A novel DFNA5 mutation, IVS8+4 A>G, in the splice donor site of intron 8 causes late-onset non-syndromic hearing loss in a Chinese family

Clin Genet. 2007 Nov;72(5):471-7. doi: 10.1111/j.1399-0004.2007.00889.x. Epub 2007 Sep 14.


We report here the clinical, genetic, and molecular characteristics of a large Chinese family exhibiting non-syndromic, late-onset autosomal dominant sensorineural hearing loss. Clinical evaluation revealed variable phenotypes of hearing loss in terms of severity and age-at-onset of disease in these subjects. Genome-wide linkage analysis mapped the disease gene to the DFNA5 locus with a maximum two-point log odds score of 5.39 at [theta] = 0 for marker D7S2457. DNA sequencing of DFNA5 revealed a novel heterozygous IVS8+4 A>G substitution in the splice donor site of intron 8. Reverse transcriptase-polymerase chain reaction (RT-PCR) showed skipping of exon 8 in the mutant transcript. This mutation faithfully cosegregated with hearing loss in the family. In addition, the mutation was absent in 100 unrelated control DNA samples of Chinese origin. The IVS8+4 A>G mutation is predicted to create a shift in the reading frame and introduce a stop codon at position 372, thereby resulting in a prematurely truncated DFNA5 protein. Up to date, a total of four mutations in DFNA5 have been reported to lead to hearing impairment, all of them result in skipping of exon 8 at the mRNA level. Our findings provide further support for the hypothesis that DFNA5-associated hearing loss is caused by a very specific gain-of-function mutation.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Base Sequence
  • China
  • DNA Mutational Analysis
  • Family*
  • Female
  • Genetic Linkage
  • Hearing Loss / genetics*
  • Humans
  • Introns*
  • Male
  • Mutation*
  • Pedigree
  • RNA Splice Sites / genetics*
  • Receptors, Estrogen / genetics*


  • GSDME protein, human
  • RNA Splice Sites
  • Receptors, Estrogen