Genomic analysis of a heterogeneous Mendelian phenotype: multiple novel alleles for inherited hearing loss in the Palest
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Genomic analysis of a heterogeneous Mendelian phenotype: Multiple novel alleles for inherited hearing loss in the Palestinian population Tom Walsh,1 Amal Abu Rayan,2 Judeh Abu Sa’ed,2 Hashem Shahin,2,3 Jeanne Shepshelovich,4 Ming K. Lee,1 Koret Hirschberg,4 Mustafa Tekin,5 Wa’el Salhab,6 Karen B. Avraham,3 Mary-Claire King1* and Moien Kanaan2 1
Departments of Medicine and Genome Sciences, University of Washington, Seattle, WA, USA Department of Life Sciences, Bethlehem University, Bethlehem, Palestinian Authority 3 Department of Human Genetics and Molecular Medicine, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 4 Department of Pathology, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel 5 Division of Paediatric Genetics, Ankara University School of Medicine, Dikimevi, Ankara, Turkey 6 Department of Otolaryngology, St. Joseph’s Hospital, Jerusalem, Israel * Correspondence to: Tel: þ 1 206 616 4294; Fax: þ 1 206 616 4295; E-mail: [email protected] 2
Date received: 19th July 2005
Abstract
Recessively inherited phenotypes are frequent in the Palestinian population, as the result of a historical tradition of marriages within extended kindreds, particularly in isolated villages. In order to characterise the genetics of inherited hearing loss in this population, we worked with West Bank schools for the deaf to identify children with prelingual, bilateral, severe to profound hearing loss not attributable to infection, trauma or other known environmental exposure. Of 156 families enrolled, hearing loss in 17 families (11 per cent) was due to mutations in GJB2 (connexin 26), a smaller fraction of GJB2-associated deafness than in other populations. In order to estimate how many different genes might be responsible for hearing loss in this population, we evaluated ten families for linkage to all 36 known human autosomal deafness-related genes, fully sequencing hearing-related genes at any linked sites in informative relatives. Four families harboured four novel alleles of TMPRSS3 (988DA ¼ 352stop), otoancorin (1067A . T ¼ D356V) and pendrin (716T . A ¼ V239D and 1001G . T ¼ 346stop). In each family, all affected individuals were homozygous for the critical mutation. Each allele was specific to one or a few families in the cohort; none were widespread. Since epidemiological tests of association of mutations with deafness were not feasible for such rare alleles, we used functional and bioinformatics approaches to evaluate their consequences. In six other families, hearing loss was not linked to any known gene, suggesting that these families harbour novel genes responsible for this phenotype. We conclude that inherited hearing loss is highly heterogeneous in this population, with most extended families acting as genetic isolates in this context. We also conclude that the same genes are responsible for hearing loss in this population as elsewhere, so that gene discovery in these families informs the genetics of hearing loss worldwide. Keywords: genetics, genomics, inherited, deafness,
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