Exonic mutations and exon skipping: Lessons learned from DFNA5

Hum Mutat. 2018 Mar;39(3):433-440. doi: 10.1002/humu.23384. Epub 2018 Jan 11.


Dysregulation of splicing is a common factor underlying many inherited diseases including deafness. For one deafness-associated gene, DFNA5, perturbation of exon 8 splicing results in a constitutively active truncated protein. To date, only intronic mutations have been reported to cause exon 8 skipping in patients with DFNA5-related deafness. In five families with postlingual progressive autosomal dominant non-syndromic hearing loss, we employed two next-generation sequencing platforms-OtoSCOPE and whole exome sequencing-followed by variant filtering and prioritization based on both minor allele frequency and functional consequence using a customized bioinformatics pipeline to identify three novel and two recurrent mutations in DFNA5 that segregated with hearing loss in these families. The three novel mutations are all missense variants within exon 8 that are predicted computationally to decrease splicing efficiency or abolish it completely. We confirmed their functional impact in vitro using mini-genes carrying each mutant DFNA5 exon 8. In so doing, we present the first exonic mutations in DFNA5 to cause deafness, expand the mutational spectrum of DFNA5-related hearing loss, and highlight the importance of assessing the effect of coding variants on splicing.

Keywords: DFNA5; RNA-splicing; deafness; exon-skipping; non-syndromic hearing loss.

Publication types

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

MeSH terms

  • Exons / genetics*
  • Family
  • Female
  • Humans
  • Male
  • Mutation / genetics*
  • Pedigree
  • RNA Splicing
  • Receptors, Estrogen / genetics*


  • GSDME protein, human
  • Receptors, Estrogen