title: SNP linkage analysis and whole exome sequencing identify a novel POU4F3 mutation in autosomal dominant late-onset nonsyndromic hearing loss (DFNA15).
abstract: Autosomal dominant non-syndromic hearing loss (AD-NSHL) is one of the most common genetic diseases in human and is well-known for the considerable genetic heterogeneity. In this study, we utilized whole exome sequencing (WES) and linkage analysis for direct genetic diagnosis in AD-NSHL. The Korean family had typical AD-NSHL running over 6 generations. Linkage analysis was performed by using genome-wide single nucleotide polymorphism (SNP) chip and pinpointed a genomic region on 5q31 with a significant linkage signal. Sequential filtering of variants obtained from WES, application of the linkage region, bioinformatic analyses, and Sanger sequencing validation identified a novel missense mutation Arg326Lys (c.977G>A) in the POU homeodomain of the POU4F3 gene as the candidate disease-causing mutation in the family. POU4F3 is a known disease gene causing AD-HSLH (DFNA15) described in 5 unrelated families until now each with a unique mutation. Arg326Lys was the first missense mutation affecting the 3(rd) alpha helix of the POU homeodomain harboring a bipartite nuclear localization signal sequence. The phenotype findings in our family further supported previously noted intrafamilial and interfamilial variability of DFNA15. This study demonstrated that WES in combination with linkage analysis utilizing bi-allelic SNP markers successfully identified the disease locus and causative mutation in AD-NSHL.
authors.affiliation: Department of Laboratory Medicine and Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
authors.forename: Hong-Hee
authors.initials: HH
authors.lastname: Won
authors.forename: Kyoung-Jin
authors.initials: KJ
authors.lastname: Park
authors.forename: Sung Hwa
authors.initials: SH
authors.lastname: Hong
authors.forename: Chang-Seok
authors.initials: CS
authors.lastname: Ki
authors.forename: Sang Sun
authors.initials: SS
authors.lastname: Cho
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.forename: Gert
authors.initials: G
authors.lastname: Vriend
authors.forename: Jong-Won
authors.initials: JW
authors.lastname: Kim
mesh_terms: D019943:Amino Acid Substitution; D044466:Asian People; D004252:DNA Mutational Analysis; D059472:Exome; D005260:Female; D030342:Genetic Diseases, Inborn; D008040:Genetic Linkage; D055106:Genome-Wide Association Study; D034381:Hearing Loss; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D020641:Polymorphism, Single Nucleotide; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D056910:Republic of Korea; D050821:Transcription Factor Brn-3C / Q000235:genetics*
chemical_list: D018398:Homeodomain Proteins; C111223:POU4F3 protein, human; D050821:Transcription Factor Brn-3C