Spectrum of DNA variants for non-syndromic deafness in a large cohort from multiple continents

Abstract

Hearing loss (HL) is the most common sensory deficit in humans with causative variants in over 140 genes. With few exceptions, however, the population-specific distribution for many of the identified variants/genes is unclear. Until recently, the extensive genetic and clinical heterogeneity of deafness precluded comprehensive genetic analysis. Here, using a custom capture panel (MiamiOtoGenes), we undertook a targeted sequencing of 180 genes in a multi-ethnic cohort of 342 GJB2 mutation-negative deaf probands from South Africa, Nigeria, Tunisia, Turkey, Iran, India, Guatemala and the United States (South Florida). We detected causative DNA variants in 25% of multiplex and 7% of simplex families. The detection rate varied between 0% and 57% based on ethnicity, with Guatemala and Iran at the lower and higher end of the spectrum, respectively. We detected causative variants within 27 genes without predominant recurring pathogenic variants. The most commonly implicated genes include MYO15A, SLC26A4, USH2A, MYO7A, MYO6 and TRIOBP. Overall, our study highlights the importance of family history and generation of databases for multiple ethnically discrete populations to improve our ability to detect and accurately interpret genetic variants for pathogenicity.

The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

“…[28][29][30][31][32][33][34] A relatively high frequency of STRC deletions was found in our Dutch population (2%), as has also been reported in other populations. 8,9 In one case (ISO31), we found causative variants in a gene that is associated with an identifiable phenotype and segregating with a recessive inheritance pattern.…”

“…Other studies using massively parallel sequencing have reported similar overall diagnostic rates, despite of using different technologies and testing different populations. [32][33][34]37,38 We found that causative variants in GJB2, USH2A, MYO6, STRC and MYO15A underlie HI in 14.0% of the cases in our cohort. This is in agreement with the previously published studies on the involvement of HI genes in other populations.…”

“…This is in agreement with the previously published studies on the involvement of HI genes in other populations. [6][7][8][9][32][33][34]36,[38][39][40] The diagnostic yield of WES targeting a panel of HI-related genes is generally higher than that of single gene testing. Therefore, we recommend to reduce prescreening of single genes to a minimum.…”

A common variant in CLDN14 causes precipitous, prelingual sensorineural hearing loss in multiple families due to founder effect

“…This represents a massive ascertainment bias, as children who are DFNB1 negative are not followed up, due to the expenses associated with genetic testing. Recently, a large, ethnically diverse, cohort study demonstrated the importance of investigating DFNB1 -negative deaf probands (Yan et al 2016). This study took a targeted panel approach in 342 probands (185 simplex and 157 multiplex families), sequenced 180 known hearing loss genes, and identified 151 variants in 119 families.…”

“…Therefore, many recessive cases may be due to genetic defects in genes yet to be identified. However, recent studies using new high-throughput technologies and broader application in multi-ethnic populations report GJB2 yields of less than 25%, suggesting a larger role for other recessive genes in prelingual severe cases (Yan et al 2016; Sloan-Heggen et al 2016). …”