABCB4	Orphanet:79305	Progressive familial intrahepatic cholestasis type 3

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
ATP8B1	HGNC:3706	ENSG00000081923	O43520	Phospholipid-transporting ATPase IC	gencc,clinvar
ABCB11	HGNC:42	ENSG00000073734	O95342	Bile salt export pump	gencc,clinvar
PLEC	HGNC:9069	ENSG00000178209	Q15149	Plectin	gencc
LSR	HGNC:29572	ENSG00000105699	Q86X29	Lipolysis-stimulated lipoprotein receptor	clinvar
GLB1	HGNC:4298	ENSG00000170266	P16278	Beta-galactosidase	clinvar
ABCB4	HGNC:45	ENSG00000005471	P21439	Phosphatidylcholine translocator ABCB4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ATP8B1	Phospholipid-transporting ATPase IC	Catalytic component of a P4-ATPase flippase complex which catalyzes the hydrolysis of ATP coupled to the transport of phospholipids, in particular phosphatidylcholines (PC), from the outer to the inner leaflet of the plasma membrane.
ABCB11	Bile salt export pump	Catalyzes the transport of the major hydrophobic bile salts, such as taurine and glycine-conjugated cholic acid across the canalicular membrane of hepatocytes in an ATP-dependent manner, therefore participates in hepatic bile acid homeosta…
PLEC	Plectin	Interlinks intermediate filaments with microtubules and microfilaments and anchors intermediate filaments to desmosomes or hemidesmosomes.
LSR	Lipolysis-stimulated lipoprotein receptor	Probable role in the clearance of triglyceride-rich lipoprotein from blood.
GLB1	Beta-galactosidase	Cleaves beta-linked terminal galactosyl residues from gangliosides, glycoproteins, and glycosaminoglycans.
ABCB4	Phosphatidylcholine translocator ABCB4	Energy-dependent phospholipid efflux translocator that acts as a positive regulator of biliary lipid secretion.

Protein-family classification

Druggable: 3 · Difficult: 2 · Unknown: 1 · Druggable fraction: 0.5

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
Transporter	2	25.9×	0.012
Antibody/Immunoglobulin	1	4.9×	0.472
Scaffold/PPI	1	2.9×	0.501
Transcription factor	1	1.4×	0.674
Other/Unknown	1	0.3×	0.993

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ATP8B1	Transcription factor	no	7.6.2.1	P_typ_ATPase, P-type_ATPase_IV, ATPase_P-typ_transduc_dom_A_sf
ABCB11	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom
PLEC	Scaffold/PPI	no		Plectin_repeat, SH3_domain, Actinin_actin-bd_CS
LSR	Antibody/Immunoglobulin	yes		Ig_sub, Ig-like_dom, LISCH7
GLB1	Other/Unknown	no		Glycoside_Hdrlase_35, Galactose-bd-like_sf, GH_hydrolase_sf
ABCB4	Transporter	yes		ABC_transporter-like_ATP-bd, AAA+_ATPase, ABC1_TM_dom

Expression context

Cohort genes with no expression data: 0.

6 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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
right lobe of liver	3
cardia of stomach	1
nipple	1
renal medulla	1
liver	1
thymus	1
hindlimb stylopod muscle	1
sural nerve	1
tibial nerve	1
body of pancreas	1
mucosa of transverse colon	1
monocyte	1
mononuclear cell	1
stromal cell of endometrium	1
oocyte	1
secondary oocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ATP8B1	289	ubiquitous	marker	cardia of stomach, nipple, renal medulla
ABCB11	125	tissue_specific	marker	right lobe of liver, liver, thymus
PLEC	283	ubiquitous	marker	sural nerve, hindlimb stylopod muscle, tibial nerve
LSR	234	ubiquitous	marker	mucosa of transverse colon, right lobe of liver, body of pancreas
GLB1	258	ubiquitous	marker	monocyte, mononuclear cell, stromal cell of endometrium
ABCB4	188	broad	marker	right lobe of liver, secondary oocyte, oocyte

Protein interactions among cohort

Intra-cohort edges: 3.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
PLEC	3,529
ABCB11	2,407
ABCB4	2,333
GLB1	1,578
LSR	1,346
ATP8B1	1,296

Intra-cohort edges

A	B	Sources
ABCB11	ABCB4	biogrid_interaction
ABCB11	ATP8B1	string_interaction
ABCB4	ATP8B1	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PLEC	Q15149	14
ATP8B1	O43520	13
ABCB11	O95342	8
GLB1	P16278	8
ABCB4	P21439	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
LSR	Q86X29	57.52

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 6 evidence-associated genes (6 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 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
ABC transporter disorders	2	146.4×	0.004	ABCB11, ABCB4
Defective ABCB11 causes PFIC2 and BRIC2	1	1903.3×	0.007	ABCB11
Defective ABCB4 causes PFIC3, ICP3 and GBD1	1	1903.3×	0.007	ABCB4
MPS IV - Morquio syndrome B (Keratin metabolism)	1	951.7×	0.007	GLB1
MPS IV - Morquio syndrome B (CS/DS degradation)	1	951.7×	0.007	GLB1
Disorders of transmembrane transporters	2	46.4×	0.007	ABCB11, ABCB4
Metabolism of lipids	3	15.8×	0.007	ABCB11, GLB1, ABCB4
Transport of small molecules	3	12.6×	0.007	ATP8B1, LSR, ABCB4
Defective NEU1 causes sialidosis	1	475.8×	0.012	GLB1
Mucopolysaccharidoses	1	317.2×	0.015	GLB1
VLDL clearance	1	317.2×	0.015	LSR
Type I hemidesmosome assembly	1	173.0×	0.025	PLEC
Caspase-mediated cleavage of cytoskeletal proteins	1	158.6×	0.025	PLEC
Diseases of carbohydrate metabolism	1	135.9×	0.025	GLB1
Keratan sulfate degradation	1	119.0×	0.025	GLB1
Diseases associated with N-glycosylation of proteins	1	105.7×	0.025	GLB1
Recycling of bile acids and salts	1	100.2×	0.025	ABCB11
Heparan sulfate/heparin (HS-GAG) metabolism	1	90.6×	0.025	GLB1
CS/DS degradation	1	90.6×	0.025	GLB1
LDL clearance	1	90.6×	0.025	LSR
Keratan sulfate/keratin metabolism	1	82.8×	0.025	GLB1
Bile acid and bile salt metabolism	1	82.8×	0.025	ABCB11
HS-GAG degradation	1	82.8×	0.025	GLB1
Disease	3	6.5×	0.025	ABCB11, GLB1, ABCB4
Metabolism	3	5.8×	0.025	ABCB11, GLB1, ABCB4
Plasma lipoprotein clearance	1	79.3×	0.025	LSR
Synthesis of bile acids and bile salts via 7alpha-hydroxycholesterol	1	76.1×	0.025	ABCB11
Synthesis of bile acids and bile salts	1	68.0×	0.027	ABCB11
Sialic acid metabolism	1	54.4×	0.033	GLB1
Glycosphingolipid metabolism	1	50.1×	0.033	GLB1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
bile acid metabolic process	2	330.4×	6e-04	ATP8B1, ABCB11
xenobiotic transmembrane transport	2	312.1×	6e-04	ATP8B1, ABCB11
bile acid and bile salt transport	2	216.1×	7e-04	ATP8B1, ABCB11
phospholipid translocation	2	208.1×	7e-04	ATP8B1, ABCB4
establishment of skin barrier	2	151.8×	0.001	LSR, PLEC
lipid homeostasis	2	112.3×	0.002	ABCB11, ABCB4
canalicular bile acid transport	1	2808.7×	0.003	ABCB11
protein-containing complex organization	1	2808.7×	0.003	PLEC
positive regulation of bile acid secretion	1	2808.7×	0.003	ABCB11
regulation of plasma membrane organization	1	2808.7×	0.003	ATP8B1
actomyosin contractile ring assembly actin filament organization	1	2808.7×	0.003	PLEC
transmembrane transport	2	56.2×	0.003	ABCB11, ABCB4
skeletal myofibril assembly	1	1404.3×	0.004	PLEC
response to cortisone	1	1404.3×	0.004	GLB1
response to fenofibrate	1	1404.3×	0.004	ABCB4
tricellular tight junction assembly	1	1404.3×	0.004	LSR
leukocyte migration involved in immune response	1	936.2×	0.004	PLEC
keratan sulfate proteoglycan catabolic process	1	936.2×	0.004	GLB1
xenobiotic export from cell	1	936.2×	0.004	ABCB11
protein localization to tricellular tight junction	1	936.2×	0.004	LSR
cellular response to hydrostatic pressure	1	936.2×	0.004	PLEC
response to Thyroglobulin triiodothyronine	1	936.2×	0.004	GLB1
obsolete regulation of bile acid metabolic process	1	936.2×	0.004	ABCB11
positive regulation of phospholipid translocation	1	702.2×	0.004	ABCB4
cellular response to bile acid	1	702.2×	0.004	ABCB4
regulation of chloride transport	1	702.2×	0.004	ATP8B1
vestibulocochlear nerve formation	1	561.7×	0.005	ATP8B1
bile acid secretion	1	561.7×	0.005	ABCB4
tight junction organization	1	561.7×	0.005	PLEC
galactose catabolic process	1	468.1×	0.005	GLB1

Therapeutics

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 3 · Undrugged: 3

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
ABCB11	TELMISARTAN
GLB1	MIGALASTAT

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCB11	327	4
GLB1	1	4
ABCB4	1	2
ATP8B1	0	0
PLEC	0	0
LSR	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GLB1	124	Binding:123, ADMET:1
ABCB11	85	Binding:37, ADMET:31, Functional:13, Toxicity:4
PLEC	12	Binding:12
ABCB4	4	ADMET:3, Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ATP8B1	7.6.2.1	P-type phospholipid transporter

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
GLB1	124

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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)
TELMISARTAN	4	ABCB11
BEXAROTENE	4	ABCB11
PROGESTERONE	4	ABCB11
CLOTRIMAZOLE	4	ABCB11
LATANOPROST	4	ABCB11
SIMVASTATIN	4	ABCB11
METHYSERGIDE	4	ABCB11
VALSARTAN	4	ABCB11
BROMFENAC	4	ABCB11
CLOPIDOGREL BISULFATE	4	ABCB11
DIBUCAINE	4	ABCB11
VALRUBICIN	4	ABCB11
RIMONABANT	4	ABCB11
ARIPIPRAZOLE	4	ABCB11
DICYCLOMINE	4	ABCB11
ACITRETIN	4	ABCB11
TELITHROMYCIN	4	ABCB11
EZETIMIBE	4	ABCB11
SAQUINAVIR	4	ABCB11
CLOBETASOL PROPIONATE	4	ABCB11
AMPRENAVIR	4	ABCB11
MOMETASONE FUROATE	4	ABCB11
NORETHINDRONE	4	ABCB11
ATAZANAVIR	4	ABCB11
FEBUXOSTAT	4	ABCB11
PONATINIB	4	ABCB11
TETRABENAZINE	4	ABCB11
CELECOXIB	4	ABCB11
VILANTEROL	4	ABCB11
EXEMESTANE	4	ABCB11

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	ABCB11, GLB1
B	Phased (≥1) drug, not yet approved	1	ABCB4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	LSR
E	Difficult family or no structure, no drug	2	ATP8B1, PLEC

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ATP8B1	0	ABCB11, ABCB4
PLEC	12	—
LSR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 23.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	14
PHASE3	5
PHASE2	2
PHASE1	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03353454	PHASE3	WITHDRAWN	A Placebo-controlled Study of Maralixibat (SHP625) in Pediatric Subjects With Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT03659916	PHASE3	COMPLETED	Long Term Safety & Efficacy Study Evaluating The Effect of A4250 in Children With PFIC
NCT03905330	PHASE3	COMPLETED	A Study to Evaluate the Efficacy and Safety of Maralixibat in Subjects With Progressive Familial Intrahepatic Cholestasis (MARCH-PFIC)
NCT04185363	PHASE3	COMPLETED	An Extension Study of Maralixibat in Patients With Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT05543187	PHASE3	COMPLETED	A Study of TAK-625 for the Treatment of Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT02057718	PHASE2	COMPLETED	Open Label Study to Evaluate Efficacy and Long Term Safety of LUM001 (Maralixibat) in the Treatment of Cholestatic Liver Disease in Patients With Progressive Familial Intrahepatic Cholestasis
NCT04729751	PHASE2	COMPLETED	A Study to Evaluate the Safety and Tolerability of Maralixibat in Infant Participants With Cholestatic Liver Diseases Including Progressive Familial Intrahepatic Cholestasis (PFIC) and Alagille Syndrome (ALGS).
NCT02963077	PHASE1	COMPLETED	A Safety and Pharmakokinetic Study of A4250 Alone or in Combination With A3384
NCT03082937	PHASE1	COMPLETED	An Open Label, Single-dose, Single Period ADME Study of A4250 in Healthy Subjects
NCT03930810	Not specified	ENROLLING_BY_INVITATION	NAtural Course and Prognosis of PFIC and Effect of Biliary Diversion
NCT06193928	Not specified	RECRUITING	Long-Term SafEty and Clinical Outcomes of LivmArli in Patients in the United States (LEAP-US)
NCT06777914	Not specified	RECRUITING	Familial Intrahepatic Cholestasis-related Genes Associated with Disease Susceptibility in Hepato-biliary Cancers
NCT06778174	Not specified	RECRUITING	Prospective Analysis of the Treatment of Progressive Familial Intrahepatic Cholestasis (TreatFIC)
NCT06781242	Not specified	RECRUITING	Genotype-phenotype Relationship Between Cryptogenic Cholestasis and Familial Intrahepatic Cholestasis
NCT07185919	Not specified	RECRUITING	A Study of the Effectiveness, Safety and the Long-term Outcomes of Participants With Progressive Familial Intrahepatic Cholestasis (PFIC) Who Take Odevixibat (Bylvay) in South Korea
NCT07293897	Not specified	RECRUITING	A Database Study of Maralixibat (TAK-625) in Participants With Alagille Syndrome (ALGS) and Progressive Familial Intrahepatic Cholestasis (PFIC)
NCT07317193	Not specified	RECRUITING	DEFINING THE GENETIC DRIVERS OF ADULT-ONSET CHOLESTATIC LIVER DISEASE
NCT07588880	Not specified	RECRUITING	A Study of the Effectiveness, Safety and the Long-term Outcomes of Participants With Progressive Familial Intrahepatic Cholestasis (PFIC) Who Take Odevixibat (Bylvay) in China
NCT02131623	Not specified	COMPLETED	Validation of the Itch Reported Outcome (ItchRO) Diaries in Pediatric Cholestatic Liver Disease
NCT04071197	Not specified	UNKNOWN	Gastrostomy-Biliary Diversion: Innovative Management for Bile Canalicular Transport Disorders
NCT04483531	Not specified	APPROVED_FOR_MARKETING	Odevixibat for the Treatment of Progressive Familial Intrahepatic Cholestasis
NCT05687474	Not specified	COMPLETED	Baby Detect : Genomic Newborn Screening
NCT05704517	Not specified	UNKNOWN	Progressive Familial Intrahepatic Cholestasis in Indian Children - Establishing an Indian PFIC Registry

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
MARALIXIBAT	4	8
ODEVIXIBAT	4	3
CHOLESTYRAMINE	4	1