Identification of Novel and Recurrent Variants in MYO15A in Ashkenazi Jewish Patients With Autosomal Recessive Nonsyndromic Hearing Loss.

Kevin T Booth,Adina Quint,Devorah Yefet,Tzvi Weiden,Anna C Vardaro,Josef Ekstein,David P Corey,Yoel Hirsch

doi:10.3389/fgene.2021.737782

Abstract

Hearing loss is a genetically and phenotypically heterogeneous disorder. The purpose of this study was to determine the genetic cause underlying hearing loss in four Ashkenazi Jewish families. We screened probands from each family using a combination of targeted mutation screening and exome sequencing to identifiy the genetic cause of hearing loss in each family. We identified four variants in MYO15A, two novel variants never previously linked to deafness (c.7212+5G>A and p.Leu2532ArgfsTer37) and two recurrent variants (p.Tyr2684His and p.Gly3287Gly). One family showed locus heterogeneity, segregrating two genetic forms of hearing loss. Mini-gene assays revealed the c.7212+5G>A variant results in abnormal splicing and is most likely a null allele. We show that families segregrating the p.Gly3287Gly variant show both inter and intra-familial phenotypic differences. These results add to the list of MYO15A deafness-causing variants, further confirm the pathogenicity of the p.Gly3287Gly variant and shed further light on the genetic etiology of hearing loss in the Ashkenazi Jewish population.

Highlights

Myosins are a superfamily of actin-based motor proteins that play an essential role in a wide variety of cellular activity ranging from intracellular transport and signaling, cell migration, and adhesion to muscle contractions (Manor and Kachar, 2008; Coluccio, 2020a; Coluccio, 2020b)
It is well established that pathogenic variants in MYO15A underlie autosomal recessive nonsyndromic hearing loss at the DFNB3 locus (Rehman et al, 2016; Hirsch et al, 2021)
We used a combination of ethnicity-specific mutation screening and Exome Sequencing to implicate MYO15A and OTOGL as the causal genes underlying ARNSHL in four families of Ashkenazi Jewish descent

Summary

Introduction

Myosins are a superfamily of actin-based motor proteins that play an essential role in a wide variety of cellular activity ranging from intracellular transport and signaling, cell migration, and adhesion to muscle contractions (Manor and Kachar, 2008; Coluccio, 2020a; Coluccio, 2020b). Pathogenic variants in the genes that encode myosin proteins have been linked to many diseases, including hearing loss (Friedman et al, 2020). Pathogenic variants in six myosin genes (MYO3A, MYO6, MYO7A, MYH14, MYH9, and MYO15A) have been linked to human deafness (Lalwani et al, 2000; Walsh et al, 2002; Donaudy et al, 2004; Friedman et al, 2020). More than 370 variants in MYO15A have been linked to DFNB3-related hearing loss (https:// deafnessvariationdatabase.org/) (Azaiez et al, 2018). This allelic diversity is strongly mimicked at the phenotypic level, with variable hearing loss thresholds (ranging from mild to profound), onset

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