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.

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Hair cells in the cochlea display highly regulated actin polymerization, which is mediated by the human diaphanous-related formin 1 gene (DIAPH1; also called DFNA1, DIA1). DFNA1, the first type of autosomal dominant nonsyndromic hearing loss (ADNSHL), is known to be associated with mutations in DIAPH1. However, no genetic study of DFNA1 in Koreans with hearing loss has yet been reported. A 51-year-old patient in a Korean family with ADNSHL was examined by pure-tone audiometry, and genetic analysis of DIAPH1 was performed. A novel variant, p.I530S (c.1589T > G), was identified in the DIAPH1 gene, and the mutation was located in the highly conserved coiled-coil domain of the DIA1 protein, where an amino acid substitution was predicted to change the domain structure. Further functional investigations will provide more information to help us understand the role of DIAPH1 in maintenance of hair cell function in the auditory pathway.

EYA4 and GRHL2 encode transcription factors that play an important role in regulating many developmental stages. Since EYA4 and GRHL2 were identified as the transcription factors for the DFNA10 and DFNA28, 8 EYA4 mutations and 2 GRHL2 mutations have been reported worldwide. However, these genes have been reported in few studies of the Korean population. In this study, we performed a genetic analysis of EYA4 and GRHL2 in 87 unrelated Korean patients with autosomal dominant non-syndromic hearing loss (NSHL). A total of 4 genetic variants in the EYA4 gene were identified, including the 2 nonsense mutations p.S288X and p.Q393X. The novel mutation p.Q393X (c.1177C>T) resulted in a change in the codon at amino acid position 393 from a glutamine to a stop codon. The p.Q393X allele was predicted to encode a truncated protein lacking the entire C-terminal Eya homolog region (Eya HR), which is essential for the interaction with the transcription factor SIX3. The p.S288X (c.863C>A) mutation was found in a Korean family from a previous study. We analyzed p.S288X-linked microsatellite markers and determined that p.S288X might be a founder mutation and a hotspot mutation in Koreans. In GRHL2, a total of 4 genetic variants were identified, but none were associated with hearing loss in Korean patients. This suggests that GRHL2 may not be a main causal gene for autosomal dominant NSHL in Korean patients. In conclusion, our data provide fundamental information to predict the genotypes of Korean patients diagnosed with autosomal dominant NSHL.

BackgroundOne of the causes of sensorineural hearing loss (SNHL) is degeneration of the inner hair cells in the organ of Corti in the cochlea. The SLC17A8 (solute carrier family 17, member 8) gene encodes vesicular glutamate transporter 3 (VGLUT3), and among its isoforms (VGLUT1-3), only VGLUT3 is expressed selectively in the inner hair cells (IHCs). VGLUT3 transports the neurotransmitter glutamate into the synaptic vesicles of the IHCs. Mutation of the SLC17A8 gene is reported to be associated with DFNA25 (deafness, autosomal dominant 25), an autosomal dominant non-syndromic hearing loss (ADNSHL) in humans.MethodsIn this study, we performed a genetic analysis of 87 unrelated Korean patients with ADNSHL to determine whether the SLC17A8 gene affects hearing ability in the Korean population.ResultsWe found a novel heterozygous frameshift mutation, 2 non-synonymous variations, and a synonymous variation. The novel frameshift mutation, p.M206Nfs*4, in which methionine is changed to asparagine at amino acid position 206, resulted in a termination codon at amino acid position 209. This alteration is predicted to encode a truncated protein lacking transmembrane domains 5 to 12. This mutation is located in a highly conserved region in VGLUT3 across multiple amino acid alignments in different vertebrate species, but it was not detected in 100 unrelated controls who had normal hearing ability. The results from our study suggest that the p.M206Nfs*4 mutation in the SLC17A8 gene is likely a pathogenic mutation that causes ADNSHL.ConclusionOur findings can facilitate the prediction of the primary cause of ADNSHL in Korean patients.