Publication: A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing
Issued Date
2021-06-01
Resource Type
ISSN
14765438
10184813
10184813
Other identifier(s)
2-s2.0-85098629040
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Mahidol University
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SCOPUS
Bibliographic Citation
European Journal of Human Genetics. Vol.29, No.6 (2021), 988-997
Suggested Citation
Yoel Hirsch, Chayada Tangshewinsirikul, Kevin T. Booth, Hela Azaiez, Devorah Yefet, Adina Quint, Tzvi Weiden, Zippora Brownstein, Michal Macarov, Bella Davidov, John Pappas, Rachel Rabin, Margaret A. Kenna, Andrea M. Oza, Katherine Lafferty, Sami S. Amr, Heidi L. Rehm, Diana L. Kolbe, Kathy Frees, Carla Nishimura, Minjie Luo, Chantal Farra, Cynthia C. Morton, Sholem Y. Scher, Josef Ekstein, Karen B. Avraham, Richard J.H. Smith, Jun Shen A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing. European Journal of Human Genetics. Vol.29, No.6 (2021), 988-997. doi:10.1038/s41431-020-00790-w Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/76175
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Title
A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing
Author(s)
Yoel Hirsch
Chayada Tangshewinsirikul
Kevin T. Booth
Hela Azaiez
Devorah Yefet
Adina Quint
Tzvi Weiden
Zippora Brownstein
Michal Macarov
Bella Davidov
John Pappas
Rachel Rabin
Margaret A. Kenna
Andrea M. Oza
Katherine Lafferty
Sami S. Amr
Heidi L. Rehm
Diana L. Kolbe
Kathy Frees
Carla Nishimura
Minjie Luo
Chantal Farra
Cynthia C. Morton
Sholem Y. Scher
Josef Ekstein
Karen B. Avraham
Richard J.H. Smith
Jun Shen
Chayada Tangshewinsirikul
Kevin T. Booth
Hela Azaiez
Devorah Yefet
Adina Quint
Tzvi Weiden
Zippora Brownstein
Michal Macarov
Bella Davidov
John Pappas
Rachel Rabin
Margaret A. Kenna
Andrea M. Oza
Katherine Lafferty
Sami S. Amr
Heidi L. Rehm
Diana L. Kolbe
Kathy Frees
Carla Nishimura
Minjie Luo
Chantal Farra
Cynthia C. Morton
Sholem Y. Scher
Josef Ekstein
Karen B. Avraham
Richard J.H. Smith
Jun Shen
Other Contributor(s)
Ramathibodi Hospital
Faculty of Biology, Medicine and Health
American University of Beirut Medical Center
Massachusetts General Hospital
Partners HealthCare Personalized Medicine
NYU Grossman School of Medicine
University of Iowa
Rabin Medical Center Israel
Maine Medical Center
Harvard Medical School Center for Hereditary Deafness
Tel Aviv University
University of Pennsylvania Perelman School of Medicine
Harvard Medical School
Broad Institute
Hadassah University Medical Centre
Dor Yeshorim
Dor Yeshorim
Faculty of Biology, Medicine and Health
American University of Beirut Medical Center
Massachusetts General Hospital
Partners HealthCare Personalized Medicine
NYU Grossman School of Medicine
University of Iowa
Rabin Medical Center Israel
Maine Medical Center
Harvard Medical School Center for Hereditary Deafness
Tel Aviv University
University of Pennsylvania Perelman School of Medicine
Harvard Medical School
Broad Institute
Hadassah University Medical Centre
Dor Yeshorim
Dor Yeshorim
Abstract
Nonsyndromic hearing loss is genetically heterogeneous. Despite comprehensive genetic testing, many cases remain unsolved because the clinical significance of identified variants is uncertain or because biallelic pathogenic variants are not identified for presumed autosomal recessive cases. Common synonymous variants are often disregarded. Determining the pathogenicity of synonymous variants may improve genetic diagnosis. We report a synonymous variant c.9861 C > T/p.(Gly3287=) in MYO15A in homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15A variant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15A were identified in 21 affected and were absent in 22 unaffected siblings. A mini-gene assay confirms that the synonymous variant leads to abnormal splicing. The variant is enriched in the Ashkenazi Jewish population. Individuals carrying biallelic variants involving c.9861 C > T often exhibit progressive post-lingual hearing loss distinct from the congenital profound deafness typically associated with biallelic loss-of-function MYO15A variants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15A and expands the phenotypic spectrum of MYO15A-related hearing loss. Our work also highlights the importance of multicenter collaboration and data sharing to establish the pathogenicity of a relatively common synonymous variant for improved diagnosis and management of hearing loss.