title: Targeted genomic capture and massively parallel sequencing to identify genes for hereditary hearing loss in Middle Eastern families.
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.
authors.affiliation: Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
authors.forename: Zippora
authors.initials: Z
authors.lastname: Brownstein
authors.forename: Lilach M
authors.initials: LM
authors.lastname: Friedman
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Varda
authors.initials: V
authors.lastname: Oron-Karni
authors.forename: Nitzan
authors.initials: N
authors.lastname: Kol
authors.forename: Amal
authors.initials: A
authors.lastname: Abu Rayyan
authors.forename: Thomas
authors.initials: T
authors.lastname: Parzefall
authors.forename: Dorit
authors.initials: D
authors.lastname: Lev
authors.forename: Stavit
authors.initials: S
authors.lastname: Shalev
authors.forename: Moshe
authors.initials: M
authors.lastname: Frydman
authors.forename: Bella
authors.initials: B
authors.lastname: Davidov
authors.forename: Mordechai
authors.initials: M
authors.lastname: Shohat
authors.forename: Michele
authors.initials: M
authors.lastname: Rahile
authors.forename: Sari
authors.initials: S
authors.lastname: Lieberman
authors.forename: Ephrat
authors.initials: E
authors.lastname: Levy-Lahad
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Noam
authors.initials: N
authors.lastname: Shomron
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
mesh_terms: D000483:Alleles; D000818:Animals; D018912:Arabs / Q000235:genetics; D000070585:Cadherin Related Proteins; D015820:Cadherins / Q000235:genetics; D019295:Computational Biology; D004252:DNA Mutational Analysis / Q000379:methods; D005091:Exons; D016326:Extracellular Matrix Proteins / Q000235:genetics; D018703:Founder Effect; D058851:GPI-Linked Proteins / Q000235:genetics; D005787:Gene Frequency; D015723:Gene Library; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D005828:Genetics, Population; D015894:Genome, Human; D034381:Hearing Loss / Q000453:epidemiology / Q000235:genetics*; D006801:Humans; D054643:INDEL Mutation; D040582:Inheritance Patterns; D007585:Jews / Q000235:genetics*; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D008877:Middle East / Q000453:epidemiology; D009218:Myosins / Q000235:genetics; D010375:Pedigree
chemical_list: C442480:CDH23 protein, human; D000070585:Cadherin Related Proteins; D015820:Cadherins; D016326:Extracellular Matrix Proteins; D058851:GPI-Linked Proteins; C485245:MYO15A protein, human; D008565:Membrane Proteins; C491350:TECTA protein, human; C451751:TMC1 protein, human; D009218:Myosins