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Hearing loss

Gene: GJB6

Amber List (moderate evidence)

GJB6 (gap junction protein beta 6)
EnsemblGeneIds (GRCh38): ENSG00000121742
EnsemblGeneIds (GRCh37): ENSG00000121742
OMIM: 604418, Gene2Phenotype
GJB6 is in 6 panels

6 reviews

Zornitza Stark (Australian Genomics)

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

Eleanor Williams (Genomics England Curator)

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.

Emma Ashton (Great Ormond Street Hospital)

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.

Jun Shen (Harvard Medical School)

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)]

Maria Bitner-Glindzicz (UCL)

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

Ellen McDonagh (Genomics England Curator)

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.

Details

Mode of Inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal
Sources
  • Expert Review Amber
  • Eligibility statement prior genetic testing
  • Expert
  • Radboud University Medical Center, Nijmegen
  • UKGTN
  • Illumina TruGenome Clinical Sequencing Services
  • Emory Genetics Laboratory
Phenotypes
  • hearing loss
  • Deafness, autosomal dominant 3B, 612643
  • Deafness, autosomal recessive 1B, 612645
  • Deafness, digenic GJB2/GJB6, 220290
  • Ectodermal dysplasia 2, Clouston type, 129500
  • Nonsyndromic Hearing Loss, Dominant
OMIM
604418
Clinvar variants
Variants in GJB6
Penetrance
Complete
Publications
Mode of Pathogenicity
Other - please provide details in the comments
Panels with this gene

History Filter Activity

12 Jun 2019, Gel status: 2

Entity classified by Genomics England curator

Eleanor Williams (Genomics England Curator)

Gene: gjb6 has been classified as Amber List (Moderate Evidence).

2 Mar 2016, Gel status: 1

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Red List (Low Evidence).

2 Mar 2016, Gel status: 2

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Amber List (Moderate Evidence).

17 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

17 Feb 2016, Gel status: 4

Set mode of pathogenicity

Ellen McDonagh (Genomics England Curator)

Mode of pathogenicity for GJB6 was changed to Other - please provide details in the comments

17 Feb 2016, Gel status: 4

Gene classified by Genomics England curator

Ellen McDonagh (Genomics England Curator)

This gene has been classified as Green List (High Evidence).

17 Feb 2016, Gel status: 4

Set Phenotypes

Ellen McDonagh (Genomics England Curator)

Phenotypes for GJB6 were set to hearing loss; Deafness, autosomal dominant 3B, 612643; Deafness, autosomal recessive 1B, 612645; Deafness, digenic GJB2/GJB6, 220290; Ectodermal dysplasia 2, Clouston type, 129500; Nonsyndromic Hearing Loss, Dominant

17 Feb 2016, Gel status: 4

Set publications

Ellen McDonagh (Genomics England Curator)

Publications for GJB6 were set to PMID:10471490; 10570462; 10610709; 11017065; 11807148; 11874494; 11896458; 12419304; 12490528; 12668604; 14571368; 15150777; 15213106; 15638823; 15994881; 17041943; 18324688; 20858605; 8663509; 9139825; 9799458

12 Aug 2015, Gel status: 4

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Eligibility statement prior genetic testing

24 Jun 2015, Gel status: 4

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene GJB6 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 4

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Emory Genetics Laboratory,Illumina TruGenome Clinical Sequencing Services,UKGTN,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 4

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene GJB6 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 4

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Emory Genetics Laboratory,Illumina TruGenome Clinical Sequencing Services,UKGTN,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 3

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene GJB6 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 3

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Emory Genetics Laboratory,Illumina TruGenome Clinical Sequencing Services,UKGTN,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 2

Set Mode of Inheritance

Ellen McDonagh (Genomics England Curator)

Model of inheritance for gene GJB6 was changed to MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

24 Jun 2015, Gel status: 2

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Emory Genetics Laboratory,Illumina TruGenome Clinical Sequencing Services,UKGTN,Radboud University Medical Center, Nijmegen,Expert

24 Jun 2015, Gel status: 1

Added New Source

Ellen McDonagh (Genomics England Curator)

GJB6 was added to Congenital hearing impairment (Profound/Severe)panel. Sources: Emory Genetics Laboratory,Illumina TruGenome Clinical Sequencing Services,UKGTN,Radboud University Medical Center, Nijmegen,Expert