Whole-exome sequencing identifies MYO15A mutations as a cause of autosomal recessive nonsyndromic hearing loss in Korean families

Abstract

BackgroundThe genetic heterogeneity of hearing loss makes genetic diagnosis expensive and time consuming using available methods. Whole-exome sequencing has recently been introduced as an alternative approach to identifying causative mutations in Mendelian disorders.MethodsTo identify the hidden mutations that cause autosomal recessive nonsyndromic hearing loss (ARNSHL), we performed whole-exome sequencing of 13 unrelated Korean small families with ARNSHL who were negative for GJB2 or SLC26A4 mutations.ResultsWe found two novel compound heterozygous mutations, IVS11 + 1 and p.R2146Q, of MYO15A in one (SR903 family) of the 13 families with ARNSHL. In addition to these causative mutations, 13 nonsynonymous variants, including variants with uncertain pathogenicity (SR285 family), were identified in the coding exons of MYO15A from Korean exomes.ConclusionThis is the first report of MYO15A mutations in an East Asian population. We suggest that close attention should be paid to this gene when performing genetic testing of patients with hearing loss in East Asia. The present results also indicate that whole-exome sequencing is a valuable method for comprehensive medical diagnosis of a genetically heterogeneous recessive disease, especially in small-sized families.

Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

“…We did not include in Figure or in Supp. Table S1 heterozygous variants of MYO15A when a second mutation was not identified that could explain recessively inherited deafness [Woo et al., ; Yang et al., ; Besnard et al., ; Park et al., ], except for heterozygous missense mutations of giant exon 2 for reasons discussed later in this review. Inframe insertions/deletions were categorized as “likely pathogenic.” Missense and splice‐site variants, other than canonical ±1 or 2, were also categorized as likely pathogenic only if, in addition to satisfying the aforementioned two criteria, they were predicted as damaging by the four in silico programs for evaluating missense variants and the two in silico programs for splice‐site variants that we used.…”

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Detection of genetic variants between different Polish Landrace and Puławska pigs by means of RNA‐seq analysis

“…; Woo et al . ). Whole‐genome sequencing is also used successfully in farm animals to gain benefits in breeding and production.…”

Mutations in the MYO15A Gene Are a Significant Cause of Nonsyndromic Hearing Loss

“…1 The clinical features of ARNSHL (hearing level, age at onset, progressiveness, associated symptoms, etc) differ according to the causative gene/genotype. [4][5][6][7] These reports suggest that MPS screening of candidate genes is an effective and useful strategy. Comprising 66 exons and 71 kbp of DNA on chromosome 17p11.2, MYO15A encodes the 3530amino acid myosin XV protein.…”