DNA Diagnostics of Hereditary Hearing Loss: A Targeted Resequencing Approach Combined with a Mutation Classification System

Hum Mutat. 2016 Aug;37(8):812-9. doi: 10.1002/humu.22999. Epub 2016 May 6.


Although there are nearly 100 different causative genes identified for nonsyndromic hearing loss (NSHL), Sanger sequencing-based DNA diagnostics usually only analyses three, namely, GJB2, SLC26A4, and OTOF. As this is seen as inadequate, there is a need for high-throughput diagnostic methods to detect disease-causing variations, including single-nucleotide variations (SNVs), insertions/deletions (Indels), and copy-number variations (CNVs). In this study, a targeted resequencing panel for hearing loss was developed including 79 genes for NSHL and selected forms of syndromic hearing loss. One-hundred thirty one presumed autosomal-recessive NSHL (arNSHL) patients of Western-European ethnicity were analyzed for SNVs, Indels, and CNVs. In addition, we established a straightforward variant classification system to deal with the large number of variants encountered. We estimate that combining prescreening of GJB2 with our panel leads to a diagnosis in 25%-30% of patients. Our data show that after GJB2, the most commonly mutated genes in a Western-European population are TMC1, MYO15A, and MYO7A (3.1%). CNV analysis resulted in the identification of causative variants in two patients in OTOA and STRC. One of the major challenges for diagnostic gene panels is assigning pathogenicity for variants. A collaborative database collecting all identified variants from multiple centers could be a valuable resource for hearing loss diagnostics.

Keywords: hereditary hearing loss; mutation classification system; targeted resequencing.

Publication types

  • Multicenter Study

MeSH terms

  • Connexin 26
  • Connexins / genetics
  • DNA Copy Number Variations
  • Exome
  • GPI-Linked Proteins / genetics
  • Genetic Predisposition to Disease*
  • Hearing Loss, Sensorineural / diagnosis*
  • Hearing Loss, Sensorineural / genetics
  • High-Throughput Nucleotide Sequencing / methods*
  • Humans
  • INDEL Mutation
  • Intercellular Signaling Peptides and Proteins
  • Membrane Proteins / genetics
  • Mutation*
  • Myosin VIIa
  • Myosins / genetics
  • Polymorphism, Single Nucleotide
  • Sequence Analysis, DNA / methods*


  • Connexins
  • GJB2 protein, human
  • GPI-Linked Proteins
  • Intercellular Signaling Peptides and Proteins
  • MYO15A protein, human
  • MYO7A protein, human
  • Membrane Proteins
  • Myosin VIIa
  • OTOA protein, human
  • STRC protein, human
  • TMC1 protein, human
  • Connexin 26
  • Myosins