KCNQ4

protein-coding

potassium voltage-gated channel subfamily Q member 4, the group of Potassium voltage-gated channels

Gene summary

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]

Previous symbols:

DFNA2

MANE transcript

NM_004700.4

Inheritance

AD, AR

ClinVar variants

P:67U:270B:97

Top phenotype

Deafness, autosomal dominant 2A

gnomAD constraint

pLI —, LoF o/e 0.22

Max pathogenic AF

—

Genomic locus

chr1:40,783,787-40,840,452

External References & Databases

Ensembl (ENSG00000117013)

Transcript & Mutation Effects

hg38 • Region Span ~56.7 kb

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GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

autosomal dominant nonsyndromic hearing loss 2ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010817

Submitter: Labcorp Genetics (formerly Invitae)

autosomal dominant nonsyndromic hearing lossSUPPORTIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019587

Submitter: Orphanet

nonsyndromic genetic hearing lossDEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0019497

Submitter: ClinGen

The KCNQ4 gene has been associated with autosomal dominant nonsyndromic hearing loss in at least 35 probands in at least 15 publications. 25 unique missense variants, 2 in-frame deletions, and 6 truncating variants have been reported in humans, and there is segregation evidence in many families (PMID: 10369879, 28340560, 18941426, 25116015, 16596322, 26036578, 23717403, 24655070). KCNQ4 was first associated with this disease in humans in 1999 (Coucke et al.). More than enough genetic evidence is available in the literature to reach the maximum score (12 pts.). The hearing loss in patients is progressive and predominantly high-frequency, however the phenotypic spectrum may be variable. The mechanism for disease is either haploinsufficiency or dominant-negative, which is strongly supported by experimental evidence. This gene-disease association is also supported by multiple mouse models, expression evidence, and in vitro functional assays (PMID: 11042367, 24555524, 10025409, 23750663, 16437162). In summary, KCNQ4 is definitively associated with autosomal dominant nonsyndromic hearing loss. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Hearing Loss Working Group on 11/21/2017.

autosomal dominant nonsyndromic hearing loss 2ASTRONG

Inheritance Pattern: AD

Disease ID:MONDO:0010817

Submitter: PanelApp Australia

autosomal dominant nonsyndromic hearing loss 2ADEFINITIVE

Inheritance Pattern: AD

Disease ID:MONDO:0010817

Submitter: Ambry Genetics

hearing loss disorderLIMITED

Inheritance Pattern: AR

Disease ID:MONDO:0005365

Submitter: Ambry Genetics

Clinical Genomic Database (CGD)

Deafness, autosomal dominant 2AAD

Manifestation: Audiologic/Otolaryngologic

Intervention: General

Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing

Comments: The onset of deafness appears postlingual

Refs: 10369879; 10025409; 16596322; 18030493; 23399560; 23443030; 23451214; 23717403

Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to KCNQ4 variants in ClinVar

12 Conditions Cataloged

not providedTotal: 346

Inborn genetic diseasesTotal: 116

Autosomal dominant nonsyndromic hearing loss 2ATotal: 105

not specifiedTotal: 82

KCNQ4-related disorderTotal: 67

Rare genetic deafnessTotal: 5

Nonsyndromic genetic hearing lossTotal: 4

Hearing impairmentTotal: 3

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_004700.4. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

Effect	PathogenicP	Likely pathogenicLP	VUS	Likely benignLB	BenignB	Sum
synonymous			7 clinvar	72 clinvar	2 clinvar	81
missense	12 clinvar	27 clinvar	252 clinvar	22 clinvar	1 clinvar	314
nonsense	3 clinvar	6 clinvar	2 clinvar			11
start loss						0
frameshift	7 clinvar	5 clinvar	2 clinvar			14
splice donor/acceptor (+/-2bp)	1 clinvar	6 clinvar	7 clinvar			14
Total	23	44	270	94	3	434

Highest pathogenic variant AF is 0.000025440859

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 15 transcripts

Transcript ID	Source	Protein ID	Coding Exons	MANE Status
NM_004700.4	RefSeq	NP_004691.2	14	MANE Select
ENST00000347132.10	Ensembl	ENSP00000262916.6	14	MANE Select
NM_172163.3	RefSeq	NP_751895.1	13	Standard
ENST00000443478.3	Ensembl	ENSP00000406735.3	13	Standard

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

Cholinergic synapse - Homo sapiens (human)
Celecoxib Pathway, Pharmacodynamics
ion channels and their functional role in vascular endothelium
Neuronal System
Voltage gated Potassium channels

Biological Process

potassium ion transport
sensory perception of sound
regulation of ion transmembrane transport
inner ear morphogenesis
potassium ion transmembrane transport

Molecular Function

voltage-gated potassium channel activity
delayed rectifier potassium channel activity
potassium channel activity
protein binding
calmodulin binding

Cellular Component

plasma membrane
voltage-gated potassium channel complex
basal plasma membrane
integral component of membrane

gnomAD Constraint

Source: gnomAD

Gene type: protein_coding
Transcript type: protein_coding
Transcript: ENST00000347132
Coding exons: 14
Length: 56441
Individuals with no LoFs: 125725
Homozygous LoFs: 0
Heterozygous LoFs: 23
Defined: 125748
p: 0.0000915

	Z-Score	Observed	Expected	Observed/Expected	Mutation Rate	Total Possible
Missense	2.17	288	412	0.699	0.0000279	4390
Missense (PolyPhen)		115	197.33	0.58279		2035
Synonymous	1.35	156	179	0.871	0.0000128	1465
Loss of Function	4.10	7	32.1	0.218	0.00000163	343

Population LoF Frequency

Population	CAF	p-value	Status
African	0.000062	0.000062	rare
Latino/Admixed American	0.000031	0.000029	rare
Ashkenazi Jewish	0	0.0	absent
East Asian	0.00027	0.00027	rare
Finnish	0.000094	0.000092	rare
European (Non-Finnish)	0.00012	0.00011	rare
South Asian	0.000033	0.000033	rare
Other	0	0.0	absent

dbNSFP Gene Annotations

Source: dbNSFP

Function: FUNCTION: Probably important in the regulation of neuronal excitability. May underlie a potassium current involved in regulating the excitability of sensory cells of the cochlea. KCNQ4 channels are blocked by linopirdin, XE991 and bepridil, whereas clofilium is without significant effect. Muscarinic agonist oxotremorine-M strongly suppress KCNQ4 current in CHO cells in which cloned KCNQ4 channels were coexpressed with M1 muscarinic receptors.;
Disease: DISEASE: Deafness, autosomal dominant, 2A (DFNA2A) [MIM:600101]: A form of non-syndromic sensorineural hearing loss. Sensorineural deafness results from damage to the neural receptors of the inner ear, the nerve pathways to the brain, or the area of the brain that receives sound information. {ECO:0000269|PubMed:10025409, ECO:0000269|PubMed:10369879, ECO:0000269|PubMed:10571947, ECO:0000269|PubMed:10925378, ECO:0000269|PubMed:21242547}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec: 0.144

Intolerance Scores

LoFtool: 0.0424
RVIS EVS: -0.67
RVIS percentile EVS: 15.76

Essentials

Essential (CRISPR): N
Essential (CRISPR2): N
Essential (gene trap): N
Indispensability pred.: N
Indispensability score: 0.311

Gene Damage Prediction

	All	Recessive	Dominant
Mendelian	Medium	Medium	Medium
Primary Immunodeficiency	Medium	Medium	Medium
Cancer	Medium	Medium	Medium