Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families

Hashem Shahin, Tom Walsh, Amal Abu Rayyan, Ming K. Lee, Jake Higgins, Diane Dickel, Kristen Lewis, James Thompson, Carl Baker, Alexander Nord, Sunday Stray, David Gurwitz, Karen B. Avraham, Mary Claire King, Moien Kanaan

Research output: Contribution to journalArticle

59 Scopus citations

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).

Original languageEnglish (US)
Pages (from-to)407-413
Number of pages7
JournalEuropean Journal of Human Genetics
Volume18
Issue number4
DOIs
StatePublished - Apr 1 2010
Externally publishedYes

Keywords

  • Deafness
  • DFNB
  • Hearing
  • Homozygosity mapping
  • Mutation
  • Protein modeling

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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    Shahin, H., Walsh, T., Rayyan, A. A., Lee, M. K., Higgins, J., Dickel, D., Lewis, K., Thompson, J., Baker, C., Nord, A., Stray, S., Gurwitz, D., Avraham, K. B., King, M. C., & Kanaan, M. (2010). Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families. European Journal of Human Genetics, 18(4), 407-413. https://doi.org/10.1038/ejhg.2009.190