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Supinger Thesis Final 4.pdf (1.3 MB)

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Process Review of GJB6 Reflex Testing in Individuals with 0 or 1 GJB2 Pathogenic Variants and Non-Syndromic Hearing Loss

Supinger, Rachel Christine
http://orcid.org/0000-0001-6207-5508
http://rave.ohiolink.edu/etdc/view?acc_num=osu1492470064058105

Abstract Details

2017, Master of Science, Ohio State University, Genetic Counseling.
The gene most commonly implicated in autosomal recessive non-syndromic hearing loss (NSHL) is GJB2. Homozygous deletions within the gene GJB6, as well as a heterozygous GJB2 mutation with one GJB6 deletion, can also lead to NSHL. The American College of Medical Genetics and Genomics (ACMG) and European Molecular Genetics Quality Network (EMQN) both recommend that genetic testing in hearing loss begin with analysis of GJB2 and GJB6 prior to panel testing that includes additional genes. At Nationwide Children's Hospital (NCH) the testing protocol in apparently NSHL is to sequence GJB2 with reflex to GJB6 deletion analysis. However, some previous studies and the testing experience at NCH indicate that GJB6 deletions may not be as prevalent as previously thought. In order to determine the most effective testing approach in NSHL, the testing strategies and the average costs of each was determined from public databases. The frequency and distribution of GJB2 mutations and GJB6 deletions in a population of NSHL cases from NCH was elucidated and compared to the frequency of GJB6 deletions in various control populations. Thirty-three different GJB2 sequencing test options from 23 different CLIA-certified laboratories within the United States were analyzed to reveal the average cost of GJB2 sequencing with reflex GJB6 deletion analysis was $802.50. The average cost of panels including GJB2, GJB6 and additional genes was $2660. Six hundred five GJB2 sequencing and 528 GJB6 deletion analysis records representing 607 unique cases from April 2009 to April 2016 at NCH were analyzed. Seventy-six total cases were provided with a genetic diagnosis for their hearing loss from GJB2 sequencing and/or GJB6 deletion analysis representing an overall diagnostic rate of 12.5% (76/607). Only one instance of the 309 kb GJB6 deletion (frequency of 0.16%; 1/607) was found in a case also carrying a likely pathogenic GJB2 variant. The frequency of GJB6 deletions within 10612 microarrays (hearing loss was not noted as an indication for testing) and the frequency of GJB6 deletions within with Database of Genomic Variants (DGV) was determined. Seven of the 10612 microarrays (0.067%; 7/10612) were found to carry a deletion within or spanning a portion of GJB6. Three studies outlined in the DGV found 37 out of 53952 total individuals (0.069%) carried a deletion within GJB6. The GJB6 deletion was found at similar frequencies in cases with hearing loss at NCH and in various control populations. These results indicate that GJB6 deletion analysis is a low yield testing option that may not be cost effective. The overall diagnostic rate of cases at NCH was also lower than found in previous literature. Based upon the data generated from this study, we recommend panel genetic testing which includes GJB2, GJB6 and additional genes be recommended as a first line test in NSHL.
Dawn Allain, MS, LGC (Advisor)
Robert Pyatt, PhD (Committee Member)
Danielle Mouhlas, MS, LGC (Committee Member)
Pamela Brock, MS, LGC (Committee Member)
86 p.
Genetics
hearing loss; GJB2; GJB6; non-syndromic hearing loss; reflex testing; process review

Recommended Citations

Citations

  • Supinger, R. C. (2017). Process Review of GJB6 Reflex Testing in Individuals with 0 or 1 GJB2 Pathogenic Variants and Non-Syndromic Hearing Loss [Master's thesis, Ohio State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492470064058105

    APA Style (7th edition)

  • Supinger, Rachel. Process Review of GJB6 Reflex Testing in Individuals with 0 or 1 GJB2 Pathogenic Variants and Non-Syndromic Hearing Loss. 2017. Ohio State University, Master's thesis. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=osu1492470064058105.

    MLA Style (8th edition)

  • Supinger, Rachel. "Process Review of GJB6 Reflex Testing in Individuals with 0 or 1 GJB2 Pathogenic Variants and Non-Syndromic Hearing Loss." Master's thesis, Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492470064058105

    Chicago Manual of Style (17th edition)

osu1492470064058105
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