Genetics of hearing loss in the Arab population of Northern Israel

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)1840-1847
Number of pages8
JournalEuropean Journal of Human Genetics
Volume26
Issue number12
DOIs
StatePublished - 1 Dec 2018

Funding

FundersFunder number
National Institutes of Health/NIDCD
National Institute on Deafness and Other Communication DisordersR01DC011835

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