A Novel Splice Site Mutation In DFNA5 Gene Causing Autosomal Dominant Non-syndromic Hearing Loss

Objective:We describe the phenotypic characterization of a large Chinese family with autosomal dominant hereditary deafness, and to explore the molecular pathogenic mechanism underlying the non-syndromic hearing loss.Methods:After obtaining informed consent, a detailed clinical evaluation was performed to the available family members. Genomic DNA was isolated from the peripheral leukocytes of the subjects using the Puregene DNA Isolation Kits. The genomic DNA of three affected individuals was then selected for targeted exome sequencing of 101 known deafness genes, as well as mitochondrial DNA and micro RNA regions. Co-segregation analysis between the hearing loss and the candidate variant was confirmed in available family members by direct PCR-Sanger sequencing. RT-PCR was performed to investigate the potential effect of the pathogenic mutation on m 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, progressive, non-syndromic, and sensorineural hearing loss. Molecular analysis identified a novel splice site mutation in DFNA5 intron 8(IVS8+1 del G). 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:Hearing loss was non-syndromic, progressive and sensorineural with late onset in this Chinese family. Targeted exome sequencing combined with co-segregation analysis led to the identification of a novel DFNA5 mutation IVS8+1 del G in intron 8. Our findings provide further support to the hypothesis that the DFNA5-associated hearing loss represents a mechanism of gain-of-function.