KCNQ4

Chr 1AD

potassium voltage-gated channel subfamily Q member 4

Also known as: DFNA2, DFNA2A, KV7.4

NCBI Gene: 9132 ENSG00000117013 UniProt: P56696 OMIM: 603537

This gene encodes a voltage-gated potassium channel subunit that regulates excitability of sensory cells in the cochlea by controlling potassium ion outflow during action potential repolarization. Mutations cause autosomal dominant nonsyndromic sensorineural hearing loss (DFNA2A) with progressive hearing impairment. The gene is moderately constrained against loss-of-function variants (LOEUF 0.41), reflecting its importance for cochlear function.

GeneReviews OMIM ResearchSummary from RefSeq, OMIM, UniProt

The protein encoded by this gene forms a potassium channel that is thought to play a critical role in the regulation of neuronal excitability, particularly in sensory cells of the cochlea. The current generated by this channel is inhibited by M1 muscarinic acetylcholine receptors and activated by retigabine, a novel anti-convulsant drug. The encoded protein can form a homomultimeric potassium channel or possibly a heteromultimeric channel in association with the protein encoded by the KCNQ3 gene. Defects in this gene are a cause of nonsyndromic sensorineural deafness type 2 (DFNA2), an autosomal dominant form of progressive hearing loss. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

GeneReviews OMIM ResearchGenerating clinical summary…

MultiplemechanismADLOEUF 0.411 OMIM phenotype

Clinical Summary— KCNQ4

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Gene-Disease Validity (ClinGen)

nonsyndromic genetic hearing loss · ADDefinitive

Definitive — sufficient evidence for diagnostic panels

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Population Constraint (gnomAD)

Constrained for loss-of-function variants (OE-LoF 0.22) despite low pLI — interpret in context.

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GeneReview available — KCNQ4

Authoritative clinical overview · Recommended first read

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Population Genetics & Constraint

gnomAD v4 — loss-of-function & missense intolerance

gnomAD

Moderate LoF intolerance

LoF Constraint?

0.41LOEUF

pLI 0.468

Z-score 4.10

OE 0.22 (0.12–0.41)

Moderately constrained

More LoF-intolerant than ~75% of genes

Missense Constraint?

2.17Z-score

OE missense 0.70 (0.63–0.77)

288 obs / 412.2 exp

Mild constraint

Moderately missense-constrained (top ~2.5%)

Observed / Expected Ratios?

LoF OE?0.22 (0.12–0.41)

0≤0.351.4

Missense OE?0.70 (0.63–0.77)

0≤0.61.4

Synonymous OE?0.87

0≤1.21.6

LoF obs/exp: 7 / 32.1Missense obs/exp: 288 / 412.2Syn Z: 1.35

This gene — mechanism propensity

0.79top 25%

GOF

0.84top 5%

LOF

0.4135th %ile

This gene has evidence for multiple mechanisms of pathogenicity (dominant-negative, gain-of-function and loss-of-function). The Badonyi & Marsh model scores gain-of-function highest among its predictions, but genomic evidence (constraint, ClinVar variant spectrum, and literature) most strongly supports dominant-negative. Different variants in this gene may act through different mechanisms — interpret in context of the specific variant.

DNprediction above median · 1 literature citation

GOFprediction above median

LOF1 literature citation · LOEUF 0.41

Note: In-silico variant effect predictors (SIFT, PolyPhen, REVEL, CADD) may underestimate pathogenicity of missense variants in genes with GOF or DN mechanisms. Consider functional evidence and clinical context.

Literature Evidence

DNDominant-negative inhibition accounts for the observed dominant inheritance of many DFNA2-associated KCNQ4 variants.1

LOFKamada et al. (2006) postulated different pathogenic mechanisms to explain the phenotypic differences: haploinsufficiency in deletion mutations and dominant-negative effects in missense mutations.2

Predictions from Badonyi M, Marsh JA. PLoS ONE. 2024;19(8):e0307312. Mechanism ranking also informed by gnomAD constraint, ClinVar, and ClinGen data.

References