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This article is part of a special issue on exome sequencing.

Open Access Highly Accessed Research

Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in middle eastern families

Zippora Brownstein1, Lilach M Friedman1, Hashem Shahin2, Varda Oron-Karni3, Nitzan Kol3, Amal Abu Rayyan2, Thomas Parzefall1, Dorit Lev4, Stavit Shalev56, Moshe Frydman7, Bella Davidov8, Mordechai Shohat18, Michele Rahile9, Sari Lieberman10, Ephrat Levy-Lahad1011, Ming K Lee12, Noam Shomron133, Mary-Claire King12, Tom Walsh12, Moien Kanaan2 and Karen B Avraham13*

Author affiliations

1 Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

2 Department of Biological Sciences, Bethlehem University, Bethlehem, Palestinian Authority

3 Genome High-Throughput Sequencing Laboratory, Tel Aviv University, Tel Aviv 69978, Israel

4 Institute of Medical Genetics, Wolfson Medical Center, Holon 58100, Israel

5 Genetics Institute, Ha'Emek Medical Center, Afula 18341, Israel

6 Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 32000, Israel

7 Danek Gartner Institute of Human Genetics, Sheba Medical Center, Tel Hashomer 52621, Israel

8 Department of Medical Genetics, Rabin Medical Center, Beilinson Campus, Petah Tikva, Israel

9 Darr Al Kalima Audiological Clinic, Bethlehem, Palestinian Authority

10 Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem 91031, Israel

11 Hebrew University Medical School, Jerusalem 91120, Israel

12 Department of Medicine (Medical Genetics) and Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA

13 Department of Cell and Developmental Biology, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel

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Citation and License

Genome Biology 2011, 12:R89  doi:10.1186/gb-2011-12-9-r89

Published: 14 September 2011

Abstract

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 genome analysis are Israeli Jewish and Palestinian Arab families with hearing loss that varies in mode of inheritance and severity.

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 single base pair and indel variants were identified by filtering sequence reads against polymorphisms in dbSNP132 and the 1000 Genomes Project. We identified deleterious mutations in CDH23, MYO15A, TECTA, TMC1, and WFS1. Critical mutations of the probands co-segregated with hearing loss. Screening of additional families in a relevant population was performed. TMC1 p.S647P proved to be a founder allele, contributing to 34% of genetic hearing loss in the Moroccan Jewish population.

Conclusions

Critical mutations were identified in 6 of the 11 original probands and their families, leading to the identification of 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 hearing loss.