Targeted next-generation sequencing of deafness genes in hearing-impaired individuals uncovers informative mutations

Genet Med. 2014 Dec;16(12):945-53. doi: 10.1038/gim.2014.65. Epub 2014 May 29.


Purpose: Targeted next-generation sequencing provides a remarkable opportunity to identify variants in known disease genes, particularly in extremely heterogeneous disorders such as nonsyndromic hearing loss. The present study attempts to shed light on the complexity of hearing impairment.

Methods: Using one of two next-generation sequencing panels containing either 80 or 129 deafness genes, we screened 30 individuals with nonsyndromic hearing loss (from 23 unrelated families) and analyzed 9 normal-hearing controls.

Results: Overall, we found an average of 3.7 variants (in 80 genes) with deleterious prediction outcome, including a number of novel variants, in individuals with nonsyndromic hearing loss and 1.4 in controls. By next-generation sequencing alone, 12 of 23 (52%) probands were diagnosed with monogenic forms of nonsyndromic hearing loss; one individual displayed a DNA sequence mutation together with a microdeletion. Two (9%) probands have Usher syndrome. In the undiagnosed individuals (10/23; 43%) we detected a significant enrichment of potentially pathogenic variants as compared to controls.

Conclusion: Next-generation sequencing combined with microarrays provides the diagnosis for approximately half of the GJB2 mutation-negative individuals. Usher syndrome was found to be more frequent in the study cohort than anticipated. The conditions in a proportion of individuals with nonsyndromic hearing loss, particularly in the undiagnosed group, may have been caused or modified by an accumulation of unfavorable variants across multiple genes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Audiometry
  • Base Sequence
  • Child
  • Child, Preschool
  • Cohort Studies
  • Connexin 26
  • Connexins / genetics
  • DNA / genetics
  • Deafness / genetics
  • Family Health
  • Female
  • Gene Deletion
  • Gene Dosage
  • Genetic Predisposition to Disease
  • Genetic Variation
  • High-Throughput Nucleotide Sequencing / methods*
  • Homozygote
  • Humans
  • Infant
  • Male
  • Molecular Sequence Data
  • Mutation*
  • Oligonucleotide Array Sequence Analysis
  • Pedigree
  • Sequence Analysis, DNA*
  • Treatment Outcome
  • Young Adult


  • Connexins
  • GJB2 protein, human
  • Connexin 26
  • DNA

Supplementary concepts

  • Nonsyndromic Deafness