Journal article
PDZD7 and hearing loss: More than just a modifier
American journal of medical genetics. Part A, Vol.167A(12), pp.2957-2965
12/2015
DOI: 10.1002/ajmg.a.37274
PMCID: PMC4741280
PMID: 26416264
Abstract
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.
Details
- Title: Subtitle
- PDZD7 and hearing loss: More than just a modifier
- Creators
- Kevin T Booth - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, IowaHela Azaiez - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, IowaKimia Kahrizi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranAllen C Simpson - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, IowaWilliam T A Tollefson - Department of Biomedical Engineering, University of Iowa, Iowa City, IowaChristina M Sloan - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, IowaNicole C Meyer - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, IowaMojgan Babanejad - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranFariba Ardalani - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranSanaz Arzhangi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranMichael J Schnieders - Department of Biomedical Engineering, University of Iowa, Iowa City, IowaHossein Najmabadi - Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, IranRichard J H Smith - Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa
- Resource Type
- Journal article
- Publication Details
- American journal of medical genetics. Part A, Vol.167A(12), pp.2957-2965
- DOI
- 10.1002/ajmg.a.37274
- PMID
- 26416264
- PMCID
- PMC4741280
- NLM abbreviation
- Am J Med Genet A
- ISSN
- 1552-4825
- eISSN
- 1552-4833
- Publisher
- United States
- Grant note
- R01 DC003544 / NIDCD NIH HHS R01 DC012049 / NIDCD NIH HHS R01 DC002842 / NIDCD NIH HHS
- Language
- English
- Date published
- 12/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Molecular Physiology and Biophysics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Iowa Neuroscience Institute; Biochemistry and Molecular Biology; Otolaryngology; Internal Medicine
- Record Identifier
- 9984006362902771
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