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. 2020 Apr;8(4):e1171.
doi: 10.1002/mgg3.1171. Epub 2020 Feb 17.

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

Arti Pandya  1 , Alexander O'Brien  1 , Michael Kovasala  1 , Guney Bademci  2 , Mustafa Tekin  2 , Kathleen S Arnos  3
Affiliations

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

Arti Pandya et al. Mol Genet Genomic Med. 2020 Apr.

Abstract

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.

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

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Conflict of interest statement

Arti Pandya, Alexander O'Brien, Michael Kovasala, Guney Bademci, Mustafa Tekin, and Kathleen S. Arnos have nothing to declare.

Figures

Figure 1
Figure 1
Representative Families from cohort with the digenic variants in both GJB2 and GJB6. (a) Compound heterozygous state in simplex and multiplex families with HL. (b) Simplex family with a 2bp frameshift deletion without GJB2 mutations that may not be the cause of HL. (c) Families requiring testing of additional members for result interpretation in proband. GJB6 del = del(GJB6‐D13S1830)
Figure 2
Figure 2
Average hearing threshold in deaf probands with del(GJB6‐D13S1830) deletion in trans with GJB2 variant, or GJB6 deletion by itself
See this image and copyright information in PMC

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