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

Autor: Hirsch Y; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA., Tangshewinsirikul C; Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University, Bangkok, 10400, Thailand.; Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Booth KT; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA.; Department of Neurobiology, Harvard Medical School, Boston, MA, 02215, USA., Azaiez H; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA., Yefet D; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel., Quint A; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel., Weiden T; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Jerusalem, 91506, Israel., Brownstein Z; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel., Macarov M; Department of Genetics and Metabolic Diseases, Hadassah Medical Center, Jerusalem, 91120, Israel., Davidov B; Department of Medical Genetics, Rabin Medical Center, Petah Tikva, 49100, Israel., Pappas J; Department of Pediatrics, New York University School of Medicine, New York, NY, 10016, USA., Rabin R; Department of Pediatrics, New York University School of Medicine, New York, NY, 10016, USA., Kenna MA; Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.; Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA., Oza AM; Department of Otolaryngology and Communication Enhancement, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA.; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA., Lafferty K; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.; Maine Medical Center, Scarborough, ME, 04074, USA., Amr SS; Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA.; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA., Rehm HL; Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA.; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.; Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, 02114, USA.; The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA., Kolbe DL; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA., Frees K; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA., Nishimura C; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA., Luo M; The Children's Hospital of Philadelphia, The University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, 19104, USA., Farra C; Medical Genetics Unit, American University of Beirut Medical Center, AUBMC, 1107 2020, Beirut, Lebanon., Morton CC; Department of Obstetrics and Gynecology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.; Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA.; The Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.; Manchester Centre for Audiology and Deafness, School of Health Sciences, The University of Manchester, Manchester, M13 9PL, UK., Scher SY; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA., Ekstein J; Dor Yeshorim, Committee for Prevention of Jewish Genetic Diseases, Brooklyn, NY, 11211, USA., Avraham KB; Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine and Sagol School of Neuroscience, Tel Aviv University, Tel Aviv, 6997801, Israel. karena@tauex.tau.ac.il., Smith RJH; Molecular Otolaryngology and Renal Research Laboratories, The University of Iowa, Iowa City, IA, 52242, USA. richard-smith@uiowa.edu., Shen J; Harvard Medical School Center for Hereditary Deafness, Boston, MA, 02115, USA. jshen5@bwh.harvard.edu.; Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine, Cambridge, MA, 02139, USA. jshen5@bwh.harvard.edu.; Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, 02115, USA. jshen5@bwh.harvard.edu.
Jazyk: angličtina
Zdroj: European journal of human genetics : EJHG [Eur J Hum Genet] 2021 Jun; Vol. 29 (6), pp. 988-997. Date of Electronic Publication: 2021 Jan 04.
DOI: 10.1038/s41431-020-00790-w
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 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.
Databáze: MEDLINE
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