IVS8+1 DelG, a Novel Splice Site Mutation Causing DFNA5 Deafness in a Chinese Family / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>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.</p><p><b>METHODS</b>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.</p><p><b>RESULTS</b>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.</p><p><b>CONCLUSIONS</b>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.</p>

Single nucleotide polymorphisms and haplotypes analysis of DFNB1 locus in Chinese sporadic hearing impairment population / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>The DFNB1 locus, which contains the gap junction beta-2 (GJB2) and gap junction beta-6 (GJB6) genes, plays a key role in the nonsyndromic and sporadic hearing impairment. Mutations of DFNB1 result in autosomal recessive nonsyndromic hearing impairment (ARNSHI). Previous researches have identified mutations in GJB2 and GJB6, but single nucleotide polymorphisms (SNPs) of DFNB1 locus have not been studied. So we chose five SNPs to evaluate whether there is difference between deafness people and normal-hearing people in Han Chinese.</p><p><b>METHODS</b>Five SNPs in the DFNB1 region were examined using a case-control association study between cases with sporadic hearing impairment and controls with normal hearing. The HWEsoft and SHEsis softwares were used to analyze the results.</p><p><b>RESULTS</b>Single-locus association analysis showed a positive association for three SNPs: rs9315400, rs2274084 and 235delC. When we compared the distributions of the haplotypes, we also found significant differences between cases and controls in the haplotype combination of rs2274084 and rs2274083 (chi(2) = 12.978, df = 3, global P = 0.004719).</p><p><b>CONCLUSIONS</b>The haplotypes composed of rs2274084 and rs2274083 suggested that C-C may be a risk haplotype for the sporadic hearing impairment while T-T may be protective against hearing impairment. From that point of view, we can conclude that the SNPs of DFNB1 locus also plays an important role in sporadic hearing impairment cases.</p>