A Monoallelic Variant in REST Is Associated with Non-Syndromic Autosomal Dominant Hearing Impairment in a South African Family.

Noluthando Manyisa,Shaheen Mowla,Edmond Wonkam-Tingang,Ambroise Wonkam,Abdul Nasir,Kevin Esoh,Cedrik Tekendo-Ngongang,Anushree Acharya,Leonardo Alves De Souza Rios,Kalinka Popel,Liz M Nouel-Saied,Carmen De Kock,Collet Dandara,Isabelle Schrauwen,Thashi Bharadwaj,Suzanne M Leal

doi:10.3390/genes12111765

Abstract

Hearing impairment (HI) is a sensory disorder with a prevalence of 0.0055 live births in South Africa. DNA samples from a South African family presenting with progressive, autosomal dominant non-syndromic HI were subjected to whole-exome sequencing, and a novel monoallelic variant in REST [c.1244GC; p.(C415S)], was identified as the putative causative variant. The co-segregation of the variant was confirmed with Sanger Sequencing. The variant is absent from databases, 103 healthy South African controls, and 52 South African probands with isolated HI. In silico analysis indicates that the p.C415S variant in REST substitutes a conserved cysteine and results in changes to the surrounding secondary structure and the disulphide bonds, culminating in alteration of the tertiary structure of REST. Localization studies using ectopically expressed GFP-tagged Wild type (WT) and mutant REST in HEK-293 cells show that WT REST localizes exclusively to the nucleus; however, the mutant protein localizes throughout the cell. Additionally, mutant REST has an impaired ability to repress its known target AF1q. The data demonstrates that the identified mutation compromises the function of REST and support its implication in HI. This study is the second report, worldwide, to implicate REST in HI and suggests that it should be included in diagnostic HI panels.

Highlights

IntroductionHearing impairment (HI) affects approximately 1 in 1000 newborns worldwide, but it has an estimated prevalence of 5.5 in 1000 live births in South Africa [2]
Hearing impairment (HI) is a sensory disorder that affects 466 million people [1]
Using data from the genome aggregation database database, for ARNSHI the prevalence of identified likely pathogenic and pathogenic (PLP) variants [11] was estimated at 96.9 per 100,000 individuals for Ashkenazi Jews for ARNSHI based on sequence data compared to only 5.2 per 100,000 individuals among Africans/African Americans [12] indicating for African populations many variants remain to be discovered

Summary

Introduction

HI affects approximately 1 in 1000 newborns worldwide, but it has an estimated prevalence of 5.5 in 1000 live births in South Africa [2]. 121 genes have been identified as being associated with non-syndromic hearing impairment (NSHI) [4]. Non-syndromic hearing impairment accounts for about 70% of HI cases of genetic origin and is inherited on an autosomal recessive (AR) mode in approximately 80% of cases, while autosomal dominant (AD) account for 15 to 20% [5]. Using data from the genome aggregation database (gnomAD) database, for ARNSHI the prevalence of identified likely pathogenic and pathogenic (PLP) variants [11] was estimated at 96.9 per 100,000 individuals for Ashkenazi Jews for ARNSHI based on sequence data compared to only 5.2 per 100,000 individuals among Africans/African Americans [12] indicating for African populations many variants remain to be discovered. There is an urgent need to investigate HI in African populations using generation sequencing and multiplex HI families

Methods

Results

Discussion

Conclusion