Identification and Clinical Implications of Novel MYO15A Mutations in a Non-consanguineous Korean Family by Targeted Exome Sequencing

Abstract

Mutations of MYO15A are generally known to cause severe to profound hearing loss throughout all frequencies. Here, we found two novel MYO15A mutations, c.3871C>T (p.L1291F) and c.5835T>G (p.Y1945X) in an affected individual carrying congenital profound sensorineural hearing loss (SNHL) through targeted resequencing of 134 known deafness genes. The variant, p.L1291F and p.Y1945X, resided in the myosin motor and IQ2 domains, respectively. The p.L1291F variant was predicted to affect the structure of the actin-binding site from three-dimensional protein modeling, thereby interfering with the correct interaction between actin and myosin. From the literature analysis, mutations in the N-terminal domain were more frequently associated with residual hearing at low frequencies than mutations in the other regions of this gene. Therefore we suggest a hypothetical genotype-phenotype correlation whereby MYO15A mutations that affect domains other than the N-terminal domain, lead to profound SNHL throughout all frequencies and mutations that affect the N-terminal domain, result in residual hearing at low frequencies. This genotype-phenotype correlation suggests that preservation of residual hearing during auditory rehabilitation like cochlear implantation should be intended for those who carry mutations in the N-terminal domain and that individuals with mutations elsewhere in MYO15A require early cochlear implantation to timely initiate speech development.

Clinical Application of Targeted Deep Sequencing in Solid-Cancer Patients and Utility for Biomarker-Selected Clinical Trials

“…The IHC protocol for PTEN , MET (MET proto‐oncogene, receptor tyrosine kinase), and HER2 for the trial were previously reported . Somatic alterations were detected by targeted deep sequencing by CancerSCAN, as previously reported . From August 2014 through January 2015, we applied CancerSCAN version 1 consisting of 83 cancer‐related genes ( n = 167), and from February 2015, CancerSCAN version 2 was applied, encompassing 381 cancer‐related genes ( n = 251).…”

Discovery of CDH23 as a Significant Contributor to Progressive Postlingual Sensorineural Hearing Loss in Koreans

“…The obtained reads were aligned to the UCSC hg19 reference genome (http://genome.ucsc.edu/index.html) and variants were filtered. Further bioinformatics analyses were performed as previously described [23]. If the results of these steps were not convincing, WES was performed.…”

Mutational Spectrum ofMYO15Aand the Molecular Mechanisms of DFNB3 Human Deafness

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