autosomal dominant nonsyndromic hearing loss 2A

Summary

autosomal dominant nonsyndromic hearing loss 2A (MONDO:0010817) is a disease caused by KCNQ4 (GenCC Definitive), with 1 cohort gene.

At a glance

• Causal gene: KCNQ4 (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 106

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	autosomal dominant nonsyndromic hearing loss 2A
Mondo ID	MONDO:0010817
MeSH	C567441
OMIM	600101
DOID	DOID:0110558
UMLS	C2677637
MedGen	436997
GARD	0018099
Is cancer (heuristic)	no

Also known as: autosomal dominant deafness 2A · autosomal dominant nonsyndromic deafness 2A · autosomal dominant nonsyndromic deafness caused by mutation in KCNQ4 · autosomal dominant nonsyndromic deafness type 2A · deafness, autosomal dominant 2A · deafness, autosomal dominant 2a · deafness, autosomal dominant type 2A · DFNA2A · KCNQ4 autosomal dominant nonsyndromic deafness

Data availability: 106 ClinVar variants · 3 GenCC gene-disease records.

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 2A

Related subtypes (75): autosomal dominant nonsyndromic hearing loss 1, 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

106 retrieved; paginated sample, class counts are floors:

34 uncertain significance, 19 pathogenic, 15 benign, 14 likely pathogenic, 7 likely benign, 6 conflicting classifications of pathogenicity, 5 benign/likely benign, 4 pathogenic/likely pathogenic, 2 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
65888	c.667_684del(664_681del)		Pathogenic	no assertion criteria provided
156337	NM_004700.4(KCNQ4):c.859G>C (p.Gly287Arg)	KCNQ4	Pathogenic	no assertion criteria provided
208364	NM_004700.4(KCNQ4):c.228_229dup (p.His77fs)	KCNQ4	Pathogenic	no assertion criteria provided
208365	NM_004700.4(KCNQ4):c.689T>A (p.Val230Glu)	KCNQ4	Pathogenic	no assertion criteria provided
208366	NM_004700.4(KCNQ4):c.803CCT[1] (p.Ser269del)	KCNQ4	Pathogenic	reviewed by expert panel
208367	NM_004700.4(KCNQ4):c.808T>C (p.Tyr270His)	KCNQ4	Pathogenic	no assertion criteria provided
208368	NM_004700.4(KCNQ4):c.823T>C (p.Trp275Arg)	KCNQ4	Pathogenic	no assertion criteria provided
208369	NM_004700.4(KCNQ4):c.871C>T (p.Pro291Ser)	KCNQ4	Pathogenic	no assertion criteria provided
208370	NM_004700.4(KCNQ4):c.872C>T (p.Pro291Leu)	KCNQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
208372	NM_004700.4(KCNQ4):c.1044_1051del (p.Ala349Profs)	KCNQ4	Pathogenic	no assertion criteria provided
585006	NM_004700.4(KCNQ4):c.140T>C (p.Leu47Pro)	KCNQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6241	NM_004700.4(KCNQ4):c.853G>A (p.Gly285Ser)	KCNQ4	Pathogenic	reviewed by expert panel
6242	NM_004700.4(KCNQ4):c.827G>C (p.Trp276Ser)	KCNQ4	Pathogenic	criteria provided, single submitter
6243	NM_004700.4(KCNQ4):c.961G>A (p.Gly321Ser)	KCNQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
6244	NM_004700.4(KCNQ4):c.853G>T (p.Gly285Cys)	KCNQ4	Pathogenic	criteria provided, single submitter
6245	NM_004700.4(KCNQ4):c.212_224del (p.Gln71fs)	KCNQ4	Pathogenic	no assertion criteria provided
6246	NM_004700.4(KCNQ4):c.842T>C (p.Leu281Ser)	KCNQ4	Pathogenic	criteria provided, multiple submitters, no conflicts
6247	NM_004700.4(KCNQ4):c.821T>A (p.Leu274His)	KCNQ4	Pathogenic	no assertion criteria provided
6248	NM_004700.4(KCNQ4):c.211del (p.Gln71fs)	KCNQ4	Pathogenic	no assertion criteria provided
6249	NM_004700.4(KCNQ4):c.886G>A (p.Gly296Ser)	KCNQ4	Pathogenic	no assertion criteria provided
625441	NM_004700.4(KCNQ4):c.261_269del (p.Tyr88_Val90del)	KCNQ4	Pathogenic	no assertion criteria provided
65893	NM_004700.4(KCNQ4):c.725G>A (p.Trp242Ter)	KCNQ4	Pathogenic	no assertion criteria provided
944908	NM_004700.4(KCNQ4):c.1438C>T (p.Gln480Ter)	KCNQ4	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1184480	NM_004700.4(KCNQ4):c.857A>C (p.Tyr286Ser)	KCNQ4	Likely pathogenic	no assertion criteria provided
1699203	NM_004700.4(KCNQ4):c.826T>C (p.Trp276Arg)	KCNQ4	Likely pathogenic	criteria provided, single submitter
1806181	NM_004700.4(KCNQ4):c.670T>C (p.Trp224Arg)	KCNQ4	Likely pathogenic	criteria provided, single submitter
2120280	NM_004700.4(KCNQ4):c.406-2A>G	KCNQ4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
2440965	NM_004700.4(KCNQ4):c.364C>T (p.Gln122Ter)	KCNQ4	Likely pathogenic	criteria provided, multiple submitters, no conflicts
3382564	NM_004700.4(KCNQ4):c.882G>A (p.Trp294Ter)	KCNQ4	Likely pathogenic	criteria provided, single submitter
3383191	NM_004700.4(KCNQ4):c.1668C>G (p.Tyr556Ter)	KCNQ4	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 6 · Orphanet: 1 · 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
KCNQ4	Definitive	Autosomal dominant	autosomal dominant nonsyndromic hearing loss 2A	6

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNQ4	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNQ4	HGNC:6298	ENSG00000117013	P56696	Potassium voltage-gated channel subfamily KQT member 4	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Ion channel	1	111.5×	0.009

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNQ4	Ion channel	yes		K_chnl_volt-dep_KCNQ, Ion_trans_dom, K_chnl_volt-dep_KCNQ_C

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus	1
lower esophagus muscularis layer	1
pigmented layer of retina	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNQ4	182	broad	marker	pigmented layer of retina, lower esophagus muscularis layer, lower esophagus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNQ4	1,992

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNQ4	P56696	13

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 1 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
Sensory processing of sound	1	308.6×	0.010	KCNQ4
Voltage gated Potassium channels	1	243.0×	0.010	KCNQ4
Sensory processing of sound by outer hair cells of the cochlea	1	203.9×	0.010	KCNQ4
Sensory processing of sound by inner hair cells of the cochlea	1	163.1×	0.010	KCNQ4
Potassium Channels	1	134.3×	0.010	KCNQ4
Sensory Perception	1	95.2×	0.012	KCNQ4
Neuronal System	1	44.3×	0.023	KCNQ4

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
inner ear morphogenesis	1	300.9×	0.010	KCNQ4
potassium ion transport	1	191.5×	0.010	KCNQ4
potassium ion transmembrane transport	1	135.9×	0.010	KCNQ4
sensory perception of sound	1	100.9×	0.010	KCNQ4

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) 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
KCNQ4	EZOGABINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNQ4	2	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EZOGABINE	4	KCNQ4
FLINDOKALNER	3	KCNQ4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNQ4	48	Binding:42, Functional:3, ADMET:2, Toxicity:1

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

2 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)
EZOGABINE	4	KCNQ4
FLINDOKALNER	3	KCNQ4

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNQ4
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 0.