Analyses of del(GJB6-D13S1830) and del(GJB6-D13S1834) deletions in a large cohort with hearing loss: Caveats to interpretation of molecular test results in multiplex families.

Publisher: John Wiley & Sons Country of Publication: United States NLM ID: 101603758 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2324-9269 (Electronic) Linking ISSN: 23249269 NLM ISO Abbreviation: Mol Genet Genomic Med Subsets: MEDLINE

Original Publication: [Hoboken, NJ] : John Wiley & Sons, [2013]-

Gene Deletion*; Connexin 30/*genetics ; Genetic Testing/*methods ; Hearing Loss/*genetics; Connexin 26/genetics ; Female ; Gene Frequency ; Genetic Testing/standards ; Hearing Loss/diagnosis ; Heterozygote ; Humans ; Male ; Multiplex Polymerase Chain Reaction/methods ; Multiplex Polymerase Chain Reaction/standards ; Pedigree ; Sequence Analysis, DNA/methods ; Sequence Analysis, DNA/standards

Background: Mutations involving the closely linked GJB2 and GJB6 at the DFNB1 locus are a common genetic cause of profound congenital hearing loss in many populations. In some deaf GJB2 heterozygotes, a 309 kb deletion involving the GJB6 has been found to be the cause for hearing loss when inherited in trans to a GJB2 mutation.
Methods: We screened 2,376 probands from a National DNA Repository of deaf individuals.
Results: Fifty-two of 318 heterozygous probands with pathogenic GJB2 sequence variants had a GJB6 deletion. Additionally, eight probands had an isolated heterozygous GJB6 deletion that did not explain their hearing loss. In two deaf subjects, including one proband, a homozygous GJB6 deletion was the cause for their hearing loss, a rare occurrence not reported to date.
Conclusion: This study represents the largest US cohort of deaf individuals harboring GJB2 and GJB6 variants, including unique subsets of families with deaf parents. Testing additional members to clarify the phase of GJB2/GJB6 variants in multiplex families was crucial in interpreting clinical significance of the variants in the proband. It highlights the importance of determining the phase of GJB2/GJB6 variants when interpreting molecular test results especially in multiplex families with assortative mating.
(© 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.)

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R01 DC009645 United States DC NIDCD NIH HHS

Keywords: GJB2/GJB6 variant; hearing loss; interpretation of results; unique family structure

0 (Connexin 30)
0 (GJB2 protein, human)
0 (GJB6 protein, human)
127120-53-0 (Connexin 26)

Date Created: 20200219 Date Completed: 20210402 Latest Revision: 20230330

20240513

PMC7196463

10.1002/mgg3.1171

32067424