Abstract
In communities with high rates of consanguinity and consequently high prevalence of recessive phenotypes, homozygosity mapping with SNP arrays is an effective approach for gene discovery. In 20 Palestinian kindreds with prelingual nonsyndromic hearing loss, we generated homozygosity profiles reflecting linkage to the phenotype. Family sizes ranged from small nuclear families with two affected children, one unaffected sibling, and parents to multigenerational kindreds with 12 affected relatives. By including unaffected parents and siblings and screening 250 K SNP arrays, even small nuclear families yielded informative profiles. In 14 families, we identified the allele responsible for hearing loss by screening a single candidate gene in the longest homozygous region. Novel alleles included missense, nonsense, and splice site mutations of CDH23, MYO7A, MYO15A, OTOF, PJVK, Pendrin/SLC26A4, TECTA, TMHS, and TMPRSS3, and a large genomic deletion of Otoancorin (OTOA). All point mutations were rare in the Palestinian population (zero carriers in 288 unrelated controls); the carrier frequency of the OTOA genomic deletion was 1%. In six families, we identified five genomic regions likely to harbor novel genes for human hearing loss on chromosomes 1p13.3 (DFNB82), 9p23–p21.2/p13.3–q21.13 (DFNB83), 12q14.3–q21.2 (DFNB84; two families), 14q23.1–q31.1, and 17p12–q11.2 (DFNB85).
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Acknowledgements
We thank the families for their generous participation in this study. We thank Dr Wael Salhab for a clinical evaluation of the patients, and Michael Rahil of the Dar Al-Kalima Audiology Clinic for audiological analyses. We thank the technical staff of the Hereditary Research Laboratory (Bethlehem University), Rob Hall at the Center for Array Technology (University of Washington), Gregory Cooper, and Heather Mefford for helpful comments and suggestions. This study was supported by the NIH/NIDCD Grant R01DC005641.
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Shahin, H., Walsh, T., Rayyan, A. et al. Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. Eur J Hum Genet 18, 407–413 (2010). https://doi.org/10.1038/ejhg.2009.190
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DOI: https://doi.org/10.1038/ejhg.2009.190
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