Spectrum of genes for inherited hearing loss in the Israeli Jewish population, including the novel human deafness gene ATOH1

Abstract

Mutations in more than 150 genes are responsible for inherited hearing loss, with thousands of different, severe causal alleles that vary among populations. The Israeli Jewish population includes communities of diverse geographic origins, revealing a wide range of deafness-associated variants and enabling clinical characterization of the associated phenotypes. Our goal was to identify the genetic causes of inherited hearing loss in this population, and to determine relationships among genotype, phenotype, and ethnicity. Genomic DNA samples from informative relatives of 88 multiplex families, all of self-identified Jewish ancestry, with either non-syndromic or syndromic hearing loss, were sequenced for known and candidate deafness genes using the HEar-Seq gene panel. The genetic causes of hearing loss were identified for 60% of the families. One gene was encountered for the first time in human hearing loss: ATOH1 (Atonal), a basic helix-loop-helix transcription factor responsible for autosomal dominant progressive hearing loss in a five-generation family. Our results show that genomic sequencing with a gene panel dedicated to hearing loss is effective for genetic diagnoses in a diverse population. Comprehensive sequencing enables well-informed genetic counseling and clinical management by medical geneticists, otolaryngologists, audiologists, and speech therapists and can be integrated into newborn screening for deafness.

Revisiting Genetic Epidemiology with a Refined Targeted Gene Panel for Hereditary Hearing Impairment in the Taiwanese Population

“…We previously implemented a 214-gene NGS panel in clinical practice, which led to a remarkable increase in the diagnostic rate—from 25% using conventional Sanger sequencing to approximately 50% using NGS [ 13 ]. The design of commercial NGS diagnostic panels for deafness differs across laboratories, with the number of sequenced genes ranging from 12 to 372 [ 16 , 17 ]. The difference in the number of sequenced genes most likely represents a trade-off between diagnostic yield and the cost of genetic examinations.…”

Biallelic ATOH1 Gene Variant in Siblings With Pontocerebellar Hypoplasia, Developmental Delay, and Hearing Loss

“…17 In addition, a recent study reported cosegregation of a heterozygous ATOH1 variant with progressive nonsyndromic hearing loss in a 5-generational pedigree. 18…”

Molecular Features of SLC26A4 Common Variant p.L117F

“…Homozygosity for SLC26A4 c.349C>T, p.L117F has also been observed in four other Ashkenazi families during screening for childhood hearing loss by genetic clinics in Israel. Based on these considerations, the variant was recently reclassified to Pathogenic [ 16 , 30 ].…”

“…Mild reductions in ion transport activity have been discussed as per se non-causative of hearing loss but possibly pathogenic in trans configuration with a different established pathogenic variant [ 21 ]. As a matter of fact, hearing loss patients homozygous for p.L117F have been described in the Ashkenazi Jewish population, thus supporting the pathogenicity of this variant independently from the association with another pathogenic variant [ 30 ].…”

“…Here, we exploited a triad of cell-based assays, specifically the determination of ion transport function, subcellular localization, and protein abundance, to conclusively assign or exclude the pathogenicity of the SLC26A4 variant NM_000441.1:c.349C>T, p.Leu117Phe (p.L117F), dbSNP: rs145254330, a founder variant of the Ashkenazi Jewish population with controversial findings regarding its pathogenicity [ 30 ]. Our assays supported the pathogenic potential of this variant and further underscored that the determination of protein levels can disclose molecular defects in the face of mild impairments in ion transport activity.…”