The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands.
Level 4 - case-series / case-control
Case series / single-cohort diagnostic yield study without a control group
PubMed 28000701 · doi:10.1038/ejhg.2016.182
What was done
Two hundred index patients, mostly of Dutch origin, with presumed hereditary hearing impairment underwent whole-exome sequencing followed by targeted analysis of a 120-gene panel, including copy number variation detection.
What was found
Causative variants were identified in 67 of 200 patients (33.5%), including 8 patients with large homozygous deletions in STRC, OTOA, or USH2A detected via copy number variation analysis. Variants of uncertain significance were found in 10 patients (5.0%), while 123 patients (61.5%) had no potentially causative variants detected. Leading genes were GJB2, USH2A, MYO15A, and STRC for autosomal recessive cases, and MYO6 for autosomal dominant cases.
Why it matters
Filtering exome sequencing to a targeted panel of hearing impairment genes resolves roughly one-third of presumed hereditary cases in a single assay, highlighting the importance of including copy number variation detection.
Limits
The cohort was predominantly Dutch, limiting generalizability across diverse populations. Over 60% of cases remained unsolved, and segregation and functional analyses for variants of uncertain significance were not reported in the abstract.
Cited by
- supports Standard genetic panels for deafness yield a definitive diagnostic result in only about 50% of tested patients, with the rest showing variants of unknown significance (VUSs).