title: IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family.
abstract: BACKGROUND
  Nonsyndromic hearing loss (NSHL) is highly heterogeneous, in which more than 90 causative genes have currently been identified. DFNA5 is one of the deafness genes that known to cause autosomal dominant NSHL. Until date, only five DFNA5 mutations have been described in eight families worldwide. In this study, we reported the identification of a novel pathogenic mutation causing DFNA5 deafness in a five-generation Chinese family.
  
  
  METHODS
  After detailed clinical evaluations of this family, the genomic DNA of three affected individuals was selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and microRNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct polymerase chain reaction (PCR)-Sanger sequencing. Real-time PCR (RT-PCR) was performed to investigate the potential effect of the pathogenic mutation on messenger RNA splicing.
  
  
  RESULTS
  Clinical evaluations revealed a similar deafness phenotype in this family to that of previously reported DFNA5 families with autosomal dominant, late-onset hearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8 (IVS8+1 delG). The mutation segregated with the hearing loss of the family and was absent in 120 unrelated control DNA samples of Chinese origin. RT-PCR showed skipping of exon 8 in the mutant transcript.
  
  
  CONCLUSIONS
  We identified a novel DFNA5 mutation IVS8+1 delG in a Chinese family which led to skipping of exon 8. This is the sixth DFNA5 mutation relates to hearing loss and the second one in DFNA5 intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.
authors.forename: Mei-Na
authors.initials: MN
authors.lastname: Li-Yang
authors.forename: Xiao-Fei
authors.initials: XF
authors.lastname: Shen
authors.forename: Qin-Jun
authors.initials: QJ
authors.lastname: Wei
authors.forename: Jun
authors.initials: J
authors.lastname: Yao
authors.forename: Ya-Jie
authors.initials: YJ
authors.lastname: Lu
authors.forename: Xin
authors.initials: X
authors.lastname: Cao
authors.affiliation: Department of Otolaryngology, First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China.
authors.forename: Guang-Qian
authors.initials: GQ
authors.lastname: Xing
mesh_terms: D000328:Adult; D003638:Deafness / Q000235:genetics*; D005091:Exons / Q000235:genetics; D005260:Female; D034381:Hearing Loss / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D055815:Young Adult