Exome Sequencing Identifies a Mutation in EYA4 as a Novel Cause of Autosomal Dominant Non-Syndromic Hearing Loss

PLoS One. 2015 May 11;10(5):e0126602. doi: 10.1371/journal.pone.0126602. eCollection 2015.

Abstract

Autosomal dominant non-syndromic hearing loss is highly heterogeneous, and eyes absent 4 (EYA4) is a disease-causing gene. Most EYA4 mutations founded in the Eya-homologous region, however, no deafness causative missense mutation in variable region of EYA4 have previously been found. In this study, we identified a pathogenic missense mutation located in the variable region of the EYA4 gene for the first time in a four-generation Chinese family with 57 members. Whole-exome sequencing (WES) was performed on samples from one unaffected and two affected individuals to systematically search for deafness susceptibility genes, and the candidate mutations and the co-segregation of the phenotype were verified by polymerase chain reaction amplification and by Sanger sequencing in all of the family members. Then, we identified a novel EYA4 mutation in exon 8, c.511G>C; p.G171R, which segregated with postlingual and progressive autosomal dominant sensorineural hearing loss (SNHL). This report is the first to describe a missense mutation in the variable region domain of the EYA4 gene, which is not highly conserved in many species, indicating that the potential unconserved role of 171G>R in human EYA4 function is extremely important.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Amino Acid Sequence
  • Amino Acid Substitution
  • Audiometry
  • Exome
  • Female
  • Genes, Dominant*
  • Genetic Association Studies*
  • Genotype
  • Hearing Loss, Sensorineural / diagnosis
  • Hearing Loss, Sensorineural / genetics*
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Phenotype
  • Sequence Alignment
  • Trans-Activators / chemistry
  • Trans-Activators / genetics*

Substances

  • EYA4 protein, human
  • Trans-Activators

Grants and funding

This study was supported by the East Raising Sun Talents Program of Shanghai East Hospital, Tongji University (2013DFYY-2), the Foundation for Development of Science and Technology, Pudong new district, Shanghai (2013 PKJ2013-Y18), National Basic Research Program of China (2011CB504502), Basic Key Program of Shanghai Scientific and Technology Committee (14DJ1400103) and Program of Shanghai Municipal Commission of Health and Family Planning (2013ZYJB0015).