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 (988ΔA = 352stop), otoancorin (1067A >T = D356V) and pendrin (716T > A = V239D and 1001G > T = 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.
Highlights
Extended kindreds from highly endogamous communities are ideally suited for identifying genes responsible for clinically important phenotypes
Probands were characterised as having prelingual, bilateral hearing loss that could not be attributed to infection or trauma
Because mutations in the gap junction GJB2 are responsible for a substantial fraction of recessive inherited hearing loss worldwide,[13] we first sequenced both exons of this gene in genomic DNA from all probands.[4]
Summary
Extended kindreds from highly endogamous communities are ideally suited for identifying genes responsible for clinically important phenotypes. Villages were often established by a few extended families and, despite their geographical proximity, remained demographically isolated. Marriages have been arranged within extended families in these villages, leading to high levels of consanguinity and high frequencies of recessive traits.[1,2]. The willingness of these kindreds to participate in research has been of enormous help to geneticists. In order to identify genes responsible for inherited hearing loss, we have worked with consanguineous kindreds from the q HENRY STEWART PUBLICATIONS 1473–9542.
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