A synonymous variant in MYO15Aenriched in the Ashkenazi Jewish population causes autosomal recessive hearing loss due to abnormal splicing

Autor: Hirsch, Yoel, Tangshewinsirikul, Chayada, Booth, Kevin T., Azaiez, Hela, Yefet, Devorah, Quint, Adina, Weiden, Tzvi, Brownstein, Zippora, Macarov, Michal, Davidov, Bella, Pappas, John, Rabin, Rachel, Kenna, Margaret A., Oza, Andrea M., Lafferty, Katherine, Amr, Sami S., Rehm, Heidi L., Kolbe, Diana L., Frees, Kathy, Nishimura, Carla, Luo, Minjie, Farra, Chantal, Morton, Cynthia C., Scher, Sholem Y., Ekstein, Josef, Avraham, Karen B., Smith, Richard J. H., Shen, Jun
Zdroj: European Journal of Human Genetics: EJHG; June 2021, Vol. 29 Issue: 6 p988-997, 10p
Abstrakt: 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 MYO15Ain homozygosity or compound heterozygosity with another pathogenic or likely pathogenic MYO15Avariant in 10 unrelated families with nonsyndromic sensorineural hearing loss. Biallelic variants in MYO15Awere 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 MYO15Avariants. This study establishes the pathogenicity of the c.9861 C > T variant in MYO15Aand 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.
Databáze: Supplemental Index
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