A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

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

doi:10.1038/s41431-020-00790-w

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A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

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A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

Yoel Hirsch, Chayada Tangshewinsirikul, Kevin T Booth, Hela Azaiez, Devorah Yefet, Adina Quint, Tzvi Weiden, Zippora Brownstein, Michal Macarov, Bella Davidov, …

European journal of human genetics : EJHG, Vol.29(6), pp.988-997

06/2021

DOI: 10.1038/s41431-020-00790-w

PMCID: PMC8187401

PMID: 33398081

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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.

Adolescent

Adult

Child

Child, Preschool

Female

Gene Frequency

Genes, Recessive

Hearing Loss - ethnology

Hearing Loss - genetics

Hearing Loss - pathology

Humans

Infant

Jews - genetics

Male

Mutation

Myosins - genetics

Pedigree

RNA Splicing

Details

Title: Subtitle: A synonymous variant in MYO15A enriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing
Creators: Yoel Hirsch - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA.
Chayada Tangshewinsirikul - Brigham and Women's Hospital
Kevin T Booth - University of Iowa
Hela Azaiez - University of Iowa
Devorah Yefet - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel.
Adina Quint - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel.
Tzvi Weiden - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel.
Zippora Brownstein - Tel Aviv University
Michal Macarov - Hadassah Medical Center
Bella Davidov - Rabin Medical Center
John Pappas - New York University
Rachel Rabin - New York University
Margaret A Kenna - Boston Children's Hospital
Andrea M Oza - Boston Children's Hospital
Katherine Lafferty - Mass General Brigham
Sami S Amr - Brigham and Women's Hospital
Heidi L Rehm - Harvard University
Diana L Kolbe - University of Iowa
Kathy Frees - University of Iowa
Carla Nishimura - University of Iowa
Minjie Luo - Children's Hospital of Philadelphia
Chantal Farra - American University of Beirut
Cynthia C Morton - University of Manchester
Sholem Y Scher - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA.
Josef Ekstein - Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA.
Karen B Avraham - Tel Aviv University
Richard J H Smith - University of Iowa
Jun Shen - Brigham and Women's Hospital
Resource Type: Journal article
Publication Details: European journal of human genetics : EJHG, Vol.29(6), pp.988-997
DOI: 10.1038/s41431-020-00790-w
PMID: 33398081
PMCID: PMC8187401
NLM abbreviation: Eur J Hum Genet
ISSN: 1018-4813
eISSN: 1476-5438
Grant note: R03 DC013866 / NIDCD NIH HHS R01 DC003544 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS Department of Health R01 DC011835 / NIDCD NIH HHS R01 DC017955 / NIDCD NIH HHS R01 DC015052 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS
Language: English
Date published: 06/2021
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Otolaryngology; Internal Medicine; Iowa Institute of Human Genetics
Record Identifier: 9984256932702771

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