Description: "Background: Identification of genes responsible for medically important traits is a major challenge in human genetics. Due to the genetic heterogeneity of hearing loss, targeted DNA capture and massively parallel sequencing are ideal tools to address this challenge. Our subjects for gene discovery are Jewish Israeli and Palestinian Arab families that vary in mode of inheritance, severity, and onset of hearing loss. Results: A custom 1.46 MB design of cRNA oligonucleotides was constructed containing 246 genes responsible for either human or mouse deafness. Paired-end libraries were prepared from 11 probands and bar-coded multiplexed samples were sequenced to high depth of coverage. Rare and private SNP and indel variants were identified by filtering the sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. The critical mutation(s) of the probands co-segregated with hearing loss. Screening of additional families in the relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of hearing loss in the Moroccan Jewish population. Conclusions: Targeted capture and sequencing of genomic DNA from persons with inherited hearing loss offers an effective screen for mutations. Critical mutations were identified in 6 probands and their families, leading to the identification of the causative alleles in 20 additional probands and their families. The integration of genomic analysis into early clinical diagnosis of hearing loss will enable prediction of related phenotypes and enhance rehabilitation. Characterization of the proteins encoded by these genes will enable an understanding of the biological mechanisms involved in the pathophysiology of hearing loss."

Data type: Other

Sample scope: Monoisolate

Release date: 2011-09-01