Genetics of hearing loss in the Arab population of Northern Israel

Nada Danial-Farran,Stavit A Shalev,Mary-Claire King,Olfat Aboleile Zoubi,Zippora Brownstein,Tom Walsh,Luna Tammer,Karen B Avraham,Suleyman Gulsuner,Elena Chervinsky,Morad Khayat,Gil Ast,Ola Aleme

doi:10.1038/s41431-018-0218-z

Abstract

For multiple generations, much of the Arab population of Northern Israel has lived in communities with consanguineous marriages and large families. These communities have been particularly cooperative and informative for understanding the genetics of recessive traits. We studied the genetics of hearing loss in this population, evaluating 168 families from 46 different villages. All families were screened for founder variants by Sanger sequencing and 13 families were further evaluated by sequencing all known genes for hearing loss using our targeted gene panel HEar-Seq. Deafness in 34 of 168 families (20%) was explained by founder variants in GJB2, SLC26A4, or OTOF. In 6 of 13 families (46%) evaluated using HEar-Seq, deafness was explained by damaging alleles of SLC26A4, MYO15A, OTOG, LOXHD1, and TBC1D24. In some genes critical to hearing, it is particularly difficult to interpret variants that might affect splicing, because the genes are not expressed in accessible tissue. To address this problem for possible splice-altering variants of MYO15A, we evaluated minigenes transfected into HEK293 cells. Results revealed exon skipping in the message of MYO15A c.9083+6T>A, and intron retention in the message of MYO15A c.8340G>A, in each case leading to a premature stop and consistent with co-segregation of homozygosity for each variant with hearing loss. The profile of genetics of hearing loss in this population reflects the genetic heterogeneity of hearing loss and the usefulness of synthetic technologies to evaluate potentially causal variants in genes not expressed in accessible tissues.

Highlights

We focused on the Arab population from northern Israel, the majority of whom live in villages that were founded by a few individuals roughly ten generations ago [3] (Fig. 1)
We screened for the SLC26A4 c.1197delT variant, as it was previously found in the northern Israel Arab population [7] and identified seven deaf individuals who were homozygous for this variant
The objective of the current study was to identify genetic causes of hearing impairment in consanguineous families living in northern Israel

Summary

Introduction

The identification of alleles causing deafness has advanced dramatically in the past decade as a result of the availability of technologies such as next-generation sequencing (NGS) [1, 2]. Applying the NGS technology to families with high consanguinity, living in isolated populations, holds promising potential for characterizing rare alleles causing recessive phenotypes, such as hereditary hearing loss. We focused on the Arab population from northern Israel, the majority of whom live in villages that were founded by a few individuals roughly ten generations ago [3] (Fig. 1). These communities are relatively isolated due to the preference for consanguineous marriages. Acknowledging the effect of genetic variation on a hearing disability might be the cornerstone of future research directed toward restoring hearing

Objectives

Methods

Results

Conclusion