Monogenic hearing loss

Gene: GJB6

Green List (high evidence)

The rating of this gene has been updated to green following NHS Genomic Medicine Service approval.

Created: 12 Dec 2025, 10:28 a.m. | Last Modified: 12 Dec 2025, 10:28 a.m.

Panel Version: 5.49

Green List (high evidence)

GJB6 is a ClinGen refuted gene with respect to non-syndromic genetic hearing loss, because loss of the gene alone (without the 5' regulatory sequence) in a mouse model, did not result in hearing loss. ClinGen goes onto comment that "deletions upstream of both GJB6 and GJB2 are pathogenic for hearing loss without disruption of GJB6 (Wilch 2010 PMID 20236118; Abou Tayoun 2016 PMID 26444186)". However, screening of hearing loss patients for the biallelic deletion del(GJB6-D13S1830)(which includes 5' end of GJB6, GJB6 regulatory region and GJB2) is routine for hearing loss diagnosis (PMID: 39498320).
Four heterozygous GJB6 missense variants have been reported in hear loss cases (PMID: 19416251; 29921236; 40369851). The variant NM_001110219.3(GJB6):c.175G>A has been reported in two unrelated cases with hearing loss and ectodermal anomalies, including palmoplantar keratoderma, pseudoainhum, knuckle pads, and nail dystrophy (PMID: 19416251; 40369851). Structural and functional studies, support the pathogenic role of this variant (PMID: 24522190).

Created: 19 May 2025, 3:44 p.m. | Last Modified: 19 May 2025, 3:44 p.m.

Panel Version: 5.5

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977; Deafness, autosomal recessive 1B, OMIM:612645; autosomal recessive nonsyndromic hearing loss 1B, MONDO:0012977

Red List (low evidence)

This gene-disease association has been rated as REFUTED by ClinGen.

Created: 2 Jan 2020, 4:35 a.m. | Last Modified: 2 Jan 2020, 4:35 a.m.

Panel Version: 2.4

Since this gene was last reviewed in 2020 there are have been two reports of the same variant in the gene associated with hearing loss in unrelated families.

PMID: 40369851 - Elmakhzen et al 2025 - reports a 3rd case with of individuals carrying the same missense variant (ENST00000647029.1 (GJB6): c.175G>A (p.(Gly59Arg)) and bilateral syndromic hearing loss identified through WGS. The patient, a 13 year old girl, who presented with both congenital hearing loss and ectodermal anomalies. Both her grandfather and one maternal uncle showed congenital bilateral deafness (no genetic analysis). However the variant was found to be de novo in this proband with neither parent carrying the variant. The variant is absent from Gnomad 4.1.0.

Duzkale et al 2022 - https://mednexus.org/doi/full/10.1097/JD9.0000000000000231 (not in PubMed). report a Turkish girl with nonsyndromic bilateral hearing loss with p. Gly59Arg heterozygous missense mutation in the GJB6 gene. The variant was identified through panel sequencing of 75 genes from the PanelApp hearing loss panel, including GJB6. The variant was also present heterozygously in the mother and grandfather, who both had hearing loss and palmoplantar hyperkeratosis. The p.Gly59Arg mutation of GJB6 was first described in 2009 in a 32-year-old Japanese woman with mild palmoplantar keratoderma, knuckle pads, and severe sensorineural HL (PMID: 19416251).

Created: 23 May 2025, 9:47 p.m. | Last Modified: 23 May 2025, 9:55 p.m.

Panel Version: 5.8

As reviewer Zornitza Stark reports this gene has Refuted status in association with hearing loss by ClinGen. However, leaving as amber, as there is still some evidence to support the possibility that SNV in this gene are associated with hearing loss (Grifa et al and Amritkumar et al).

Created: 22 Dec 2020, 4:19 p.m. | Last Modified: 22 Dec 2020, 4:19 p.m.

Panel Version: 2.139

Comment on list classification: After consideration by the Genomics England rare disease clinical team it was decided to rate this gene Amber until there is further evidence for the role of SNVs in this gene causing hearing loss.

Created: 12 Jun 2019, 2:55 p.m.

Associated with Deafness, autosomal dominant 3B (612643) (AD), Deafness, autosomal recessive 1B (612645) (AR) and Deafness, digenic GJB2/GJB6 (220290) (AR) in OMIM.

Monoallelic cases
PMID: 10471490 - Grifa et al. (1999) - identified a thr-to-met mutation at position 5 in GJB6 in a family with autosomal dominant, bilateral, middle to high frequency hearing loss. In vitro functional expression studies in Xenopus oocytes showed that the mutant protein did not induce membrane potential coupling and suppressed the wildtype protein, consistent with a dominant-negative effect.

PMID: 5150777 Feldmann et al. 2004 - A GJB6 deletion was found in one family in the 57% of the families which had no GJB2 mutation. This was a family with a sporadic case and the patient was heterozygous for the GJB6 deletion without any mutation in the two exons of GJB2.

PMID: 29921236 Amritkumar et al 2018 - report two cases of point mutations in GJB6. p.Q57R and p.E101Q. Each observed in one family only and in heterozygous condition. However, only GJB2 and GJB6 genes were analysed so variants in other genes causing deafness are not excluded.

Biallelic cases
PMID: 11896458 - Pallares-Ruiz et al. 2002 - 1 case where a homozygous deletion of a minimal 150 kb region encompassing GJB6 causes NSHL.

Digenic cases
Numerous cases of patients with hearing loss and variants in the GJB2 gene and deletions in the GJB6 gene (PMID: 11807148 Del Castillo et al. 2002 - 342-kb deletion in the GJB6 gene, PMID: 15150777 Feldmann et al. 2004 - 6 familial and 9 sporadic patients were heterozygous for a GJB2 mutation and a GJB6 deletion, only deletions were looked for in GJB6).

Created: 27 Feb 2019, 4:24 p.m.

Green List (high evidence)

Multiple DM variants HGMD and publications reporting deafness/hearing loss/NSHL. DFNA3B #612643 ; DFNB1B #612645. Also digenic with DJB2, 309kb and 342kb deletions.

Created: 17 Feb 2019, 4:35 p.m.

I don't know

Inheritance:Autosomal dominant;Autosomal recessive;Digenic dominant. Clear inheritance for ectodermal features only. Digenic with GJB2 due to involvement of regulator elements that impact GJB2 expression.

Created: 17 Feb 2016, 5:33 p.m.

Mode of inheritance
Other

Phenotypes
#129500:Ectodermal dysplasia 2, Clouston type[Short stature; CataractPhotophobiaStrabismusConjunctivitisBlepharitisSparse eyelashesSparse eyebrows; Normal teeth; Thick, dyskeratotic palmsClubbed digits; Thick, dyskeratotic soles; Normal sweating capacityPalmoplantar hyperkeratosisHyperpigmentation (knuckles, elbows, axillae, areolae, pubic area); Onychodystrophy, severeOnycholysisHypoplastic nailsThick, discolored nails; Fine, brittle, slow-growing hairTotal alopecia (females)Focal alopecia to complete baldness (males)Sparse eyelashesSparse eyebrowsAbsent axillary hairAbsent pubic hairReduced tensile strength of hairDisorganized structure of hairDecreased cysteine and disulfide bonds in hair]; #220290:Deafness, digenic GJB2/GJB6[Hearing loss, sensorineural, prelingual profoundVestibular dysfunction (in some patients)]; #612643:Deafness, autosomal dominant 3B[Hearing loss, bilateral (middle-to-high frequency)]; #612645:Deafness, autosomal recessive 1B[Hearing loss, sensorineural, prelingual profoundVestibular dysfunction (in some patients)]

I don't know

whole gene deletions are definitely pathogenic as they remove enhancer elements acting on GJB2. Role of missense changes much less well proven.

Created: 30 Sep 2015, 2:38 p.m.

Mode of inheritance
Other

Phenotypes
Clouston ectodermal dysplasia; dominant deafness?; recessive deafness

Comment on list classification: This gene has been discussed internally and with DDD G2P team members, and there is agreement that this should be on the red list, as a large deletions of GJB6 affects expression of GJB2, but variants within the GJB6 gene are not associated with deafness.

Created: 2 Mar 2016, 6:26 p.m.

Comment on mode of pathogenicity: Is a confirmed DD gene for deafness autosomal recesssive type 1B, and a loss of function mutations are relevant according to G2P, however there may be more evidence for large deletions/copy number variants.

Created: 17 Feb 2016, 3:27 p.m.

Both recessive and dominant forms of nonsyndromic hearing loss are reported by Illumina for this gene.

Created: 2 Jul 2015, 7:24 a.m.