title: Five novel loci for inherited hearing loss mapped by SNP-based homozygosity profiles in Palestinian families.
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).
authors.affiliation: Department of Life Sciences, Bethlehem University, Bethlehem, Palestine.
authors.forename: Hashem
authors.initials: H
authors.lastname: Shahin
authors.forename: Tom
authors.initials: T
authors.lastname: Walsh
authors.forename: Amal Abu
authors.initials: AA
authors.lastname: Rayyan
authors.forename: Ming K
authors.initials: MK
authors.lastname: Lee
authors.forename: Jake
authors.initials: J
authors.lastname: Higgins
authors.forename: Diane
authors.initials: D
authors.lastname: Dickel
authors.forename: Kristen
authors.initials: K
authors.lastname: Lewis
authors.forename: James
authors.initials: J
authors.lastname: Thompson
authors.forename: Carl
authors.initials: C
authors.lastname: Baker
authors.forename: Alex S
authors.initials: AS
authors.lastname: Nord
authors.forename: Sunday
authors.initials: S
authors.lastname: Stray
authors.forename: David
authors.initials: D
authors.lastname: Gurwitz
authors.forename: Karen B
authors.initials: KB
authors.lastname: Avraham
authors.forename: Mary-Claire
authors.initials: MC
authors.lastname: King
authors.forename: Moien
authors.initials: M
authors.lastname: Kanaan
mesh_terms: D018912:Arabs; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D002883:Chromosomes, Human, Pair 14 / Q000235:genetics; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002899:Chromosomes, Human, Pair 9 / Q000235:genetics; D003241:Consanguinity; D005260:Female; D056726:Genetic Association Studies; D034381:Hearing Loss / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*
chemical_list: D008565:Membrane Proteins