title: PDZD7 and hearing loss: More than just a modifier.
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.
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Kevin T
authors.initials: KT
authors.lastname: Booth
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Hela
authors.initials: H
authors.lastname: Azaiez
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Kimia
authors.initials: K
authors.lastname: Kahrizi
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Allen C
authors.initials: AC
authors.lastname: Simpson
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors.forename: William T A
authors.initials: WT
authors.lastname: Tollefson
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Sloan
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Nicole C
authors.initials: NC
authors.lastname: Meyer
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Babanejad
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Fariba
authors.initials: F
authors.lastname: Ardalani
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Sanaz
authors.initials: S
authors.lastname: Arzhangi
authors.affiliation: Department of Biomedical Engineering, University of Iowa, Iowa City, Iowa.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Schnieders
authors.affiliation: Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
authors.forename: Hossein
authors.initials: H
authors.lastname: Najmabadi
authors.affiliation: Department of Otolaryngology-Head Neck Surgery, Molecular Otolaryngology Renal Research Laboratories, University of Iowa, Iowa City, Iowa.
authors.forename: Richard J H
authors.initials: RJ
authors.lastname: Smith
mesh_terms: D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D002879:Chromosomes, Human, Pair 10; D003638:Deafness / Q000235:genetics*; D005260:Female; D005808:Genes, Recessive; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D006239:Haplotypes; D034381:Hearing Loss / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree
chemical_list: D002352:Carrier Proteins; C000611545:PDZD7 protein, human
keywords: PDZD7; Usher syndrome; deafness; modifier; non-syndromic hearing loss