Autosomal dominant nonsyndromic hearing loss 10

Summary

Autosomal dominant nonsyndromic hearing loss 10 (MONDO:0011031) is a disease caused by EYA4 (GenCC Definitive), with 3 cohort genes.

At a glance

• Causal gene: EYA4 (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 149

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 10
Mondo ID	MONDO:0011031
MeSH	C563354
OMIM	601316
DOID	DOID:0110542
UMLS	C1832476
MedGen	321966
GARD	0018103
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 10 · autosomal dominant nonsyndromic deafness 10 · autosomal dominant nonsyndromic deafness caused by mutation in EYA4 · autosomal dominant nonsyndromic deafness type 10 · autosomal dominant nonsyndromic hearing loss 10 · deafness, autosomal dominant 10 · deafness, autosomal dominant type 10 · DFNA10 · EYA4 autosomal dominant nonsyndromic deafness

Data availability: 149 ClinVar variants · 2 GenCC gene-disease records · 4 cell lines.

Disease family

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 › autosomal dominant nonsyndromic hearing loss 10

Related subtypes (75): 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 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

149 retrieved; paginated sample, class counts are floors:

68 uncertain significance, 25 conflicting classifications of pathogenicity, 17 benign/likely benign, 14 likely pathogenic, 12 pathogenic, 9 benign, 3 likely benign, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1185054	NM_004100.5(EYA4):c.964C>T (p.Gln322Ter)	EYA4	Pathogenic	no assertion criteria provided
1185629	NM_004100.5(EYA4):c.804+2T>A	EYA4	Pathogenic	no assertion criteria provided
1185652	NM_004100.5(EYA4):c.804+2del	EYA4	Pathogenic	no assertion criteria provided
1210331	NM_004100.5(EYA4):c.1154C>A (p.Ser385Ter)	EYA4	Pathogenic	criteria provided, single submitter
1322847	NM_004100.5(EYA4):c.1026_1027dup (p.Thr343fs)	EYA4	Pathogenic	no assertion criteria provided
1322854	NM_004100.5(EYA4):c.1048_1049dup (p.Arg352fs)	EYA4	Pathogenic	no assertion criteria provided
236032	NM_004100.5(EYA4):c.441del (p.Tyr148fs)	EYA4	Pathogenic	no assertion criteria provided
2445629	NM_004100.5(EYA4):c.992dup (p.Ser331fs)	EYA4	Pathogenic	criteria provided, single submitter
3632752	NM_004100.5(EYA4):c.243del (p.Trp81fs)	EYA4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
4073547	NM_004100.5(EYA4):c.517C>T (p.Gln173Ter)	EYA4	Pathogenic	criteria provided, single submitter
813822	NM_004100.5(EYA4):c.1720_1722delinsAAA (p.Tyr574Lys)	EYA4	Pathogenic	criteria provided, single submitter
523780	NM_004100.5(EYA4):c.1759C>T (p.Arg587Ter)	TARID	Pathogenic	criteria provided, multiple submitters, no conflicts
6240	NM_004100.5(EYA4):c.1282-12T>A	TARID	Pathogenic	no assertion criteria provided
1687435	NM_004100.5(EYA4):c.1468G>T (p.Glu490Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
3338283	NM_004100.5(EYA4):c.1745_1748del (p.Glu582fs)	EYA4	Likely pathogenic	criteria provided, single submitter
3370331	NM_004100.5(EYA4):c.1122G>A (p.Trp374Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
3377569	NM_004100.5(EYA4):c.905del (p.Gly302fs)	EYA4	Likely pathogenic	criteria provided, single submitter
3601116	NM_004100.5(EYA4):c.1173T>A (p.Tyr391Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
3601117	NM_004100.5(EYA4):c.1173T>G (p.Tyr391Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
3601118	NM_004100.5(EYA4):c.1200dup (p.Met401fs)	EYA4	Likely pathogenic	criteria provided, single submitter
3601123	NM_004100.5(EYA4):c.725-2A>G	EYA4	Likely pathogenic	criteria provided, single submitter
3601124	NM_004100.5(EYA4):c.838C>T (p.Gln280Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
982918	NM_004100.5(EYA4):c.472C>T (p.Gln158Ter)	EYA4	Likely pathogenic	criteria provided, single submitter
3601121	NM_004100.5(EYA4):c.310_314del (p.Asn104fs)	EYA4-AS2	Likely pathogenic	criteria provided, single submitter
3601119	NM_004100.5(EYA4):c.1486A>T (p.Lys496Ter)	TARID	Likely pathogenic	criteria provided, single submitter
3601120	NM_004100.5(EYA4):c.1519A>T (p.Lys507Ter)	TARID	Likely pathogenic	criteria provided, single submitter
623134	NM_004100.5(EYA4):c.1347C>G (p.Tyr449Ter)	TARID	Likely pathogenic	criteria provided, single submitter
1205113	NM_004100.5(EYA4):c.1739-89_1739-85del	EYA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1372072	NM_004100.5(EYA4):c.213A>C (p.Glu71Asp)	EYA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
163446	NM_004100.5(EYA4):c.866C>T (p.Thr289Met)	EYA4	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 7 · Orphanet: 2 · 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
EYA4	Definitive	Autosomal dominant	nonsyndromic genetic hearing loss	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
EYA4	Orphanet:217622	Sensorineural deafness with dilated cardiomyopathy
EYA4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

3 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
EYA4	HGNC:3522	ENSG00000112319	O95677	Protein phosphatase EYA4	gencc,clinvar
TARID	HGNC:50506	ENSG00000227954		TCF21 antisense RNA inducing promoter demethylation	clinvar
EYA4-AS2	HGNC:58230	ENSG00000234567		EYA4 antisense RNA 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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…

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.0

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
Other/Unknown	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
EYA4	Other/Unknown	no		EYA_dom, EYA, EYA_dom_sf
TARID	Other/Unknown	no
EYA4-AS2	Other/Unknown	no

Expression context

Cohort genes with no expression data: 0.

2 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
biceps brachii	1
seminal vesicle	1
skeletal muscle tissue of biceps brachii	1
left ovary	1
ovary	1
sural nerve	1
calcaneal tendon	1
corpus callosum	1
primordial germ cell in gonad	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
EYA4	208	broad	marker	biceps brachii, skeletal muscle tissue of biceps brachii, seminal vesicle
TARID	123	tissue_specific	marker	sural nerve, left ovary, ovary
EYA4-AS2	108		yes	calcaneal tendon, primordial germ cell in gonad, corpus callosum

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EYA4	1,679
TARID	0
EYA4-AS2	0

Structural data

PDB: 0 · AlphaFold-only: 1 · No structure: 2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
EYA4	O95677	63.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 1. Enrichment computed across 3 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks	1	146.4×	0.007	EYA4

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of extrinsic apoptotic signaling pathway in absence of ligand	1	411.0×	0.007	EYA4
inner ear development	1	374.5×	0.007	EYA4
positive regulation of DNA repair	1	358.6×	0.007	EYA4
anatomical structure morphogenesis	1	139.3×	0.014	EYA4
chromatin organization	1	99.1×	0.016	EYA4
visual perception	1	79.5×	0.017	EYA4
DNA repair	1	63.8×	0.018	EYA4
cell differentiation	1	29.1×	0.034	EYA4

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 3

Druggability breadth: 0 of 3 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EYA4	0	0
TARID	0	0
EYA4-AS2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

0 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.

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	0
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	EYA4, TARID, EYA4-AS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
EYA4	0	—
TARID	0	—
EYA4-AS2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.