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PDZD7 and hearing loss: More than just a modifier
Author(s) -
Booth Kevin T.,
Azaiez Hela,
Kahrizi Kimia,
Simpson Allen C.,
Tollefson William T.A.,
Sloan Christina M.,
Meyer Nicole C.,
Babanejad Mojgan,
Ardalani Fariba,
Arzhangi Sanaz,
Schnieders Michael J.,
Najmabadi Hossein,
Smith Richard J.H.
Publication year - 2015
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.37274
Subject(s) - genetics , sanger sequencing , missense mutation , biology , disease gene identification , hearing loss , locus (genetics) , loss of heterozygosity , nonsense mutation , genetic heterogeneity , genetic linkage , allele , candidate gene , compound heterozygosity , gene , exome sequencing , phenotype , mutation , medicine , audiology
Deafness is the most frequent sensory disorder. With over 90 genes and 110 loci causally implicated in non‐syndromic hearing loss, it is phenotypically and genetically heterogeneous. Here, we investigate the genetic etiology of deafness in four families of Iranian origin segregating autosomal recessive non‐syndromic hearing loss (ARNSHL). We used a combination of linkage analysis, homozygosity mapping, and a targeted genomic enrichment platform to simultaneously screen 90 known deafness‐causing genes for pathogenic variants. Variant segregation was confirmed by Sanger sequencing. Linkage analysis and homozygosity mapping showed segregation with the DFNB57 locus on chromosome 10 in two families. Targeted genomic enrichment with massively parallel sequencing identified causal variants in PDZD7 : a homozygous missense variant (p.Gly103Arg) in one family and compound heterozygosity for missense (p.Met285Arg) and nonsense (p.Tyr500Ter) variants in the second family. Screening of two additional families identified two more variants: (p.Gly228Arg) and (p.Gln526Ter). Variant segregation with the hearing loss phenotype was confirmed in all families by Sanger sequencing. The missense variants are predicted to be deleterious, and the two nonsense mutations produce null alleles. This report is the first to show that mutations in PDZD7 cause ARNSHL, a finding that offers addition insight into the USH2 interactome. We also describe a novel likely disease‐causing mutation in CIB2 and illustrate the complexity associated with gene identification in diseases that exhibit large genetic and phenotypic heterogeneity. © 2015 Wiley Periodicals, Inc.

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