Autoinflammatory syndrome

Summary

Autoinflammatory syndrome (MONDO:0019751) is a disease (an umbrella term covering 37 Mondo subtypes) caused by variants in DPP9, GIMAP6, IL36RN, and 1 other genes, with 42 cohort genes and 4 clinical trials. The dominant Reactome pathway is Lanosterol biosynthesis (3 cohort genes). Top therapeutic interventions include givinostat.

At a glance

• Causal genes: DPP9 (GenCC Strong), GIMAP6 (GenCC Strong), IL36RN (GenCC Strong), UNC93B1 (GenCC Strong)
• Umbrella term: 37 Mondo subtypes
• Cohort genes: 42
• ClinVar variants: 1,482
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autoinflammatory syndrome
Mondo ID	MONDO:0019751
Orphanet	93665
DOID	DOID:0051000
ICD-10-CM	M04-M04
NCIT	C119050
UMLS	C3890737
MedGen	855741
MedDRA	10072220
Is cancer (heuristic)	no

Data availability: 1,482 ClinVar variants · 9 GenCC gene-disease records.

Disease family

An umbrella term covering 37 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › syndromic disease › autoinflammatory 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, 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 (37): cherubism, chronic recurrent multifocal osteomyelitis, Pelger-Huet-like anomaly and episodic fever with abdominal pain, pyogenic arthritis-pyoderma gangrenosum-acne syndrome, psoriasis 14, pustular, autoinflammation-PLCG2-associated antibody deficiency-immune dysregulation, periodic fever syndrome, infantile onset panniculitis with uveitis and systemic granulomatosis, idiopathic recurrent pericarditis, pyoderma gangrenosum-acne-suppurative hidradenitis syndrome, neonatal inflammatory skin and bowel disease, magic syndrome, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, Schnitzler syndrome, PFAPA syndrome, pyoderma gangrenosum, SAPHO syndrome, sarcoidosis, adult-onset Still disease, systemic-onset juvenile idiopathic arthritis, VEXAS syndrome, autoinflammatory syndrome, familial, Behcet-like, CEBPE-associated autoinflammation-immunodeficiency-neutrophil dysfunction syndrome, type 1 interferonopathy, autoinflammatory disease, X-linked, autoinflammatory syndrome with immunodeficiency, early-onset pulmonary and cutaneous vasculitis, autoinflammatory syndrome due to TBK1 deficiency, F12-associated cold autoinflammatory syndrome, neonatal-onset severe multisystemic autoinflammatory disease with increased IL18, SAMD9L-associated autoinflammatory syndrome, autoinflammatory syndrome of childhood, autoinflammatory disease, systemic, with vasculitis, granulomatous autoinflammatory syndrome of childhood, autoinflammatory disease, multisystem, with immune dysregulation, X-linked, PAPASH syndrome, Sharpin-related autoinflammatory syndrome

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:

301 uncertain significance, 183 conflicting classifications of pathogenicity, 38 benign/likely benign, 21 likely pathogenic, 20 likely benign, 17 pathogenic/likely pathogenic, 10 benign, 9 pathogenic, 1 conflicting classifications of pathogenicity; risk factor

ClinVar	Variant (HGVS)	Gene	Classification	Review
1076271	NM_001282225.2(ADA2):c.139G>C (p.Gly47Arg)	ADA2	Pathogenic	criteria provided, multiple submitters, no conflicts
120299	NM_001282225.2(ADA2):c.1358A>G (p.Tyr453Cys)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120302	NM_001282225.2(ADA2):c.336C>G (p.His112Gln)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120303	NM_001282225.2(ADA2):c.506G>A (p.Arg169Gln)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
120304	NM_001282225.2(ADA2):c.139G>A (p.Gly47Arg)	ADA2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
224763	NM_003664.5(AP3B1):c.177del (p.Lys59fs)	AP3B1	Pathogenic	criteria provided, multiple submitters, no conflicts
16740	NM_001972.4(ELANE):c.182C>T (p.Ala61Val)	ELANE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694293	NM_001375808.2(LPIN2):c.1204_1205dup (p.Asp402fs)	LPIN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11929	NM_000431.4(MVK):c.1129G>A (p.Val377Ile)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11932	NM_000431.4(MVK):c.803T>C (p.Ile268Thr)	MVK	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
11934	NM_000431.4(MVK):c.928G>A (p.Val310Met)	MVK	Pathogenic	criteria provided, multiple submitters, no conflicts
13709	NM_001083116.3(PRF1):c.1122G>A (p.Trp374Ter)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
13711	NM_001083116.3(PRF1):c.673C>T (p.Arg225Trp)	PRF1	Pathogenic	criteria provided, multiple submitters, no conflicts
1406224	NM_001083116.3(PRF1):c.902C>A (p.Ser301Ter)	PRF1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1385379	NM_148919.4(PSMB8):c.481C>T (p.Gln161Ter)	PSMB8	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1074135	NM_183235.3(RAB27A):c.400_401del (p.Lys134fs)	RAB27A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694156	NM_183235.3(RAB27A):c.239+1G>T	RAB27A	Pathogenic	criteria provided, multiple submitters, no conflicts
1455661	NM_002351.5(SH2D1A):c.2T>C (p.Met1Thr)	SH2D1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1070748	NM_199242.3(UNC13D):c.1055+1G>A	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1411105	NM_199242.3(UNC13D):c.1807G>T (p.Glu603Ter)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1454697	NM_199242.3(UNC13D):c.640C>T (p.Arg214Ter)	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
1694203	NM_199242.3(UNC13D):c.1229_1230dup (p.Arg411fs)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694206	NM_199242.3(UNC13D):c.1947G>A (p.Trp649Ter)	UNC13D	Pathogenic	criteria provided, single submitter
1694217	NM_199242.3(UNC13D):c.570-2A>T	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1999	NM_199242.3(UNC13D):c.1389+1G>A	UNC13D	Pathogenic	criteria provided, multiple submitters, no conflicts
2000	NM_199242.3(UNC13D):c.766C>T (p.Arg256Ter)	UNC13D	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1694267	NM_001972.4(ELANE):c.159C>G (p.His53Gln)	ELANE	Likely pathogenic	criteria provided, single submitter
1694275	NM_001972.4(ELANE):c.91del (p.Val31fs)	ELANE	Likely pathogenic	criteria provided, single submitter
1694277	NM_173841.3(IL1RN):c.10+2T>C	IL1RN	Likely pathogenic	criteria provided, single submitter
1694318	NM_000081.4(LYST):c.2741_2742del (p.Glu914fs)	LYST	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 32 · Orphanet: 57 · 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
DPP9	Strong	Autosomal dominant	autoinflammatory syndrome	3
GIMAP6	Strong	Autosomal recessive	autoinflammatory syndrome
IL36RN	Strong	Semidominant	autoinflammatory syndrome	8
UNC93B1	Strong	Autosomal dominant	autoinflammatory syndrome	3
FGL2	Moderate	Autosomal recessive	autoinflammatory syndrome
PMVK	Moderate	Autosomal recessive	autoinflammatory syndrome	8
PSTPIP1	Moderate	Autosomal dominant	autoinflammatory syndrome	7
PTPN1	Limited	Autosomal dominant	autoinflammatory syndrome

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
IL36RN	Orphanet:163927	Pustulosis palmaris et plantaris
IL36RN	Orphanet:163931	Acrodermatitis continua of Hallopeau
IL36RN	Orphanet:247353	Generalized pustular psoriasis
IL36RN	Orphanet:404546	DITRA
PSTPIP1	Orphanet:251523	Hyperzincemia and hypercalprotectinemia
PSTPIP1	Orphanet:69126	PAPA syndrome
UNC93B1	Orphanet:1930	Herpes simplex virus encephalitis
DPP9	Orphanet:2032	Idiopathic pulmonary fibrosis
PMVK	Orphanet:735	Porokeratosis of Mibelli
SGSH	Orphanet:79269	Sanfilippo syndrome type A
SH2D1A	Orphanet:538931	X-linked lymphoproliferative disease due to SAP deficiency
SLC7A7	Orphanet:470	Lysinuric protein intolerance
STX11	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
STXBP2	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
TNFRSF1A	Orphanet:32960	Tumor necrosis factor receptor 1 associated periodic syndrome
TNFRSF1A	Orphanet:329967	Intermittent hydrarthrosis
CD27	Orphanet:238505	Combined immunodeficiency due to CD27 deficiency
LPIN2	Orphanet:77297	Majeed syndrome
NLRP3	Orphanet:1451	CINCA syndrome
NLRP3	Orphanet:47045	Familial cold urticaria
NLRP3	Orphanet:575	Muckle-Wells syndrome
NLRP3	Orphanet:647815	Keratitis fugax hereditaria
NLRC4	Orphanet:436166	Periodic fever-infantile enterocolitis-autoinflammatory syndrome
NLRC4	Orphanet:576349	NLRC4-related familial cold autoinflammatory syndrome
CARD14	Orphanet:2897	Pityriasis rubra pilaris
ADA2	Orphanet:124	Diamond-Blackfan anemia
ADA2	Orphanet:404553	Deficiency of adenosine deaminase 2
ADA2	Orphanet:820	Sneddon syndrome
MMAB	Orphanet:79311	Vitamin B12-responsive methylmalonic acidemia type cblB
LYST	Orphanet:167	Chédiak-Higashi syndrome
LYST	Orphanet:352723	Attenuated Chédiak-Higashi syndrome
NLRP12	Orphanet:247868	NLRP12-associated hereditary periodic fever syndrome
UNC13D	Orphanet:540	Familial hemophagocytic lymphohistiocytosis
STING1	Orphanet:425120	STING-associated vasculopathy with onset in infancy
STING1	Orphanet:481662	Familial Chilblain lupus
ELANE	Orphanet:2686	Cyclic neutropenia
ELANE	Orphanet:486	Autosomal dominant severe congenital neutropenia
HMGCR	Orphanet:653725	Autosomal recessive limb-girdle muscular dystrophy, type 28
NOD2	Orphanet:90340	Blau syndrome
AP3B1	Orphanet:664500	Hermansky-Pudlak syndrome due to AP3B1 deficiency
XIAP	Orphanet:538934	X-linked lymphoproliferative disease due to XIAP deficiency
IL1RN	Orphanet:210115	Sterile multifocal osteomyelitis with periostitis and pustulosis
ITK	Orphanet:538963	Combined immunodeficiency due to ITK deficiency
MEFV	Orphanet:117	Behçet disease
MEFV	Orphanet:3243	Sweet syndrome
MEFV	Orphanet:329967	Intermittent hydrarthrosis
MEFV	Orphanet:342	Familial Mediterranean fever
MVK	Orphanet:29	Mevalonic aciduria
MVK	Orphanet:343	Hyperimmunoglobulinemia D with periodic fever
MVK	Orphanet:735	Porokeratosis of Mibelli

Cohort genes → proteins

42 cohort genes, 40 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	42

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
IL36RN	HGNC:15561	ENSG00000136695	Q9UBH0	Interleukin-36 receptor antagonist protein	gencc,clinvar
PSTPIP1	HGNC:9580	ENSG00000140368	O43586	Proline-serine-threonine phosphatase-interacting protein 1	gencc,clinvar
UNC93B1	HGNC:13481	ENSG00000110057	Q9H1C4	Protein unc-93 homolog B1	gencc
DPP9	HGNC:18648	ENSG00000142002	Q86TI2	Dipeptidyl peptidase 9	gencc
GIMAP6	HGNC:21918	ENSG00000133561	Q6P9H5	GTPase IMAP family member 6	gencc
FGL2	HGNC:3696	ENSG00000127951	Q14314	Fibroleukin	gencc
PMVK	HGNC:9141	ENSG00000163344	Q15126	Phosphomevalonate kinase	gencc
PTPN1	HGNC:9642	ENSG00000196396	P18031	Tyrosine-protein phosphatase non-receptor type 1	gencc
SGSH	HGNC:10818	ENSG00000181523	P51688	N-sulphoglucosamine sulphohydrolase	clinvar
SH2D1A	HGNC:10820	ENSG00000183918	O60880	SH2 domain-containing protein 1A	clinvar
SLC7A7	HGNC:11065	ENSG00000155465	Q9UM01	Y+L amino acid transporter 1	clinvar
STX11	HGNC:11429	ENSG00000135604	O75558	Syntaxin-11	clinvar
STXBP2	HGNC:11445	ENSG00000076944	Q15833	Syntaxin-binding protein 2	clinvar
TNFRSF1A	HGNC:11916	ENSG00000067182	P19438	Tumor necrosis factor receptor superfamily member 1A	clinvar
CD27	HGNC:11922	ENSG00000139193	P26842	CD27 antigen	clinvar
LPIN2	HGNC:14450	ENSG00000101577	Q92539	Phosphatidate phosphatase LPIN2	clinvar
NLRP3	HGNC:16400	ENSG00000162711	Q96P20	NACHT, LRR and PYD domains-containing protein 3	clinvar
NLRC4	HGNC:16412	ENSG00000091106	Q9NPP4	NLR family CARD domain-containing protein 4	clinvar
CARD14	HGNC:16446	ENSG00000141527	Q9BXL6	Caspase recruitment domain-containing protein 14	clinvar
ADA2	HGNC:1839	ENSG00000093072	Q9NZK5	Adenosine deaminase 2	clinvar
MMAB	HGNC:19331	ENSG00000139428	Q96EY8	Corrinoid adenosyltransferase MMAB	clinvar
LYST	HGNC:1968	ENSG00000143669	Q99698	Lysosomal-trafficking regulator	clinvar
NLRP12	HGNC:22938	ENSG00000142405	P59046	NACHT, LRR and PYD domains-containing protein 12	clinvar
UNC13D	HGNC:23147	ENSG00000092929	Q70J99	Protein unc-13 homolog D	clinvar
PALD1	HGNC:23530	ENSG00000107719	Q9ULE6	Paladin	clinvar
FAM227B	HGNC:26543	ENSG00000166262	Q96M60	Protein FAM227B	clinvar
STING1	HGNC:27962	ENSG00000184584	Q86WV6	Stimulator of interferon genes protein	clinvar
ELANE	HGNC:3309	ENSG00000197561	P08246	Neutrophil elastase	clinvar
CD27-AS1	HGNC:43896	ENSG00000215039		CD27 antisense RNA 1	clinvar
HMGCR	HGNC:5006	ENSG00000113161	P04035	3-hydroxy-3-methylglutaryl-coenzyme A reductase	clinvar
NOD2	HGNC:5331	ENSG00000167207	Q9HC29	Nucleotide-binding oligomerization domain-containing protein 2	clinvar
CYLD-AS1	HGNC:55352	ENSG00000261644		CYLD antisense RNA 1	clinvar
AP3B1	HGNC:566	ENSG00000132842	O00203	AP-3 complex subunit beta-1	clinvar
XIAP	HGNC:592	ENSG00000101966	P98170	E3 ubiquitin-protein ligase XIAP	clinvar
IL1RN	HGNC:6000	ENSG00000136689	P18510	Interleukin-1 receptor antagonist protein	clinvar
ITK	HGNC:6171	ENSG00000113263	Q08881	Tyrosine-protein kinase ITK/TSK	clinvar
MEFV	HGNC:6998	ENSG00000103313	O15553	Pyrin	clinvar
MVK	HGNC:7530	ENSG00000110921	Q03426	Mevalonate kinase	clinvar
BLOC1S6	HGNC:8549	ENSG00000104164	Q9UL45	Biogenesis of lysosome-related organelles complex 1 subunit 6	clinvar
PRF1	HGNC:9360	ENSG00000180644	P14222	Perforin-1	clinvar
PSMB8	HGNC:9545	ENSG00000204264	P28062	Proteasome subunit beta type-8	clinvar
RAB27A	HGNC:9766	ENSG00000069974	P51159	Ras-related protein Rab-27A	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
IL36RN	Interleukin-36 receptor antagonist protein	Inhibits the activity of interleukin-36 (IL36A,IL36B and IL36G) by binding to receptor IL1RL2 and preventing its association with the coreceptor IL1RAP for signaling.
PSTPIP1	Proline-serine-threonine phosphatase-interacting protein 1	Involved in regulation of the actin cytoskeleton.
UNC93B1	Protein unc-93 homolog B1	Plays an important role in innate and adaptive immunity by regulating nucleotide-sensing Toll-like receptor (TLR) signaling.
DPP9	Dipeptidyl peptidase 9	Dipeptidyl peptidase that cleaves off N-terminal dipeptides from proteins having a Pro or Ala residue at position 2.
FGL2	Fibroleukin	May play a role in physiologic lymphocyte functions at mucosal sites.
PMVK	Phosphomevalonate kinase	Catalyzes the reversible ATP-dependent phosphorylation of mevalonate 5-phosphate to produce mevalonate diphosphate and ADP, a key step in the mevalonic acid mediated biosynthesis of isopentenyl diphosphate and other polyisoprenoid metaboli…
PTPN1	Tyrosine-protein phosphatase non-receptor type 1	Tyrosine-protein phosphatase which acts as a regulator of endoplasmic reticulum unfolded protein response.
SGSH	N-sulphoglucosamine sulphohydrolase	Catalyzes a step in lysosomal heparan sulfate degradation.
SH2D1A	SH2 domain-containing protein 1A	Cytoplasmic adapter regulating receptors of the signaling lymphocytic activation molecule (SLAM) family such as SLAMF1, CD244, LY9, CD84, SLAMF6 and SLAMF7.
SLC7A7	Y+L amino acid transporter 1	Heterodimer with SLC3A2, that functions as an antiporter which operates as an efflux route by exporting cationic amino acids from inside the cells in exchange with neutral amino acids plus sodium ions and may participate in nitric oxide sy…
STX11	Syntaxin-11	SNARE that acts to regulate protein transport between late endosomes and the trans-Golgi network.
STXBP2	Syntaxin-binding protein 2	Involved in intracellular vesicle trafficking and vesicle fusion with membranes.
TNFRSF1A	Tumor necrosis factor receptor superfamily member 1A	Receptor for TNFSF2/TNF and homotrimeric TNFSF1/lymphotoxin-alpha.
CD27	CD27 antigen	Costimulatory immune-checkpoint receptor expressed at the surface of T-cells, NK-cells and B-cells which binds to and is activated by its ligand CD70/CD27L expressed by B-cells.
LPIN2	Phosphatidate phosphatase LPIN2	Acts as a magnesium-dependent phosphatidate phosphatase enzyme which catalyzes the conversion of phosphatidic acid to diacylglycerol during triglyceride, phosphatidylcholine and phosphatidylethanolamine biosynthesis in the endoplasmic reti…
NLRP3	NACHT, LRR and PYD domains-containing protein 3	Sensor component of the NLRP3 inflammasome, which mediates inflammasome activation in response to defects in membrane integrity, leading to secretion of inflammatory cytokines IL1B and IL18 and pyroptosis.
NLRC4	NLR family CARD domain-containing protein 4	Key component of inflammasomes that indirectly senses specific proteins from pathogenic bacteria and fungi and responds by assembling an inflammasome complex that promotes caspase-1 activation, cytokine production and macrophage pyroptosis.
CARD14	Caspase recruitment domain-containing protein 14	Acts as a scaffolding protein that can activate the inflammatory transcription factor NF-kappa-B and p38/JNK MAP kinase signaling pathways.
ADA2	Adenosine deaminase 2	Adenosine deaminase that may contribute to the degradation of extracellular adenosine, a signaling molecule that controls a variety of cellular responses.
MMAB	Corrinoid adenosyltransferase MMAB	Converts cob(I)alamin to adenosylcobalamin (adenosylcob(III)alamin), a coenzyme for methylmalonyl-CoA mutase, therefore participates in the final step of the vitamin B12 conversion.
LYST	Lysosomal-trafficking regulator	Adapter protein that regulates and/or fission of intracellular vesicles such as lysosomes.
NLRP12	NACHT, LRR and PYD domains-containing protein 12	Plays an essential role as an potent mitigator of inflammation.
UNC13D	Protein unc-13 homolog D	Plays a role in cytotoxic granule exocytosis in lymphocytes.
STING1	Stimulator of interferon genes protein	Facilitator of innate immune signaling that acts as a sensor of cytosolic DNA from bacteria and viruses and promotes the production of type I interferon (IFN-alpha and IFN-beta).
ELANE	Neutrophil elastase	Serine protease that modifies the functions of natural killer cells, monocytes and granulocytes.
HMGCR	3-hydroxy-3-methylglutaryl-coenzyme A reductase	Catalyzes the conversion of (3S)-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid, the rate-limiting step in the synthesis of cholesterol and other isoprenoids, thus plays a critical role in cellular cholesterol homeostasis.
NOD2	Nucleotide-binding oligomerization domain-containing protein 2	Pattern recognition receptor (PRR) that detects bacterial peptidoglycan fragments and other danger signals and plays an important role in gastrointestinal immunity.
AP3B1	AP-3 complex subunit beta-1	Subunit of non-clathrin- and clathrin-associated adaptor protein complex 3 (AP-3) that plays a role in protein sorting in the late-Golgi/trans-Golgi network (TGN) and/or endosomes.
XIAP	E3 ubiquitin-protein ligase XIAP	Multi-functional protein which regulates not only caspases and apoptosis, but also modulates inflammatory signaling and immunity, copper homeostasis, mitogenic kinase signaling, cell proliferation, as well as cell invasion and metastasis.
IL1RN	Interleukin-1 receptor antagonist protein	Anti-inflammatory antagonist of interleukin-1 family of proinflammatory cytokines such as interleukin-1beta/IL1B and interleukin-1alpha/IL1A.
ITK	Tyrosine-protein kinase ITK/TSK	Tyrosine kinase that plays an essential role in regulation of the adaptive immune response.
MEFV	Pyrin	Involved in the regulation of innate immunity and the inflammatory response in response to IFNG/IFN-gamma.
MVK	Mevalonate kinase	Catalyzes the phosphorylation of mevalonate to mevalonate 5-phosphate, a key step in isoprenoid and cholesterol biosynthesis.
BLOC1S6	Biogenesis of lysosome-related organelles complex 1 subunit 6	Component of the BLOC-1 complex, a complex that is required for normal biogenesis of lysosome-related organelles (LRO), such as platelet dense granules and melanosomes.
PRF1	Perforin-1	Pore-forming protein that plays a key role in granzyme-mediated programmed cell death, and in defense against virus-infected or neoplastic cells.
PSMB8	Proteasome subunit beta type-8	The proteasome is a multicatalytic proteinase complex which is characterized by its ability to cleave peptides with Arg, Phe, Tyr, Leu, and Glu adjacent to the leaving group at neutral or slightly basic pH.
RAB27A	Ras-related protein Rab-27A	The small GTPases Rab are key regulators of intracellular membrane trafficking, from the formation of transport vesicles to their fusion with membranes.

Protein-family classification

Druggable: 13 · Difficult: 7 · Unknown: 22 · Druggable fraction: 0.31

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
Phosphatase	3	6.0×	0.123
Complement	1	6.4×	0.603
Transporter	1	1.9×	0.603
Protease	2	1.7×	0.603
Scaffold/PPI	4	1.6×	0.603
Kinase	2	1.3×	0.603
Enzyme (other)	4	1.1×	0.603
Other/Unknown	22	0.9×	0.819
Transcription factor	3	0.6×	0.898

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
IL36RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
PSTPIP1	Scaffold/PPI	no		FCH_dom, SH3_domain, AH/BAR_dom_sf
UNC93B1	Other/Unknown	no		UNC93B1
DPP9	Protease	yes	3.4.13.19	Peptidase_S9_cat, Peptidase_S9B_N, AB_hydrolase_fold
GIMAP6	Other/Unknown	no		G_AIG1, P-loop_NTPase, GIMA/IAN/Toc
FGL2	Other/Unknown	no		Fibrinogen_a/b/g_C_dom, Fibrinogen_a/b/g_C_1, Fibrinogen_CS
PMVK	Enzyme (other)	yes	2.7.4.2	Pmev_kin_anim, P-loop_NTPase
PTPN1	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
SGSH	Phosphatase	yes	3.10.1.1	Sulfatase_N, Alkaline_phosphatase_core_sf, Sulfatase_CS
SH2D1A	Scaffold/PPI	no		SH2, SH2_prot_1A, SH2D1A_SH2
SLC7A7	Transporter	yes		AA/rel_permease1, AminoAcid_Transporter
STX11	Other/Unknown	no		T_SNARE_dom, Syntaxin_N, Syntaxin/epimorphin_CS
STXBP2	Other/Unknown	no		Sec1-like, Sec1-like_dom2, Sec1-like_sf
TNFRSF1A	Other/Unknown	no		Death_dom, TNFR/NGFR_Cys_rich_reg, DEATH-like_dom_sf
CD27	Other/Unknown	no		TNFR/NGFR_Cys_rich_reg, TNFR_7, TNFRSF7_N
LPIN2	Other/Unknown	no		Lipin_N, LNS2, LIPIN
NLRP3	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
NLRC4	Transcription factor	no		CARD, NACHT_NTPase, DEATH-like_dom_sf
CARD14	Scaffold/PPI	no		CARD, PDZ, Guanylate_kin-like_dom
ADA2	Enzyme (other)	yes	3.5.4.4	A_deaminase_dom, Ado/ade_deaminase, ADGF
MMAB	Enzyme (other)	yes	2.5.1.17	CblAdoTrfase-like, PduO-typ, CblAdoTrfase-like_sf
LYST	Scaffold/PPI	no		BEACH_dom, WD40_rpt, PH-like_dom_sf
NLRP12	Other/Unknown	no		Leu-rich_rpt, DAPIN, NACHT_NTPase
UNC13D	Other/Unknown	no		C2_dom, MUN_dom, Munc13_1
PALD1	Phosphatase	yes		Tyr_Pase_cat, Prot-tyrosine_phosphatase-like, PTP
FAM227B	Other/Unknown	no		FAM227
STING1	Other/Unknown	no		STING, STING_C_sf, STING_C_chordates
ELANE	Protease	yes	3.4.21.37	Trypsin_dom, Peptidase_S1A, Peptidase_S1_PA
CD27-AS1	Other/Unknown	no
HMGCR	Enzyme (other)	yes	1.1.1.34	SSD, HMG_CoA_Rdtase, HMG_CoA_Rdtase_eu_arc
NOD2	Other/Unknown	no		CARD, Leu-rich_rpt, NACHT_NTPase
CYLD-AS1	Other/Unknown	no
AP3B1	Other/Unknown	no		Clathrin/coatomer_adapt-like_N, ARM-like, B-adaptin_app_sub_C
XIAP	Transcription factor	no		BIR_rpt, Znf_RING, DEATH-like_dom_sf
IL1RN	Other/Unknown	no		IL-1_fam, IL-1RA/IL-36, IL1/FGF
ITK	Kinase	yes	2.7.10.2	Prot_kinase_dom, SH2, Ser-Thr/Tyr_kinase_cat_dom
MEFV	Transcription factor	no		Znf_B-box, B30.2/SPRY, SPRY_dom
MVK	Kinase	yes	2.7.1.36	GHMP_knse_ATP-bd_CS, GHMP_kinase_N_dom, Mev_gal_kin
BLOC1S6	Other/Unknown	no		BLOC-1_pallidin, Snapin/Pallidin/Snn1
PRF1	Complement	yes		C2_dom, MACPF_CS, MACPF
PSMB8	Other/Unknown	no		Pept_T1A_subB, Proteasome_sua/b, Proteasome_bsu_CS
RAB27A	Other/Unknown	no		Small_GTPase, Small_GTP-bd, P-loop_NTPase

Expression context

Cohort genes with no expression data: 0.

39 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)	42
unknown	0

Top tissues across cohort

Tissue	Cohort genes
monocyte	16
leukocyte	13
granulocyte	11
mononuclear cell	8
right lobe of liver	5
lower esophagus mucosa	4
spleen	4
blood	4
buccal mucosa cell	4
thymus	3
tendon of biceps brachii	3
lower lobe of lung	2
right lung	2
lymph node	2
bone marrow cell	2
amniotic fluid	1
gingiva	1
upper arm skin	1
gastrocnemius	1
hindlimb stylopod muscle	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
IL36RN	106	tissue_specific	yes	amniotic fluid, upper arm skin, gingiva
PSTPIP1	179	broad	marker	granulocyte, monocyte, leukocyte
UNC93B1	174	ubiquitous	marker	granulocyte, monocyte, leukocyte
DPP9	236	ubiquitous	marker	gastrocnemius, hindlimb stylopod muscle, right lobe of liver
GIMAP6	257	broad	marker	granulocyte, lower lobe of lung, superficial temporal artery
FGL2	275	broad	marker	monocyte, mononuclear cell, leukocyte
PMVK	283	ubiquitous	marker	apex of heart, lower esophagus mucosa, right lobe of liver
PTPN1	232	ubiquitous	marker	upper lobe of left lung, right lung, upper lobe of lung
SGSH	272	ubiquitous	marker	left adrenal gland, left adrenal gland cortex, adrenal cortex
SH2D1A	170	broad	marker	thymus, lymph node, granulocyte
SLC7A7	215	ubiquitous	marker	secondary oocyte, monocyte, mononuclear cell
STX11	193	broad	marker	monocyte, mononuclear cell, leukocyte
STXBP2	227	ubiquitous	marker	granulocyte, monocyte, leukocyte
TNFRSF1A	292	ubiquitous	marker	tendon of biceps brachii, gall bladder, left uterine tube
CD27	132	tissue_specific	marker	lymph node, spleen, vermiform appendix
LPIN2	281	ubiquitous	marker	jejunal mucosa, liver, right lobe of liver
NLRP3	172	broad	marker	monocyte, mononuclear cell, leukocyte
NLRC4	166	broad	marker	monocyte, leukocyte, blood
CARD14	179	tissue_specific	yes	lower esophagus mucosa, skin of leg, skin of abdomen
ADA2	254	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
MMAB	235	ubiquitous	marker	right lobe of liver, right adrenal gland cortex, right adrenal gland
LYST	278	ubiquitous	marker	monocyte, mononuclear cell, leukocyte
NLRP12	117	tissue_specific	marker	blood, monocyte, leukocyte
UNC13D	195	ubiquitous	marker	granulocyte, bone marrow cell, spleen
PALD1	194	broad	marker	tendon of biceps brachii, medial globus pallidus, right lung
FAM227B	171	ubiquitous	marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, primordial germ cell in gonad
STING1	134	ubiquitous	marker	right uterine tube, olfactory segment of nasal mucosa, granulocyte
ELANE	124	tissue_specific	marker	bone marrow, bone marrow cell, monocyte
CD27-AS1	137	ubiquitous	marker	thymus, spinal cord, C1 segment of cervical spinal cord
HMGCR	286	ubiquitous	marker	adrenal tissue, ventricular zone, cortical plate

Protein interactions among cohort

Intra-cohort edges: 48.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
XIAP	5,252
HMGCR	5,062
TNFRSF1A	4,523
PTPN1	4,220
NLRP3	3,797
NOD2	3,527
MVK	3,424
PRF1	3,299
PSMB8	3,188
ELANE	2,758

Intra-cohort edges

A	B	Sources
AP3B1	BLOC1S6	string_interaction
AP3B1	LYST	string_interaction
AP3B1	NLRP3	biogrid_interaction
AP3B1	STX11	string_interaction
AP3B1	STXBP2	string_interaction
AP3B1	UNC13D	string_interaction
BLOC1S6	LYST	string_interaction
BLOC1S6	STX11	biogrid_interaction, intact
CARD14	IL36RN	string_interaction
CARD14	NOD2	string_interaction
HMGCR	MVK	string_interaction
HMGCR	PMVK	string_interaction
HMGCR	UNC93B1	intact
IL1RN	NLRP3	string_interaction
IL1RN	PSTPIP1	string_interaction
LPIN2	MVK	string_interaction
LPIN2	PSTPIP1	string_interaction
LYST	RAB27A	string_interaction
LYST	SH2D1A	string_interaction
LYST	STX11	string_interaction
LYST	STXBP2	string_interaction
LYST	UNC13D	string_interaction
MEFV	NLRC4	string_interaction
MEFV	NLRP12	string_interaction
MEFV	NLRP3	biogrid_interaction, string_interaction
MEFV	PSTPIP1	intact, string_interaction
MMAB	MVK	string_interaction
MVK	PMVK	string_interaction
MVK	PSTPIP1	string_interaction
NLRC4	NLRP12	string_interaction
NLRC4	NLRP3	biogrid_interaction, string_interaction
NLRC4	NOD2	biogrid_interaction
NLRP12	NLRP3	string_interaction
NOD2	XIAP	intact
PRF1	STX11	string_interaction
PRF1	STXBP2	string_interaction
PRF1	UNC13D	string_interaction
RAB27A	STX11	string_interaction
RAB27A	STXBP2	string_interaction
RAB27A	UNC13D	biogrid_interaction, intact, string_interaction
SH2D1A	STX11	string_interaction
SH2D1A	STXBP2	string_interaction
SH2D1A	UNC13D	string_interaction
SH2D1A	XIAP	string_interaction
STX11	STXBP2	intact, string_interaction
STX11	UNC13D	string_interaction
STXBP2	UNC13D	string_interaction
UNC13D	XIAP	string_interaction

Structural data

PDB: 29 · AlphaFold-only: 11 · No structure: 2

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PTPN1	P18031	439
STING1	Q86WV6	119
XIAP	P98170	74
ELANE	P08246	38
ITK	Q08881	37
NLRP3	Q96P20	24
HMGCR	P04035	24
PSMB8	P28062	22
DPP9	Q86TI2	14
TNFRSF1A	P19438	13
MEFV	O15553	11
RAB27A	P51159	11
SH2D1A	O60880	6
NLRC4	Q9NPP4	6
MMAB	Q96EY8	6
SLC7A7	Q9UM01	5
CD27	P26842	5
AP3B1	O00203	5
IL1RN	P18510	5
PSTPIP1	O43586	4
IL36RN	Q9UBH0	3
NLRP12	P59046	3
UNC93B1	Q9H1C4	2
SGSH	P51688	2
ADA2	Q9NZK5	2
PMVK	Q15126	1
STXBP2	Q15833	1
UNC13D	Q70J99	1
MVK	Q03426	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRF1	P14222	91.01
GIMAP6	Q6P9H5	86.32
NOD2	Q9HC29	84.76
PALD1	Q9ULE6	84.20
BLOC1S6	Q9UL45	84.10
FGL2	Q14314	79.48
STX11	O75558	79.08
CARD14	Q9BXL6	75.89
FAM227B	Q96M60	71.40
LPIN2	Q92539	61.12
LYST	Q99698

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 145. Enrichment computed across 42 evidence-associated genes (33 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 33 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Lanosterol biosynthesis	3	69.2×	0.001	HMGCR, MVK, PMVK
The NLRP3 inflammasome	3	61.1×	0.001	PSTPIP1, NLRP3, MEFV
Purinergic signaling in leishmaniasis infection	3	38.5×	0.003	PSTPIP1, NLRP3, MEFV
Activation of gene expression by SREBF (SREBP)	3	23.6×	0.010	HMGCR, MVK, PMVK
SARS-CoV-2 activates/modulates innate and adaptive immune responses	4	10.8×	0.014	NLRP3, NLRP12, STING1, NOD2
MPS IIIA - Sanfilippo syndrome A	1	346.1×	0.050	SGSH
TNFR1-induced proapoptotic signaling	2	26.6×	0.050	TNFRSF1A, XIAP
TNFs bind their physiological receptors	2	23.9×	0.050	TNFRSF1A, CD27
Neutrophil degranulation	6	4.2×	0.050	ADA2, UNC13D, STING1, ELANE, FGL2, RAB27A
Turbulent (oscillatory, disturbed) flow shear stress activates signaling by PIEZO1 and integrins in endothelial cells	2	21.6×	0.055	NLRP3, PTPN1
Defective MMAB causes MMA, cblB type	1	173.0×	0.056	MMAB
UNC93B1 deficiency - HSE	1	173.0×	0.056	UNC93B1
Defective amino acid transport by SLC7A7 causes lysinuric protein intolerance (LPI)	1	173.0×	0.056	SLC7A7
The IPAF inflammasome	1	173.0×	0.056	NLRC4
TNFR1-induced NF-kappa-B signaling pathway	2	20.4×	0.056	TNFRSF1A, XIAP
SARS-CoV-1 activates/modulates innate immune responses	2	16.5×	0.059	NLRP3, STING1
trans-Golgi Network Vesicle Budding	2	15.4×	0.063	AP3B1, BLOC1S6
STAT6-mediated induction of chemokines	1	115.3×	0.067	STING1
Interleukin-10 signaling	2	14.1×	0.067	TNFRSF1A, IL1RN
Regulation of TNFR1 signaling	2	13.6×	0.069	TNFRSF1A, XIAP
PTK6 Down-Regulation	1	86.5×	0.074	PTPN1
Golgi Associated Vesicle Biogenesis	2	12.1×	0.074	AP3B1, BLOC1S6
Immune System	7	2.8×	0.074	SH2D1A, STXBP2, CD27, ADA2, STING1, ITK, MEFV
Expression of NOTCH2NL genes	1	69.2×	0.087	ELANE
Activation of caspases through apoptosome-mediated cleavage	1	57.7×	0.092	XIAP
Mucopolysaccharidoses	1	57.7×	0.092	SGSH
TNFR1-mediated ceramide production	1	57.7×	0.092	TNFRSF1A
SMAC (DIABLO) binds to IAPs	1	49.4×	0.094	XIAP
SMAC(DIABLO)-mediated dissociation of IAP:caspase complexes	1	49.4×	0.094	XIAP
SMAC, XIAP-regulated apoptotic response	1	49.4×	0.094	XIAP

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 37 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
pattern recognition receptor signaling pathway	5	134.0×	9e-08	NLRP3, NLRC4, STING1, NOD2, MEFV
pyroptotic inflammatory response	5	69.0×	2e-06	NLRP3, NLRC4, DPP9, ELANE, MEFV
positive regulation of interleukin-1 beta production	5	35.0×	3e-05	NLRP3, NLRC4, NLRP12, NOD2, MEFV
negative regulation of inflammatory response	6	22.2×	3e-05	TNFRSF1A, NLRP3, NLRP12, ELANE, MEFV, MVK
defense response to bacterium	6	17.5×	8e-05	TNFRSF1A, NLRC4, LYST, ELANE, NOD2, XIAP
regulation of inflammatory response	5	22.8×	2e-04	NLRP3, NLRP12, STING1, NOD2, XIAP
inflammatory response	8	8.2×	3e-04	IL36RN, PSTPIP1, TNFRSF1A, NLRP3, NLRC4, AP3B1, IL1RN, MEFV
positive regulation of inflammatory response	5	19.6×	3e-04	TNFRSF1A, NLRP3, NLRC4, NLRP12, MEFV
innate immune response	8	7.3×	5e-04	IL36RN, PSTPIP1, UNC93B1, NLRP3, NLRC4, STING1, NOD2, MEFV
isopentenyl diphosphate biosynthetic process, mevalonate pathway	2	303.6×	5e-04	MVK, PMVK
positive regulation of non-canonical NF-kappaB signal transduction	4	27.6×	5e-04	CD27, NLRP3, NLRP12, NOD2
melanosome organization	3	52.5×	8e-04	LYST, AP3B1, BLOC1S6
detection of biotic stimulus	2	227.7×	9e-04	NLRP3, NOD2
obsolete positive regulation of NF-kappaB transcription factor activity	4	22.2×	9e-04	NLRP3, NLRC4, CARD14, NOD2
positive regulation of regulated secretory pathway	2	182.2×	0.001	UNC13D, RAB27A
positive regulation of JNK cascade	4	17.7×	0.002	CD27, NOD2, XIAP, PTPN1
positive regulation of type 2 immune response	2	130.1×	0.002	NLRP3, NOD2
natural killer cell degranulation	2	130.1×	0.002	UNC13D, RAB27A
cholesterol biosynthetic process	3	34.2×	0.002	HMGCR, MVK, PMVK
regulation of mast cell degranulation	2	101.2×	0.003	STXBP2, UNC13D
defense response to virus	5	9.4×	0.003	UNC93B1, LYST, UNC13D, STING1, PRF1
isoprenoid biosynthetic process	2	91.1×	0.003	HMGCR, MVK
sterol biosynthetic process	2	91.1×	0.003	HMGCR, PMVK
cellular defense response	3	25.8×	0.003	SH2D1A, ITK, PRF1
nucleotide-binding oligomerization domain containing 2 signaling pathway	2	82.8×	0.004	NOD2, XIAP
detection of bacterium	2	75.9×	0.005	NLRC4, NOD2
protein transmembrane transport	2	70.1×	0.005	BLOC1S6, PRF1
phagocytosis	3	19.5×	0.007	LYST, UNC13D, ELANE
anterograde synaptic vesicle transport	2	53.6×	0.008	AP3B1, BLOC1S6
respiratory system process	2	50.6×	0.009	AP3B1, BLOC1S6

Therapeutics

Drug target analysis

Approved (phase 4): 10 · Phase ≥3: 11 · Phased (≥1): 13 · Undrugged: 29

Druggability breadth: 20 of 42 evidence-associated genes (48%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

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

Symbol	Example approved molecule
DPP9	SITAGLIPTIN
PTPN1	AMINOSALICYLIC ACID
NLRP3	CLOMIPHENE
STING1	PALBOCICLIB
ELANE	BOCEPREVIR
HMGCR	SIMVASTATIN
NOD2	PACLITAXEL
ITK	FEDRATINIB
PSMB8	BORTEZOMIB
RAB27A	COPANLISIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ITK	39	4
PTPN1	23	4
HMGCR	15	4
NLRP3	11	4
ELANE	11	4
DPP9	8	4
PSMB8	7	4
NOD2	6	4
XIAP	6	3
STING1	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
SITAGLIPTIN	4	DPP9
VILDAGLIPTIN	4	DPP9
TENELIGLIPTIN	4	DPP9
LINAGLIPTIN	4	DPP9
SAXAGLIPTIN ANHYDROUS	4	DPP9
GOSOGLIPTIN	4	DPP9
AMINOSALICYLIC ACID	4	PTPN1
EVANS BLUE	4	PTPN1
TRYPAN BLUE	4	PTPN1
ESTRAMUSTINE PHOSPHATE	4	PTPN1
BERBERINE	4	PTPN1
BENZBROMARONE	4	PTPN1
TROGLITAZONE	4	PTPN1
CANTHARIDIN	4	PTPN1
CARBENOXOLONE	4	PTPN1
PIOGLITAZONE	4	PTPN1
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
PALBOCICLIB	4	STING1
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE, PSMB8
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 10.

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

Symbol	Assays	Type breakdown
PTPN1	1,225	Binding:1210, Functional:10, ADMET:4, Toxicity:1
STING1	890	Binding:890
ELANE	801	Binding:758, Functional:35, ADMET:6, Toxicity:2
ITK	563	Binding:547, Functional:10, ADMET:6
NLRP3	534	Binding:527, Functional:6, ADMET:1
XIAP	499	Binding:468, Functional:24, ADMET:7
PSMB8	262	Binding:250, ADMET:9, Functional:3
DPP9	160	Binding:154, ADMET:6
HMGCR	153	Binding:148, Functional:5
NOD2	126	Binding:121, Functional:5
PRF1	34	Binding:34
IL1RN	26	Binding:26
TNFRSF1A	24	Binding:23, Functional:1
NLRC4	13	Binding:13
AP3B1	8	Binding:8
SH2D1A	5	Binding:5
RAB27A	3	Binding:3
UNC93B1	1	Binding:1
CD27	1	Binding:1
MMAB	1	Binding:1
MEFV	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
DPP9	3.4.13.19	membrane dipeptidase
PMVK	2.7.4.2	phosphomevalonate kinase
PTPN1	3.1.3.48	protein-tyrosine-phosphatase
SGSH	3.10.1.1	N-sulfoglucosamine sulfohydrolase
ADA2	3.5.4.4	adenosine deaminase
MMAB	2.5.1.17	corrinoid adenosyltransferase
ELANE	3.4.21.37	leukocyte elastase
HMGCR	1.1.1.34	hydroxymethylglutaryl-CoA reductase (NADPH)
ITK	2.7.10.2	non-specific protein-tyrosine kinase
MVK	2.7.1.36	mevalonate kinase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
DPP9	160
PTPN1	1,225
NLRP3	534
STING1	890
ELANE	801
HMGCR	153
NOD2	126
XIAP	499
ITK	563
PSMB8	262

Pharmacogenomics

Cohort genes with a PharmGKB record: 40; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
HMGCR	1

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)
SITAGLIPTIN	4	DPP9
VILDAGLIPTIN	4	DPP9
TENELIGLIPTIN	4	DPP9
LINAGLIPTIN	4	DPP9
SAXAGLIPTIN ANHYDROUS	4	DPP9
GOSOGLIPTIN	4	DPP9
AMINOSALICYLIC ACID	4	PTPN1
EVANS BLUE	4	PTPN1
TRYPAN BLUE	4	PTPN1
ESTRAMUSTINE PHOSPHATE	4	PTPN1
BERBERINE	4	PTPN1
BENZBROMARONE	4	PTPN1
TROGLITAZONE	4	PTPN1
CANTHARIDIN	4	PTPN1
CARBENOXOLONE	4	PTPN1
PIOGLITAZONE	4	PTPN1
CLOMIPHENE	4	NLRP3
GLYBURIDE	4	NLRP3
PALBOCICLIB	4	STING1
BOCEPREVIR	4	ELANE
TELAPREVIR	4	ELANE
BORTEZOMIB	4	ELANE, PSMB8
SIMVASTATIN	4	HMGCR
PRAVASTATIN	4	HMGCR
PITAVASTATIN CALCIUM	4	HMGCR
CERIVASTATIN	4	HMGCR
ATORVASTATIN	4	HMGCR
ROSUVASTATIN	4	HMGCR
CISAPRIDE	4	HMGCR
FLUVASTATIN	4	HMGCR

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	10	DPP9, PTPN1, NLRP3, STING1, ELANE, HMGCR, NOD2, ITK, PSMB8, RAB27A
B	Phased (≥1) drug, not yet approved	3	TNFRSF1A, AP3B1, XIAP
C	Druggable family + PDB, no drug	6	PMVK, SGSH, SLC7A7, ADA2, MMAB, MVK
D	Druggable family + AlphaFold only, no drug	2	PALD1, PRF1
E	Difficult family or no structure, no drug	21	IL36RN, PSTPIP1, UNC93B1, GIMAP6, FGL2, SH2D1A, STX11, STXBP2, CD27, LPIN2 (+11 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
PMVK	0	HMGCR
STX11	0	RAB27A
NLRC4	13	NLRP3
LYST	0	AP3B1
NLRP12	0	NLRP3
UNC13D	0	RAB27A
MVK	0	HMGCR
IL36RN	0	—
PSTPIP1	0	—
UNC93B1	1	—
GIMAP6	0	—
FGL2	0	—
SGSH	0	—
SH2D1A	5	—
SLC7A7	0	—
STXBP2	0	—
CD27	1	—
LPIN2	0	—
CARD14	0	—
ADA2	0	—
MMAB	1	—
PALD1	0	—
FAM227B	0	—
CD27-AS1	0	—
CYLD-AS1	0	—
IL1RN	26	—
MEFV	1	—
BLOC1S6	0	—
PRF1	34	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00442182	PHASE2	UNKNOWN	The Efficacy and Safety of ITF2357 in AIS
NCT03510442	Not specified	RECRUITING	Natural History, Genetics, and Pathophysiology of Systemic Juvenile Idiopathic Arthritis, Adult-Onset Still’s Disease, and Related Conditions
NCT06248957	Not specified	RECRUITING	SYSTEMS-LEVEL ANALYSES OF IMMUNE DYSREGULATION
NCT00887939	Not specified	COMPLETED	Pathogenesis of Physical Induced Urticarial Syndromes

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
GIVINOSTAT	4	1