Comprehensive analysis via exome sequencing uncovers genetic etiology in autosomal recessive nonsyndromic deafness in a large multiethnic cohort

Abstract

PurposeAutosomal recessive non-syndromic deafness (ARNSD) is characterized by a high degree of genetic heterogeneity with reported mutations in 58 different genes. This study was designed to detect deafness causing variants in a multiethnic cohort with ARNSD by using whole-exome sequencing (WES).MethodsAfter excluding mutations in the most common gene, GJB2, we performed WES in 160 multiplex families with ARNSD from Turkey, Iran, Mexico, Ecuador and Puerto Rico to screen for mutations in all known ARNSD genes.ResultsWe detected ARNSD-causing variants in 90 (56%) families, 54% of which had not been previously reported. Identified mutations were located in 31 known ARNSD genes. The most common genes with mutations were MYO15A (13%), MYO7A (11%), SLC26A4 (10%), TMPRSS3 (9%), TMC1 (8%), ILDR1 (6%) and CDH23 (4%). Nine mutations were detected in multiple families with shared haplotypes suggesting founder effects.ConclusionWe report on a large multiethnic cohort with ARNSD in which comprehensive analysis of all known ARNSD genes identifies causative DNA variants in 56% of the families. In the remaining families, WES allows us to search for causative variants in novel genes, thus improving our ability to explain the underlying etiology in more families.

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

“…This patient had an incomplete partition of the cochlea and mutations in SLC26A4. 35 We did not find other cases with an identifiable phenotype such as progressive HI with a downsloping audiogram caused by TMPRSS3 mutations, 7,36 and the stable HI with a cookie-bite audiogram configuration caused by mutations in TECTA. 7 This is most likely due to the fact that these genes are generally pretested in patients with these identifiable phenotypes.…”

“…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.…”

Mutation spectra and founder effect of TMC1 in patients with non‐syndromic deafness in Xiamen area, China

“…Kitajiri et al (2007) designed three short‐tandem repeats (STRs) and one SNP to test 10 families with p.R34X; the results strongly suggested a single ancestral origin of this mutation. In past years, there were few reports of hot spots; most reports were about novel mutations of TMC1 , suggesting that TMC1 is a highly conserved gene and its variants are rarely tolerated (Bademci et al, 2016). …”

Identification and Clinical Implications of a Novel MYO15A Variant in a Consanguineous Iranian Family by Targeted Exome Sequencing

“…New sequencing technologies are affordable to use for early diagnosis of HL [Bademci et al, 2016b]. Here, a novel variant identified by panel-based exome sequencing is reported within an Iranian family.…”

“…Although exome sequencing covers thousands annotated exons, the sequence coverage of regions of interest may be decreased in targeted regions. In comparison, targeted enrichment sequencing covers the target regions more efficiently and could reduce the analysis duration and cost [Bademci et al, 2016a]. NGS platforms have made their way into clinical laboratories, especially in diagnostic testing for hereditary disorders like HL.…”