Autosomal dominant nonsyndromic hearing loss

Summary

Autosomal dominant nonsyndromic hearing loss (MONDO:0019587) is a disease (an umbrella term covering 76 Mondo subtypes) caused by variants in ATP2B2 and LMX1A, with 55 cohort genes. The dominant Reactome pathway is Sensory processing of sound by inner hair cells of the cochlea (10 cohort genes).

At a glance

• Prevalence: Unknown (Worldwide)
• Causal genes: ATP2B2 (GenCC Definitive), LMX1A (GenCC Definitive)
• Umbrella term: 76 Mondo subtypes
• Cohort genes: 55
• ClinVar variants: 27

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss
Mondo ID	MONDO:0019587
OMIM	124900
Orphanet	90635
DOID	DOID:0050564
UMLS	C5779548
MedGen	1843285
GARD	0016791
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness · autosomal dominant isolated deafness · autosomal dominant isolated neurosensory deafness type DFNA · autosomal dominant isolated neurosensory hearing loss type DFNA · autosomal dominant isolated sensorineural deafness type DFNA · autosomal dominant isolated sensorineural hearing loss type DFNA · autosomal dominant non-syndromic neurosensory deafness type DFNA · autosomal dominant non-syndromic neurosensory hearing loss type DFNA · autosomal dominant non-syndromic sensorineural deafness type DFNA · autosomal dominant non-syndromic sensorineural hearing loss type DFNA · autosomal dominant nonsyndromic deafness · autosomal dominant nonsyndromic genetic deafness · autosomal dominant nonsyndromic hearing impairment · autosomal dominant nonsyndromic hearing loss · autosomal dominant nonsyndromic hearing loss and deafness · deafness, autosomal dominant · nonsyndromic deafness, autosomal dominant · nonsyndromic genetic deafness, autosomal dominant

Data availability: 27 ClinVar variants · 53 GenCC gene-disease records · 12 cell lines.

Disease family

An umbrella term covering 76 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › autosomal dominant nonsyndromic hearing loss

Related subtypes (191): autosomal dominant polycystic liver disease, cerebral arteriopathy, autosomal dominant, with subcortical infarcts and leukoencephalopathy, type 1, tuberous sclerosis, Treacher-Collins syndrome, hereditary breast ovarian cancer syndrome, autosomal dominant polycystic kidney disease, Lynch syndrome, branchio-oto-renal syndrome, autosomal dominant Aarskog syndrome, acroosteolysis dominant type, ADULT syndrome, autosomal dominant Alport syndrome, amelogenesis imperfecta type 1B, Townes-Brocks syndrome, nevoid basal cell carcinoma syndrome, blepharophimosis, ptosis, and epicanthus inversus syndrome, autosomal dominant brachyolmia, branchiooculofacial syndrome, pheochromocytoma/paraganglioma syndrome 4, cataract-aberrant oral frenula-growth delay syndrome, cherubism, autosomal dominant chondrodysplasia punctata, autosomal dominant popliteal pterygium syndrome, blepharocheilodontic syndrome, cochleosaccular degeneration-cataract syndrome, renal coloboma syndrome, Beare-Stevenson cutis gyrata syndrome, autosomal dominant vibratory urticaria, neurohypophyseal diabetes insipidus, autosomal dominant Kenny-Caffey syndrome, Rapp-Hodgkin syndrome, Ehlers-Danlos syndrome, classic type, autosomal dominant Ehlers-Danlos syndrome, vascular type, multiple endocrine neoplasia type 1, Coffin-Siris syndrome 1, isolated congenital adermatoglyphia, Flynn-Aird syndrome, Frasier syndrome, hand-foot-genital syndrome, Holt-Oram syndrome, hyperkeratosis-hyperpigmentation syndrome, autosomal dominant ichthyosis vulgaris, hyper-IgE recurrent infection syndrome 1, autosomal dominant, autosomal dominant keratitis, autosomal dominant keratitis-ichthyosis-hearing loss syndrome, LADD syndrome, trichorhinophalangeal syndrome type II, Noonan syndrome with multiple lentigines, microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability, Marfan syndrome, melanoma, cutaneous malignant, susceptibility to, 2, autosomal dominant primary microcephaly, autosomal dominant progressive external ophthalmoplegia, monilethrix, Muir-Torre syndrome, autosomal dominant myoglobinuria, autosomal dominant centronuclear myopathy, nail-patella syndrome, multiple endocrine neoplasia type 2B, autosomal dominant omodysplasia, pheochromocytoma/paraganglioma syndrome 1, Pelger-Huet anomaly, multiple endocrine neoplasia type 2A, piebaldism, autosomal dominant medullary cystic kidney disease with or without hyperuricemia, generalized juvenile polyposis/juvenile polyposis coli, juvenile polyposis/hereditary hemorrhagic telangiectasia syndrome, Peutz-Jeghers syndrome, contractures, pterygia, and spondylocarpotarsal fusion syndrome 1A, autosomal dominant distal renal tubular acidosis, retinoschisis, autosomal dominant, autosomal dominant Robinow syndrome, scapuloperoneal spinal muscular atrophy, autosomal dominant, autosomal dominant sideroblastic anemia, spondyloepiphyseal dysplasia tarda, autosomal dominant, proximal symphalangism, calcaneonavicular coalition, thanatophoric dysplasia type 1, trichorhinophalangeal syndrome type I, Muckle-Wells syndrome, autosomal dominant hypophosphatemic rickets, von Hippel-Lindau disease, Denys-Drash syndrome, autosomal dominant severe congenital neutropenia, Costello syndrome, EEC syndrome, multiple cutaneous and mucosal venous malformations, diffuse nonepidermolytic palmoplantar keratoderma, Timothy syndrome, pheochromocytoma/paraganglioma syndrome 2, spondyloepimetaphyseal dysplasia with multiple dislocations, Brooke-Spiegler syndrome, macrocephaly-autism syndrome, pheochromocytoma/paraganglioma syndrome 3, Duane-radial ray syndrome, PCWH syndrome, heart-hand syndrome, Slovenian type, congenital stationary night blindness autosomal dominant 3, mandibulofacial dysostosis-microcephaly syndrome, multiple endocrine neoplasia type 4, juvenile cataract-microcornea-renal glucosuria syndrome, Crouzon syndrome-acanthosis nigricans syndrome, Birk-Barel syndrome, thrombophilia due to protein S deficiency, autosomal dominant, dyskeratosis congenita, autosomal dominant 2, dyskeratosis congenita, autosomal dominant 3, colorectal cancer, hereditary nonpolyposis, type 6, colorectal cancer, hereditary nonpolyposis, type 7, brain small vessel disease 2A, autosomal dominant, intellectual disability, autosomal dominant 14, intellectual disability, autosomal dominant 15, intellectual disability, autosomal dominant 16, hypopigmentation-punctate palmoplantar keratoderma syndrome, intellectual disability-facial dysmorphism syndrome due to SETD5 haploinsufficiency, postaxial polydactyly-anterior pituitary anomalies-facial dysmorphism syndrome, intellectual developmental disorder with microcephaly and with or without ocular malformations or hypogonadotropic hypogonadism, intellectual disability, autosomal dominant 29, intellectual disability, autosomal dominant 30, Houge-Janssens syndrome 2, severe achondroplasia-developmental delay-acanthosis nigricans syndrome, dyskeratosis congenita, autosomal dominant 6, epidermolysis bullosa simplex 6, generalized, with scarring and hair loss, autosomal dominant complex spastic paraplegia, early-onset autosomal dominant Alzheimer disease, muscular dystrophy, limb-girdle, autosomal dominant, Feingold syndrome, Carney complex, neuronopathy, distal hereditary motor, autosomal dominant, autosomal dominant coarctation of aorta, autosomal dominant spondylocostal dysostosis, autosomal dominant hypohidrotic ectodermal dysplasia, Cowden disease, autosomal dominant distal myopathy, autosomal dominant rhegmatogenous retinal detachment, palmoplantar keratoderma-spastic paralysis syndrome, Alagille syndrome due to a JAG1 point mutation, PTEN hamartoma tumor syndrome, gastric adenocarcinoma and proximal polyposis of the stomach, autosomal dominant proximal renal tubular acidosis, autosomal dominant spastic ataxia, Waardenburg syndrome, hereditary retinoblastoma, autosomal dominant hypocalcemia, Li-Fraumeni syndrome, Loeys-Dietz syndrome, hereditary hemorrhagic telangiectasia, hereditary inclusion body myopathy-joint contractures-ophthalmoplegia syndrome, microcephalic osteodysplastic dysplasia, Saul-Wilson type, autosomal dominant intermediate Charcot-Marie-Tooth disease, autosomal dominant cutis laxa, autosomal dominant optic atrophy, autosomal dominant Emery-Dreifuss muscular dystrophy, autosomal dominant cerebellar ataxia, autosomal dominant osteopetrosis, autosomal dominant epidermolytic ichthyosis, ventricular arrhythmias due to cardiac ryanodine receptor calcium release deficiency syndrome, distal arthrogryposis type 2B1, neurofibromatosis, autosomal dominant cataract, arthrogryposis, distal, type 2B2, arthrogryposis, distal, type 2B3, Charcot-Marie-Tooth disease, demyelinating, type 1G, Delpire-McNeill syndrome, LAMA5-related multisystemic syndrome, autosomal dominant oculocutaneous albinism, Charcot-Marie-tooth disease, axonal, type 2DD, Pilarowski-Bjornsson syndrome, intellectual disability, autosomal dominant, fatty acyl-CoA reductase 1 upregulation, GUCY2D-related dominant retinopathy, RPE65-related dominant retinopathy, autosomal dominant titinopathy, NOG-related symphalangism spectrum disorder, ALPL-related autosomal dominant hypophosphatasia, MYH10-related neurodevelopmental disorder with congenital anomalies, spastic paraplegia 30A, autosomal dominant, TMEM127-related tumor predisposition, MAX-related tumor predisposition, BMPR1A-related juvenile polyposis syndrome, RP1-related dominant retinopathy, Birt-Hogg-Dube syndrome, inclusion body myopathy and brain white matter abnormalities, KINSSHIP syndrome, autosomal dominant nebulin-related myopathy, IMPG1-related dominant retinopathy, PROM1-related dominant retinopathy, PURA-related severe neonatal hypotonia-seizures-encephalopathy syndrome, ALG8-related autosomal dominant polycystic kidney and/or liver disease, NOTCH1-related AOS spectrum disorder, FLNB-associated autosomal dominant filamin related bone disorder, familial antiphospholipid syndrome

Subtypes (76): autosomal dominant nonsyndromic hearing loss 1, autosomal dominant nonsyndromic hearing loss 2A, autosomal dominant nonsyndromic hearing loss 4A, autosomal dominant nonsyndromic hearing loss 6, autosomal dominant nonsyndromic hearing loss 5, autosomal dominant nonsyndromic hearing loss 10, autosomal dominant nonsyndromic hearing loss 11, autosomal dominant nonsyndromic hearing loss 9, autosomal dominant nonsyndromic hearing loss 7, autosomal dominant nonsyndromic hearing loss 12, autosomal dominant nonsyndromic hearing loss 3A, autosomal dominant nonsyndromic hearing loss 13, autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss 17, autosomal dominant nonsyndromic hearing loss 16, autosomal dominant nonsyndromic hearing loss 20, autosomal dominant nonsyndromic hearing loss 23, autosomal dominant nonsyndromic hearing loss 25, autosomal dominant nonsyndromic hearing loss 18, autosomal dominant nonsyndromic hearing loss 24, autosomal dominant nonsyndromic hearing loss 22, autosomal dominant nonsyndromic hearing loss 30, autosomal dominant nonsyndromic hearing loss 36, autosomal dominant nonsyndromic hearing loss 21, autosomal dominant nonsyndromic hearing loss 44, autosomal dominant nonsyndromic hearing loss 48, autosomal dominant nonsyndromic hearing loss 41, autosomal dominant nonsyndromic hearing loss 49, autosomal dominant nonsyndromic hearing loss 43, autosomal dominant nonsyndromic hearing loss 28, autosomal dominant nonsyndromic hearing loss 31, autosomal dominant nonsyndromic hearing loss 47, autosomal dominant auditory neuropathy 1, autosomal dominant nonsyndromic hearing loss 53, autosomal dominant nonsyndromic hearing loss 27, autosomal dominant nonsyndromic hearing loss 59, autosomal dominant nonsyndromic hearing loss 3B, autosomal dominant nonsyndromic hearing loss 2B, autosomal dominant nonsyndromic hearing loss 50, autosomal dominant nonsyndromic hearing loss 51, autosomal dominant nonsyndromic hearing loss 64, autosomal dominant nonsyndromic hearing loss 33, autosomal dominant nonsyndromic hearing loss 4B, autosomal dominant nonsyndromic hearing loss 56, autosomal dominant nonsyndromic hearing loss 54, autosomal dominant nonsyndromic hearing loss 58, autosomal dominant nonsyndromic hearing loss 65, autosomal dominant nonsyndromic hearing loss 67, autosomal dominant nonsyndromic hearing loss 40, autosomal dominant nonsyndromic hearing loss 69, autosomal dominant nonsyndromic hearing loss 68, autosomal dominant nonsyndromic hearing loss 70, autosomal dominant nonsyndromic hearing loss 66, hearing loss, autosomal dominant 74, hearing loss, autosomal dominant 77, hearing loss, autosomal dominant 81, hearing loss, autosomal dominant 82, hearing loss, autosomal dominant 83, hearing loss, autosomal dominant 84, hearing loss, autosomal dominant 80, hearing loss, autosomal dominant 37, hearing loss, autosomal dominant 75, hearing loss, autosomal dominant 76, hearing loss, autosomal dominant 71, hearing loss, autosomal dominant 72, hearing loss, autosomal dominant 73, hearing loss, autosomal dominant 34, with or without inflammation, hearing loss, autosomal dominant 78, hearing loss, autosomal dominant 79, hearing loss, autosomal dominant 85, hearing loss, autosomal dominant 86, hearing loss, autosomal dominant 87, hearing loss, autosomal dominant 88, hearing loss, autosomal dominant 89, hearing loss, autosomal dominant 90, autosomal dominant nonsyndromic hearing loss 91

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

27 retrieved; paginated sample, class counts are floors:

12 uncertain significance, 7 likely pathogenic, 3 pathogenic/likely pathogenic, 3 conflicting classifications of pathogenicity, 2 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
917514	NM_001001331.4(ATP2B2):c.1033C>T (p.Gln345Ter)	ATP2B2	Pathogenic	no assertion criteria provided
1679197	NM_004999.4(MYO6):c.560del (p.Pro187fs)	MYO6	Pathogenic	criteria provided, single submitter
433528	NM_001191057.4(PDE1C):c.778G>T (p.Ala260Ser)	PDE1C	Pathogenic/Likely pathogenic	no assertion criteria provided
30556	NM_006005.3(WFS1):c.2051C>T (p.Ala684Val)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4526	NM_006005.3(WFS1):c.2590G>A (p.Glu864Lys)	WFS1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3387802	NM_001354604.2(MITF):c.984T>A (p.Asn328Lys)	MITF	Likely pathogenic	criteria provided, single submitter
3340149	NM_170682.4(P2RX2):c.121dup (p.Leu41fs)	P2RX2	Likely pathogenic	criteria provided, single submitter
4084990	NM_001145319.2(PLS1):c.981+1G>A	PLS1	Likely pathogenic	criteria provided, single submitter
633603	NM_001145319.2(PLS1):c.383T>C (p.Phe128Ser)	PLS1	Likely pathogenic	criteria provided, single submitter
1686854	NM_005612.5(REST):c.1244G>C (p.Cys415Ser)	REST	Likely pathogenic	criteria provided, single submitter
1327912	NM_005982.4(SIX1):c.316G>T (p.Val106Leu)	SIX1	Likely pathogenic	criteria provided, single submitter
3387796	NM_006005.3(WFS1):c.2141A>G (p.Asn714Ser)	WFS1	Likely pathogenic	criteria provided, single submitter
4072164	NM_014208.3(DSPP):c.3267_3401del (p.Asn1092_Ser1136del)	DMP1-AS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
632608	NM_001145319.2(PLS1):c.805G>A (p.Glu269Lys)	PLS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
517360	NM_006005.3(WFS1):c.2389G>A (p.Asp797Asn)	WFS1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
3780320	NM_004996.4(ABCC1):c.3317T>C (p.Ile1106Thr)	ABCC1	Uncertain significance	criteria provided, single submitter
3780374	NM_004996.4(ABCC1):c.3605G>A (p.Arg1202Gln)	ABCC1	Uncertain significance	criteria provided, single submitter
3767304	NM_001854.4(COL11A1):c.4978A>G (p.Ile1660Val)	COL11A1	Uncertain significance	criteria provided, single submitter
1279938	NM_001371333.1(DIABLO):c.219G>C (p.Leu73Phe)	DIABLO	Uncertain significance	criteria provided, single submitter
929431	NM_001142966.3(GREB1L):c.347C>T (p.Thr116Ile)	GREB1L	Uncertain significance	criteria provided, single submitter
2093853	NM_004700.4(KCNQ4):c.746T>C (p.Leu249Pro)	KCNQ4	Uncertain significance	criteria provided, multiple submitters, no conflicts
3361725	NM_001384474.1(LOXHD1):c.6520G>A (p.Val2174Ile)	LOXHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3767852	NM_001384474.1(LOXHD1):c.5585G>A (p.Arg1862Gln)	LOXHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
3767853	NM_001384474.1(LOXHD1):c.5180G>C (p.Cys1727Ser)	LOXHD1	Uncertain significance	criteria provided, single submitter
3767854	NM_001384474.1(LOXHD1):c.2279G>A (p.Gly760Asp)	LOXHD1	Uncertain significance	criteria provided, multiple submitters, no conflicts
1188774	NM_001145809.2(MYH14):c.2300G>A (p.Arg767His)	MYH14	Uncertain significance	criteria provided, multiple submitters, no conflicts
4074876	NM_001145809.2(MYH14):c.2184C>A (p.Asn728Lys)	MYH14	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 429 · Orphanet: 117 · 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
ACTG1	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	9
ATP2B2	Definitive	Autosomal dominant	hearing loss, autosomal dominant 82	6
COCH	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	4
COL11A2	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 13	20
EYA4	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	7
GJB2	Definitive	Autosomal dominant	hearing loss disorder	26
GRHL2	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	14
KCNQ4	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 2A	6
LMX1A	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss	7
MYH14	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 4A	9
MYH9	Definitive	Autosomal dominant	macrothrombocytopenia and granulocyte inclusions with or without nephritis or sensorineural hearing loss	9
MYO6	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 22	11
MYO7A	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	15
POU4F3	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 15	5
PTPRQ	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 84A	11
PTPRR	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 84A	11
SIX1	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 23	10
TECTA	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	10
TMC1	Definitive	Autosomal recessive	autosomal recessive nonsyndromic hearing loss 7	11
CEACAM16	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 4B	5
COL11A1	Strong	Autosomal dominant	hearing loss, autosomal dominant 37	17
GJB6	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 3B	18
GSDME	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 5	4
HOMER2	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 68	5
KITLG	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 69	11
MCM2	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 70	5
OSBPL2	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 67	5
P2RX2	Strong	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 41	5
PLS1	Strong	Autosomal dominant	hearing loss, autosomal dominant 76	5
RIPOR2	Strong	Autosomal recessive	nonsyndromic genetic hearing loss	8

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SIX1	Orphanet:107	BOR syndrome
SIX1	Orphanet:52429	Branchiootic syndrome
SIX1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:3463	Wolfram syndrome
WFS1	Orphanet:411590	Wolfram-like syndrome
WFS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
WFS1	Orphanet:98991	Early-onset nuclear cataract
P2RX2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
DIABLO	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:2021	Fibrochondrogenesis
COL11A1	Orphanet:440354	Autosomal dominant myopia-midfacial retrusion-sensorineural hearing loss-rhizomelic dysplasia syndrome
COL11A1	Orphanet:560	Marshall syndrome
COL11A1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A1	Orphanet:90654	Stickler syndrome type 2
MYH14	Orphanet:397744	MYH14-related peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
MYH14	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ABCC1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
KCNQ4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO6	Orphanet:228012	Progressive sensorineural hearing loss-hypertrophic cardiomyopathy syndrome
MYO6	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MYO6	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
ATP2B2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
PDE1C	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
PLS1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TECTA	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TECTA	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
TJP2	Orphanet:238475	Familial hypercholanemia
TJP2	Orphanet:480483	Progressive familial intrahepatic cholestasis type 4
TJP2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TRRAP	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
MACF1	Orphanet:572013	Posterior-predominant lissencephaly-broad flat pons and medulla-midline crossing defects syndrome
RIPOR2	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
SLC44A4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:2995	Baraitser-Winter cerebrofrontofacial syndrome
ACTG1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
ACTG1	Orphanet:98942	Coloboma of choroid and retina
ACTG1	Orphanet:98944	Coloboma of iris
DIAPH3	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
OSBPL2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CD164	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMC1	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TMC1	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
HOMER2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
CCDC50	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
SLC17A8	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COCH	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
COL11A2	Orphanet:1427	Autosomal recessive otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:166100	Autosomal dominant otospondylomegaepiphyseal dysplasia
COL11A2	Orphanet:2021	Fibrochondrogenesis
COL11A2	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

55 cohort genes, 54 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	55

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SIX1	HGNC:10887	ENSG00000126778	Q15475	Homeobox protein SIX1	gencc,clinvar
WFS1	HGNC:12762	ENSG00000109501	O76024	Wolframin	gencc,clinvar
P2RX2	HGNC:15459	ENSG00000187848	Q9UBL9	P2X purinoceptor 2	gencc,clinvar
DIABLO	HGNC:21528	ENSG00000184047	Q9NR28	Diablo IAP-binding mitochondrial protein	gencc,clinvar
COL11A1	HGNC:2186	ENSG00000060718	P12107	Collagen alpha-1(XI) chain	gencc,clinvar
MYH14	HGNC:23212	ENSG00000105357	Q7Z406	Myosin-14	gencc,clinvar
ABCC1	HGNC:51	ENSG00000103222	P33527	Multidrug resistance-associated protein 1	gencc,clinvar
KCNQ4	HGNC:6298	ENSG00000117013	P56696	Potassium voltage-gated channel subfamily KQT member 4	gencc,clinvar
MYO6	HGNC:7605	ENSG00000196586	Q9UM54	Unconventional myosin-VI	gencc,clinvar
ATP2B2	HGNC:815	ENSG00000157087	Q01814	Plasma membrane calcium-transporting ATPase 2	gencc,clinvar
PDE1C	HGNC:8776	ENSG00000154678	Q14123	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	gencc,clinvar
PLS1	HGNC:9090	ENSG00000120756	Q14651	Plastin-1	gencc,clinvar
TECTA	HGNC:11720	ENSG00000109927	O75443	Alpha-tectorin	gencc
TJP2	HGNC:11828	ENSG00000119139	Q9UDY2	Tight junction protein 2	gencc
TRRAP	HGNC:12347	ENSG00000196367	Q9Y4A5	Transformation/transcription domain-associated protein	gencc
MACF1	HGNC:13664	ENSG00000127603	O94854	Microtubule-actin cross-linking factor 1, isoforms 6/7	gencc
RIPOR2	HGNC:13872	ENSG00000111913	Q9Y4F9	Rho family-interacting cell polarization regulator 2	gencc
SLC44A4	HGNC:13941	ENSG00000204385	Q53GD3	Choline transporter-like protein 4	gencc
ACTG1	HGNC:144	ENSG00000184009	P63261	Actin, cytoplasmic 2	gencc
DIAPH3	HGNC:15480	ENSG00000139734	Q9NSV4	Protein diaphanous homolog 3	gencc
OSBPL2	HGNC:15761	ENSG00000130703	Q9H1P3	Oxysterol-binding protein-related protein 2	gencc
CD164	HGNC:1632	ENSG00000135535	Q04900	Sialomucin core protein 24	gencc
TMC1	HGNC:16513	ENSG00000165091	Q8TDI8	Transmembrane channel-like protein 1	gencc
HOMER2	HGNC:17513	ENSG00000103942	Q9NSB8	Homer protein homolog 2	gencc
CCDC50	HGNC:18111	ENSG00000152492	Q8IVM0	Coiled-coil domain-containing protein 50	gencc
SLC17A8	HGNC:20151	ENSG00000179520	Q8NDX2	Vesicular glutamate transporter 3	gencc
COCH	HGNC:2180	ENSG00000100473	O43405	Cochlin	gencc
COL11A2	HGNC:2187	ENSG00000204248	P13942	Collagen alpha-2(XI) chain	gencc
CRYM	HGNC:2418	ENSG00000103316	Q14894	Ketimine reductase mu-crystallin	gencc
GRHL2	HGNC:2799	ENSG00000083307	Q6ISB3	Grainyhead-like protein 2 homolog	gencc
GSDME	HGNC:2810	ENSG00000105928	O60443	Gasdermin-E	gencc
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	gencc
DMXL2	HGNC:2938	ENSG00000104093	Q8TDJ6	DmX-like protein 2	gencc
CEACAM16	HGNC:31948	ENSG00000213892	Q2WEN9	Cell adhesion molecule CEACAM16	gencc
EYA4	HGNC:3522	ENSG00000112319	O95677	Protein phosphatase EYA4	gencc
GJB2	HGNC:4284	ENSG00000165474	P29033	Gap junction beta-2 protein	gencc
GJB3	HGNC:4285	ENSG00000188910	O75712	Gap junction beta-3 protein	gencc
GJB6	HGNC:4288	ENSG00000121742	O95452	Gap junction beta-6 protein	gencc
TNC	HGNC:5318	ENSG00000041982	P24821	Tenascin	gencc
KITLG	HGNC:6343	ENSG00000049130	P21583	Kit ligand	gencc
LMX1A	HGNC:6653	ENSG00000162761	Q8TE12	LIM homeobox transcription factor 1-alpha	gencc
MCM2	HGNC:6944	ENSG00000073111	P49736	DNA replication licensing factor MCM2	gencc
MYH9	HGNC:7579	ENSG00000100345	P35579	Myosin-9	gencc
MYO1C	HGNC:7597	ENSG00000197879	O00159	Unconventional myosin-Ic	gencc
MYO1E	HGNC:7599	ENSG00000157483	Q12965	Unconventional myosin-Ie	gencc
MYO7A	HGNC:7606	ENSG00000137474	Q13402	Unconventional myosin-VIIa	gencc
NCOA3	HGNC:7670	ENSG00000124151	Q9Y6Q9	Nuclear receptor coactivator 3	gencc
POU4F3	HGNC:9220	ENSG00000091010	Q15319	POU domain, class 4, transcription factor 3	gencc
PTPRQ	HGNC:9679	ENSG00000139304	Q9UMZ3	Phosphatidylinositol phosphatase PTPRQ	gencc
PTPRR	HGNC:9680	ENSG00000153233	Q15256	Receptor-type tyrosine-protein phosphatase R	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SIX1	Homeobox protein SIX1	Transcription factor that is involved in the regulation of cell proliferation, apoptosis and embryonic development.
WFS1	Wolframin	Participates in the regulation of cellular Ca(2+) homeostasis, at least partly, by modulating the filling state of the endoplasmic reticulum Ca(2+) store.
P2RX2	P2X purinoceptor 2	ATP-gated nonselective transmembrane cation channel permeable to potassium, sodium and calcium.
DIABLO	Diablo IAP-binding mitochondrial protein	Promotes apoptosis by activating caspases in the cytochrome c/Apaf-1/caspase-9 pathway.
COL11A1	Collagen alpha-1(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
MYH14	Myosin-14	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
ABCC1	Multidrug resistance-associated protein 1	Mediates export of organic anions and drugs from the cytoplasm.
KCNQ4	Potassium voltage-gated channel subfamily KQT member 4	Pore-forming subunit of the voltage-gated potassium (Kv) channel involved in the regulation of sensory cells excitability in the cochlea.
MYO6	Unconventional myosin-VI	Myosins are actin-based motor molecules with ATPase activity.
ATP2B2	Plasma membrane calcium-transporting ATPase 2	ATP-driven Ca(2+) ion pump involved in the maintenance of basal intracellular Ca(2+) levels in specialized cells of cerebellar circuit and vestibular and cochlear systems.
PDE1C	Dual specificity calcium/calmodulin-dependent 3’,5’-cyclic nucleotide phosphodiesterase 1C	Calmodulin-dependent cyclic nucleotide phosphodiesterase with a dual specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
PLS1	Plastin-1	Actin-bundling protein.
TECTA	Alpha-tectorin	One of the major non-collagenous components of the tectorial membrane.
TJP2	Tight junction protein 2	Plays a role in tight junctions and adherens junctions.
TRRAP	Transformation/transcription domain-associated protein	Adapter protein, which is found in various multiprotein chromatin complexes with histone acetyltransferase activity (HAT), which gives a specific tag for epigenetic transcription activation.
RIPOR2	Rho family-interacting cell polarization regulator 2	Acts as an inhibitor of the small GTPase RHOA and plays several roles in the regulation of myoblast and hair cell differentiation, lymphocyte T proliferation and neutrophil polarization.
SLC44A4	Choline transporter-like protein 4	Choline transporter that plays a role in the choline-acetylcholine system and is required to the efferent innervation of hair cells in the olivocochlear bundle for the maintenance of physiological function of outer hair cells and the prote…
ACTG1	Actin, cytoplasmic 2	Actins are highly conserved proteins that are involved in various types of cell motility and are ubiquitously expressed in all eukaryotic cells.
DIAPH3	Protein diaphanous homolog 3	Actin nucleation and elongation factor required for the assembly of F-actin structures, such as actin cables and stress fibers.
OSBPL2	Oxysterol-binding protein-related protein 2	Intracellular transport protein that binds sterols and phospholipids and mediates lipid transport between intracellular compartments.
CD164	Sialomucin core protein 24	Sialomucin that may play a key role in hematopoiesis by facilitating the adhesion of CD34(+) cells to the stroma and by negatively regulating CD34(+)CD38(lo/-) cell proliferation.
TMC1	Transmembrane channel-like protein 1	Pore-forming subunit of the mechanotransducer (MET) non-selective cation channel complex located at the tips of stereocilia of cochlear hair cells and that mediates sensory transduction in the auditory system.
HOMER2	Homer protein homolog 2	Postsynaptic density scaffolding protein.
CCDC50	Coiled-coil domain-containing protein 50	Involved in EGFR signaling.
SLC17A8	Vesicular glutamate transporter 3	Multifunctional transporter that transports L-glutamate as well as multiple ions such as chloride, sodium and phosphate.
COCH	Cochlin	Plays a role in the control of cell shape and motility in the trabecular meshwork.
COL11A2	Collagen alpha-2(XI) chain	May play an important role in fibrillogenesis by controlling lateral growth of collagen II fibrils.
CRYM	Ketimine reductase mu-crystallin	Catalyzes the NAD(P)H-dependent reduction of imine double bonds of a number of cyclic ketimine substrates, including sulfur-containing cyclic ketimines.
GRHL2	Grainyhead-like protein 2 homolog	Transcription factor playing an important role in primary neurulation and in epithelial development.
GSDME	Gasdermin-E	Precursor of a pore-forming protein that converts non-inflammatory apoptosis to pyroptosis.
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
DMXL2	DmX-like protein 2	May serve as a scaffold protein for MADD and RAB3GA on synaptic vesicles.
CEACAM16	Cell adhesion molecule CEACAM16	Required for proper hearing, plays a role in maintaining the integrity of the tectorial membrane.
EYA4	Protein phosphatase EYA4	Tyrosine phosphatase that specifically dephosphorylates ‘Tyr-142’ of histone H2AX (H2AXY142ph). ‘Tyr-142’ phosphorylation of histone H2AX plays a central role in DNA repair and acts as a mark that distinguishes between apoptotic and repair…
GJB2	Gap junction beta-2 protein	Structural component of gap junctions.
GJB3	Gap junction beta-3 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
GJB6	Gap junction beta-6 protein	One gap junction consists of a cluster of closely packed pairs of transmembrane channels, the connexons, through which materials of low MW diffuse from one cell to a neighboring cell.
TNC	Tenascin	Extracellular matrix protein implicated in guidance of migrating neurons as well as axons during development, synaptic plasticity as well as neuronal regeneration.
KITLG	Kit ligand	Ligand for the receptor-type protein-tyrosine kinase KIT.
LMX1A	LIM homeobox transcription factor 1-alpha	Acts as a transcriptional activator by binding to an A/T-rich sequence, the FLAT element, in the insulin gene promoter.
MCM2	DNA replication licensing factor MCM2	Acts as a component of the MCM2-7 complex (MCM complex) which is the replicative helicase essential for ‘once per cell cycle’ DNA replication initiation and elongation in eukaryotic cells.
MYH9	Myosin-9	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
MYO1C	Unconventional myosin-Ic	Myosins are actin-based motor molecules with ATPase activity.
MYO1E	Unconventional myosin-Ie	Actin-based motor molecule with ATPase activity.
MYO7A	Unconventional myosin-VIIa	Myosins are actin-based motor molecules with ATPase activity.
NCOA3	Nuclear receptor coactivator 3	Nuclear receptor coactivator that directly binds nuclear receptors and stimulates the transcriptional activities in a hormone-dependent fashion.
POU4F3	POU domain, class 4, transcription factor 3	Acts as a transcriptional activator.
PTPRQ	Phosphatidylinositol phosphatase PTPRQ	Dephosphorylates phosphatidylinositol phosphates, such as phosphatidylinositol 3,4,5-trisphosphate (PIP3) and phosphatidylinositol 3,5-diphosphates, with preference for PIP3.
PTPRR	Receptor-type tyrosine-protein phosphatase R	Sequesters mitogen-activated protein kinases (MAPKs) such as MAPK1, MAPK3 and MAPK14 in the cytoplasm in an inactive form.
LOXHD1	Lipoxygenase homology domain-containing protein 1	Involved in hearing.

Protein-family classification

Druggable: 9 · Difficult: 17 · Unknown: 29 · Druggable fraction: 0.16

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
Scaffold/PPI	8	2.5×	0.119
Phosphatase	2	3.0×	0.472
Transporter	2	2.8×	0.472
Transcription factor	9	1.4×	0.487
Ion channel	1	2.0×	0.704
Antibody/Immunoglobulin	2	1.1×	0.850
Other/Unknown	29	0.9×	0.933
Kinase	1	0.5×	0.976
Enzyme (other)	1	0.2×	0.992

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SIX1	Transcription factor	no		HD, KN_HD, Homeodomain-like_sf
WFS1	Other/Unknown	no		TPR-like_helical_dom_sf, Wolframin, Wolframin_fam
P2RX2	Other/Unknown	no		P2X_purnocptor, P2X2_purnocptor, P2X_extracellular_dom_sf
DIABLO	Other/Unknown	no		Smac/DIABLO-like_sf, Smac_DIABLO
COL11A1	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
MYH14	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
ABCC1	Transporter	yes	7.6.2.2	ABC_transporter-like_ATP-bd, AAA+_ATPase, MRP
KCNQ4	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C
MYO6	Scaffold/PPI	no		Myosin_head_motor_dom-like, SH3_Myosin, Myosin_S1_N
ATP2B2	Transcription factor	no	7.2.2.10	P_typ_ATPase, ATPase_P-typ_cation-transptr_N, ATPase_P-typ_cation-transptr_C
PDE1C	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, HD/PDEase_dom, PDE1_N
PLS1	Other/Unknown	no		Actinin_actin-bd_CS, CH_dom, EF_hand_dom
TECTA	Other/Unknown	no		EGF, VWF_dom, ZP_dom
TJP2	Scaffold/PPI	no		SH3_domain, PDZ, ZO
TRRAP	Kinase	yes		PI3/4_kinase_cat_dom, PIK-rel_kinase_FAT, FATC_dom
MACF1	Scaffold/PPI	no		Spectrin_repeat, EF_hand_dom, GAR_dom
RIPOR2	Other/Unknown	no		ARM-like, ARM-type_fold, RIPOR3
SLC44A4	Other/Unknown	no		Choline_transptr-like
ACTG1	Other/Unknown	no		Actin, Actin_CS, Actin/actin-like_CS
DIAPH3	Other/Unknown	no		FH3_dom, GTPase-bd, ARM-like
OSBPL2	Other/Unknown	no		Oxysterol-bd, Oxysterol-bd_CS, OSBP_sf
CD164	Other/Unknown	no		CD164_MGC24
TMC1	Other/Unknown	no		TMC_dom, TMC
HOMER2	Other/Unknown	no		WH1/EVH1_dom, PH-like_dom_sf, Homer_EVH1
CCDC50	Other/Unknown	no		CCDC50_N, CCDC50
SLC17A8	Transporter	yes		MFS, MFS_dom, MFS_trans_sf
COCH	Other/Unknown	no		VWF_A, LCCL, vWFA_dom_sf
COL11A2	Other/Unknown	no		Fib_collagen_C, Laminin_G, Collagen
CRYM	Enzyme (other)	yes	1.5.1.21	ODC_Mu_crystall, ODC_N, NAD(P)-bd_dom_sf
GRHL2	Transcription factor	no		CP2, TF_CP2-like, GRHL1/CP2_C
GSDME	Other/Unknown	no		Gasdermin_pore, Gasdermin_PUB, GSDME
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
DMXL2	Scaffold/PPI	no		WD40_rpt, WD40/YVTN_repeat-like_dom_sf, Rav1p_C
CEACAM16	Antibody/Immunoglobulin	yes		Ig_sub2, Ig_sub, Ig-like_dom
EYA4	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
GJB2	Other/Unknown	no		Connexin, Connexin26, Connexin_N
GJB3	Other/Unknown	no		Connexin, Connexin31, Connexin_N
GJB6	Other/Unknown	no		Connexin, Connexin_N, Connexin_CS
TNC	Antibody/Immunoglobulin	yes		EGF, Fibrinogen_a/b/g_C_dom, FN3_dom
KITLG	Other/Unknown	no		SCF, 4_helix_cytokine-like_core
LMX1A	Transcription factor	no		HD, Znf_LIM, Homeodomain-like_sf
MCM2	Other/Unknown	no		MCM_dom, MCM2, NA-bd_OB-fold
MYH9	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
MYO1C	Other/Unknown	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_TH1
MYO1E	Scaffold/PPI	no		SH3_domain, Myosin_head_motor_dom-like, Myosin_TH1
MYO7A	Scaffold/PPI	no		IQ_motif_EF-hand-BS, FERM_domain, MyTH4_dom
NCOA3	Transcription factor	no	2.3.1.48	PAS, Nuc_rcpt_coact, NCO_DUF1518
POU4F3	Transcription factor	no		POU_dom, HD, Homeodomain-like_sf
PTPRQ	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat
PTPRR	Phosphatase	yes	3.1.3.48	PTP_cat, Tyr_Pase_dom, Tyr_Pase_cat

Expression context

Cohort genes with no expression data: 0.

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

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	1
broad (>20)	54
unknown	0

Top tissues across cohort

Tissue	Cohort genes
male germ line stem cell (sensu Vertebrata) in testis	7
skeletal muscle tissue of biceps brachii	4
right lung	4
ileal mucosa	4
secondary oocyte	4
ventricular zone	4
buccal mucosa cell	4
parotid gland	3
mucosa of transverse colon	3
corpus callosum	3
endothelial cell	3
sperm	3
primordial germ cell in gonad	3
biceps brachii	2
left testis	2
right testis	2
gastrocnemius	2
lower esophagus	2
lower esophagus mucosa	2
lower esophagus muscularis layer	2

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SIX1	188	ubiquitous	marker	skeletal muscle tissue of biceps brachii, biceps brachii, parotid gland
WFS1	280	ubiquitous	marker	right ovary, left ovary, body of uterus
P2RX2	134	tissue_specific	yes	mucosa of stomach, esophagogastric junction muscularis propria, right lung
DIABLO	142	ubiquitous	marker	right testis, left testis, islet of Langerhans
COL11A1	209	broad	marker	tibia, cartilage tissue, periodontal ligament
MYH14	227	broad	marker	mucosa of transverse colon, ileal mucosa, gastrocnemius
ABCC1	134	ubiquitous	marker	lower esophagus mucosa, lower esophagus, lower esophagus muscularis layer
KCNQ4	182	broad	marker	pigmented layer of retina, lower esophagus muscularis layer, lower esophagus
MYO6	278	ubiquitous	marker	amniotic fluid, medial globus pallidus, corpus callosum
ATP2B2	203	tissue_specific	marker	lateral nuclear group of thalamus, endothelial cell, Brodmann (1909) area 46
PDE1C	222	broad	marker	endothelial cell, heart right ventricle, corpus callosum
PLS1	236	ubiquitous	marker	secondary oocyte, jejunal mucosa, ileal mucosa
TECTA	166		marker	oocyte, secondary oocyte, parotid gland
TJP2	134	ubiquitous	marker	corpus callosum, descending thoracic aorta, thoracic aorta
TRRAP	241	ubiquitous	marker	ventricular zone, sural nerve, ganglionic eminence
MACF1	303	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, right lung
RIPOR2	250	broad	marker	blood, monocyte, mononuclear cell
SLC44A4	130	tissue_specific	marker	mucosa of transverse colon, right uterine tube, rectum
ACTG1	288	ubiquitous	marker	ileal mucosa, ventricular zone, amniotic fluid
DIAPH3	204	ubiquitous	marker	sperm, ventricular zone, male germ cell
OSBPL2	288	ubiquitous	marker	lateral nuclear group of thalamus, lower esophagus mucosa, skin of leg
CD164	303	ubiquitous	marker	mucosa of sigmoid colon, bronchial epithelial cell, colonic mucosa
TMC1	150		marker	male germ line stem cell (sensu Vertebrata) in testis, buccal mucosa cell, primordial germ cell in gonad
HOMER2	237	ubiquitous	marker	body of pancreas, olfactory segment of nasal mucosa, pancreas
CCDC50	256	ubiquitous	marker	oviduct epithelium, ileal mucosa, calcaneal tendon
SLC17A8	81	tissue_specific	marker	male germ line stem cell (sensu Vertebrata) in testis, primordial germ cell in gonad, small intestine Peyer’s patch
COCH	272	broad	marker	buccal mucosa cell, saphenous vein, skeletal muscle tissue of biceps brachii
COL11A2	134	broad	yes	pituitary gland, male germ line stem cell (sensu Vertebrata) in testis, adenohypophysis
CRYM	252	broad	marker	cortical plate, cerebellar vermis, frontal pole
GRHL2	200	broad	marker	buccal mucosa cell, oviduct epithelium, cervix squamous epithelium

Protein interactions among cohort

Intra-cohort edges: 52.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MYH9	5,533
TRRAP	4,847
MCM2	4,472
ATP2B2	3,932
WFS1	3,409
KITLG	3,075
ABCC1	3,018
MYO6	2,972
TJP2	2,916
MITF	2,908

Intra-cohort edges

A	B	Sources
ACTG1	MYH9	biogrid_interaction
ACTG1	MYO1C	biogrid_interaction
ATP2B2	PTPRQ	intact
CCDC50	MYH9	intact
CEACAM16	LOXHD1	string_interaction
CEACAM16	MYH14	string_interaction
CEACAM16	TECTA	string_interaction
COCH	GJB2	string_interaction
COCH	TECTA	string_interaction
COCH	WFS1	intact
COL11A2	TECTA	string_interaction
CRYM	GJB3	string_interaction
CRYM	MYH9	string_interaction
CRYM	SLC17A8	string_interaction
CRYM	TMC1	string_interaction
EYA4	KCNQ4	string_interaction
EYA4	SIX1	biogrid_interaction, intact, string_interaction
GJB2	GJB3	biogrid_interaction, string_interaction
GJB2	GJB6	string_interaction
GJB2	KCNQ4	string_interaction
GJB2	MYH14	string_interaction
GJB2	TECTA	string_interaction
GJB2	TMC1	string_interaction
GJB2	WFS1	string_interaction
GJB3	GJB6	string_interaction
GJB3	KCNQ4	string_interaction
GJB3	TMC1	string_interaction
GJB3	WFS1	string_interaction
GJB6	TJP2	string_interaction
GJB6	WFS1	string_interaction
GRHL2	KCNQ4	string_interaction
KCNQ4	MYH14	string_interaction
KCNQ4	MYO6	string_interaction
KCNQ4	POU4F3	string_interaction
KCNQ4	SLC17A8	string_interaction
KCNQ4	TMC1	string_interaction
LOXHD1	TMC1	string_interaction
MYH14	TECTA	string_interaction
MYH9	MYO1E	biogrid_interaction, intact
MYO1C	MYO1E	string_interaction
MYO6	POU4F3	string_interaction
MYO6	PTPRQ	string_interaction
MYO6	SLC44A4	biogrid_interaction
MYO6	TMC1	string_interaction
NCOA3	SIX1	string_interaction
P2RX2	WFS1	biogrid_interaction
POU4F3	SLC17A8	string_interaction
POU4F3	TMC1	string_interaction
PTPRQ	TMC1	string_interaction
SLC17A8	TMC1	string_interaction

Structural data

PDB: 32 · AlphaFold-only: 22 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MCM2	P49736	39
GJB2	P29033	24
TNC	P24821	21
P2RX2	Q9UBL9	18
DIABLO	Q9NR28	16
KCNQ4	P56696	13
MITF	O75030	12
ACTG1	P63261	10
TRRAP	Q9Y4A5	9
MYO6	Q9UM54	8
MYH9	P35579	8
KITLG	P21583	6
NCOA3	Q9Y6Q9	6
ABCC1	P33527	5
MACF1	O94854	3
GSDME	O60443	3
LMX1A	Q8TE12	3
REST	Q13127	3
MYH14	Q7Z406	2
TJP2	Q9UDY2	2
DIAPH3	Q9NSV4	2
SIX1	Q15475	1
OSBPL2	Q9H1P3	1
TMC1	Q8TDI8	1
CCDC50	Q8IVM0	1
COCH	O43405	1
CRYM	Q14894	1
GRHL2	Q6ISB3	1
MYO1C	O00159	1
MYO7A	Q13402	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
CEACAM16	Q2WEN9	90.50
HOMER2	Q9NSB8	89.20
PLS1	Q14651	87.52
TBC1D24	Q9ULP9	84.46
LOXHD1	Q8IVV2	84.00
SLC44A4	Q53GD3	83.79
GJB6	O95452	82.33
MYO1E	Q12965	80.46
GJB3	O75712	79.29
SLC17A8	Q8NDX2	77.81
TECTA	O75443	77.64
WFS1	O76024	73.85
ATP2B2	Q01814	73.83
GREB1L	Q9C091	72.90
PDE1C	Q14123	71.53
CD164	Q04900	67.15
RIPOR2	Q9Y4F9	66.28
POU4F3	Q15319	65.58
EYA4	O95677	63.79
COL11A1	P12107	53.06
COL11A2	P13942	50.18
DMXL2	Q8TDJ6

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 243. Enrichment computed across 55 evidence-associated genes (40 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 40 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Sensory processing of sound by inner hair cells of the cochlea	10	40.8×	7e-12	KCNQ4, ATP2B2, PLS1, RIPOR2, ACTG1, TMC1, SLC17A8, MYH9 (+2 more)
Sensory processing of sound by outer hair cells of the cochlea	9	45.9×	2e-11	KCNQ4, ATP2B2, PLS1, RIPOR2, ACTG1, TMC1, MYH9, MYO1C (+1 more)
Sensory processing of sound	5	38.6×	1e-05	KCNQ4, ACTG1, MYH9, MYO1C, MYO7A
Sensory Perception	5	11.9×	0.004	KCNQ4, ACTG1, MYH9, MYO1C, MYO7A
Non-integrin membrane-ECM interactions	4	15.4×	0.006	COL11A1, ACTG1, COL11A2, TNC
Release of apoptotic factors from the mitochondria	2	81.6×	0.007	DIABLO, GSDME
Regulation of MITF-M-dependent genes involved in DNA replication, damage repair and senescence	2	81.6×	0.007	MCM2, MITF
Parasite infection	3	25.9×	0.007	ACTG1, MYH9, MYO1C
Leishmania phagocytosis	3	25.9×	0.007	ACTG1, MYH9, MYO1C
Gap junction assembly	3	22.0×	0.008	GJB2, GJB3, GJB6
Fcgamma receptor (FCGR) dependent phagocytosis	3	20.9×	0.009	ACTG1, MYH9, MYO1C
Gap junction degradation	2	47.6×	0.016	MYO6, ACTG1
RHOBTB GTPase Cycle	2	40.8×	0.020	MYO6, ACTG1
FCGR3A-mediated phagocytosis	3	14.0×	0.021	ACTG1, MYH9, MYO1C
Regulation of actin dynamics for phagocytic cup formation	3	13.8×	0.021	ACTG1, MYH9, MYO1C
Sema4D in semaphorin signaling	2	33.6×	0.023	MYH14, MYH9
RHO GTPases activate CIT	2	30.1×	0.023	MYH14, MYH9
RHO GTPases Activate ROCKs	2	30.1×	0.023	MYH14, MYH9
EPH-Ephrin signaling	3	12.4×	0.023	MYH14, ACTG1, MYH9
Leishmania infection	3	12.2×	0.023	ACTG1, MYH9, MYO1C
Parasitic Infection Pathways	3	12.2×	0.023	ACTG1, MYH9, MYO1C
Sema4D induced cell migration and growth-cone collapse	2	28.6×	0.023	MYH14, MYH9
Translocation of SLC2A4 (GLUT4) to the plasma membrane	3	11.6×	0.023	ACTG1, MYH9, MYO1C
RHO GTPases activate PAKs	2	27.2×	0.024	MYH14, MYH9
Gap junction trafficking and regulation	2	23.8×	0.028	MYO6, ACTG1
Gap junction trafficking	2	23.8×	0.028	MYO6, ACTG1
RHOBTB2 GTPase cycle	2	23.8×	0.028	MYO6, ACTG1
Defective SLC17A8 causes autosomal dominant deafness 25 (DFNA25)	1	285.5×	0.030	SLC17A8
Membrane Trafficking	5	4.6×	0.035	MYO6, ACTG1, TBC1D24, MYH9, MYO1C
Semaphorin interactions	2	19.7×	0.037	MYH14, MYH9

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 54 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sensory perception of sound	24	44.9×	9e-32	SIX1, WFS1, P2RX2, COL11A1, MYH14, KCNQ4, MYO6, ATP2B2 (+16 more)
actin filament-based movement	5	74.3×	1e-06	MYH14, MYO6, MYH9, MYO1C, MYO7A
detection of mechanical stimulus involved in sensory perception of sound	4	69.3×	5e-05	COL11A1, TMC1, PTPRQ, REST
auditory receptor cell stereocilium organization	4	62.4×	6e-05	PLS1, TECTA, MYO7A, REST
inner ear morphogenesis	5	27.9×	1e-04	SIX1, COL11A1, KCNQ4, MYO6, POU4F3
inner ear auditory receptor cell differentiation	3	66.9×	0.001	MYO6, GSDME, POU4F3
gap junction-mediated intercellular transport	2	104.0×	0.012	GJB2, GJB6
maintenance of blood-brain barrier	3	26.8×	0.012	TJP2, ACTG1, GJB6
cochlea development	3	26.0×	0.012	SLC17A8, MCM2, MYO7A
gap junction assembly	2	78.0×	0.015	GJB2, GJB6
transmembrane transport	4	12.5×	0.015	ABCC1, SLC44A4, GJB2, GJB6
olfactory behavior	2	69.3×	0.016	WFS1, LMX1A
negative regulation of cell adhesion	3	21.3×	0.016	RIPOR2, CD164, TNC
inner ear development	3	20.8×	0.016	SIX1, EYA4, GJB6
visual perception	5	7.4×	0.021	WFS1, COL11A1, EYA4, MYO7A, POU4F3
nervous system process	2	44.6×	0.030	WFS1, REST
actin filament organization	4	8.8×	0.035	MYO6, MYO1C, MYO1E, MYO7A
protein-containing complex remodeling	1	312.1×	0.047	DIAPH3
neuromast hair cell development	1	312.1×	0.047	SLC44A4
antigen processing and presentation of lipid antigen via MHC class Ib	1	312.1×	0.047	ABCC1
regulation of acetylcholine uptake	1	312.1×	0.047	SLC17A8
pigment granule transport	1	312.1×	0.047	MYO7A
vestibular receptor cell stereocilium organization	1	312.1×	0.047	PLS1
acetylcholine secretion	1	312.1×	0.047	SLC44A4
cyclic nucleotide transport	1	312.1×	0.047	ABCC1
mesonephric tubule formation	1	312.1×	0.047	SIX1
mesenchymal cell proliferation involved in ureter development	1	312.1×	0.047	SIX1
epithelium migration	1	312.1×	0.047	GRHL2
sphingolipid translocation	1	312.1×	0.047	ABCC1
intracellular nitrogen homeostasis	1	312.1×	0.047	ABCC1

Therapeutics

Drug target analysis

Approved (phase 4): 8 · Phase ≥3: 8 · Phased (≥1): 9 · Undrugged: 46

Druggability breadth: 20 of 55 evidence-associated genes (36%) 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
P2RX2	GEFAPIXANT
MYH14	TUCATINIB
ABCC1	RIMONABANT
KCNQ4	EZOGABINE
PDE1C	VARDENAFIL
GJB2	KANAMYCIN
NCOA3	METHOTREXATE
MITF	PERHEXILINE MALEATE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ABCC1	23	4
PDE1C	15	4
P2RX2	4	4
NCOA3	4	4
MITF	3	4
KCNQ4	2	4
MYH14	1	4
GJB2	1	4
MYH9	1	2
SIX1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
GEFAPIXANT	4	P2RX2
TUCATINIB	4	MYH14
RIMONABANT	4	ABCC1
VINBLASTINE	4	ABCC1
CYCLOSPORINE	4	ABCC1
DAUNORUBICIN	4	ABCC1
ETRAVIRINE	4	ABCC1
BENZBROMARONE	4	ABCC1
ESTRONE SULFURIC ACID	4	ABCC1
DOXORUBICIN	4	ABCC1
MITOXANTRONE	4	ABCC1
INDOMETHACIN	4	ABCC1
IVERMECTIN	4	ABCC1
VERAPAMIL	4	ABCC1
VINCRISTINE	4	ABCC1
EZOGABINE	4	KCNQ4
VARDENAFIL	4	PDE1C
SILDENAFIL	4	PDE1C
VINPOCETINE	4	PDE1C
DIPYRIDAMOLE	4	PDE1C
NIMODIPINE	4	PDE1C
KANAMYCIN	4	GJB2
METHOTREXATE	4	NCOA3
ETOPOSIDE	4	NCOA3
CYTARABINE	4	NCOA3
METHYLENE BLUE ANHYDROUS	4	NCOA3
PERHEXILINE MALEATE	4	MITF
SURAMIN	3	P2RX2
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX2
VALSPODAR	3	ABCC1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 7.

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

Symbol	Assays	Type breakdown
ABCC1	459	Binding:270, Functional:166, ADMET:23
PDE1C	185	Binding:175, ADMET:5, Functional:5
P2RX2	96	Binding:67, Functional:29
KCNQ4	48	Binding:42, Functional:3, ADMET:2, Toxicity:1
NCOA3	42	Binding:39, Functional:3
MCM2	22	Binding:22
SIX1	12	Binding:12
MYH9	10	Binding:10
MITF	10	Functional:10
GJB2	5	Binding:5
PTPRR	3	Binding:3
WFS1	1	Binding:1
MYH14	1	Binding:1
TRRAP	1	Binding:1
KITLG	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ABCC1	7.6.2.2, 7.6.2.3	ABC-type xenobiotic transporter, ABC-type glutathione-S-conjugate transporter
ATP2B2	7.2.2.10	P-type Ca2+ transporter
PDE1C	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
CRYM	1.5.1.21, 1.5.1.25	1-piperideine-2-carboxylate/1-pyrroline-2-carboxylate reductase (NADPH), thiomorpholine-carboxylate dehydrogenase
NCOA3	2.3.1.48	histone acetyltransferase
PTPRQ	3.1.3.48	protein-tyrosine-phosphatase
PTPRR	3.1.3.48	protein-tyrosine-phosphatase

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
ABCC1	459
PDE1C	185

Pharmacogenomics

Cohort genes with a PharmGKB record: 54; 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)
GEFAPIXANT	4	P2RX2
TUCATINIB	4	MYH14
RIMONABANT	4	ABCC1
VINBLASTINE	4	ABCC1
CYCLOSPORINE	4	ABCC1
DAUNORUBICIN	4	ABCC1
ETRAVIRINE	4	ABCC1
BENZBROMARONE	4	ABCC1
ESTRONE SULFURIC ACID	4	ABCC1
DOXORUBICIN	4	ABCC1
MITOXANTRONE	4	ABCC1
INDOMETHACIN	4	ABCC1
IVERMECTIN	4	ABCC1
VERAPAMIL	4	ABCC1
VINCRISTINE	4	ABCC1
EZOGABINE	4	KCNQ4
VARDENAFIL	4	PDE1C
SILDENAFIL	4	PDE1C
VINPOCETINE	4	PDE1C
DIPYRIDAMOLE	4	PDE1C
NIMODIPINE	4	PDE1C
KANAMYCIN	4	GJB2
METHOTREXATE	4	NCOA3
ETOPOSIDE	4	NCOA3
CYTARABINE	4	NCOA3
METHYLENE BLUE ANHYDROUS	4	NCOA3
PERHEXILINE MALEATE	4	MITF
SURAMIN	3	P2RX2
PYRIDOXAL PHOSPHATE ANHYDROUS	3	P2RX2
VALSPODAR	3	ABCC1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	8	P2RX2, MYH14, ABCC1, KCNQ4, PDE1C, GJB2, NCOA3, MITF
B	Phased (≥1) drug, not yet approved	1	MYH9
C	Druggable family + PDB, no drug	5	TRRAP, CRYM, TNC, PTPRQ, PTPRR
D	Druggable family + AlphaFold only, no drug	2	SLC17A8, CEACAM16
E	Difficult family or no structure, no drug	39	SIX1, WFS1, DIABLO, COL11A1, MYO6, ATP2B2, PLS1, TECTA, TJP2, MACF1 (+29 more)

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WFS1	1	GJB2
GJB3	0	KCNQ4, GJB2
GJB6	0	GJB2
SIX1	12	—
DIABLO	0	—
COL11A1	0	—
MYO6	0	—
ATP2B2	0	—
PLS1	0	—
TECTA	0	—
TJP2	0	—
TRRAP	1	—
MACF1	0	—
RIPOR2	0	—
SLC44A4	0	—
ACTG1	0	—
DIAPH3	0	—
OSBPL2	0	—
CD164	0	—
TMC1	0	—
HOMER2	0	—
CCDC50	0	—
SLC17A8	0	—
COCH	0	—
COL11A2	0	—
CRYM	0	—
GRHL2	0	—
GSDME	0	—
TBC1D24	0	—
DMXL2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.