Introduction: Over the past decades, many deafness genes have been identified to cause hereditary hearing impairment (HI). It therefore, has become possible to screen for these genes in the out-patient clinic. The importance of genetic screening of HI is that patients can be counseled about the cause and prognosis of their hearing loss and effects of rehabilitation.
Hearing impairment is genetically heterogeneous and testing of several single HI-related genes is laborious and expensive. This study evaluates the diagnostic utility of whole exome sequencing (WES) targeting a panel of HI-related genes.
Methods: Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of approximately 100 genes. 206 additional patients underwent single gene testing guided by phenotype analyses.
Results: We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving a known HI gene, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 11 patients (5.5%). In the remaining 122 cases no potentially causative variants were detected (61%). The diagnostic yield of single gene testing in the 206 additional patients was 7.6%.
Conclusion: The diagnostic yield for HI using WES targeting a HI gene panel is higher (33.5%) than targeted sequencing of single genes (7.6%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A, STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis of variants of uncertain significance will further increase the diagnostic yield of WES. A practical workflow for genetic testing of hereditary HI for screening in the out-patient clinic will be presented.
