The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in The Netherlands

Celia Zazo Seco, Mieke Wesdorp, Ilse Feenstra, Rolph Pfundt, Jayne Y Hehir-Kwa, Stefan H Lelieveld, Steven Castelein, Christian Gilissen, Ilse J de Wijs, Ronald JC Admiraal, Ronald JE Pennings, Henricus PM Kunst, Jiddeke M van de Kamp, Saskia Tamminga, Arjan C Houweling, Astrid S Plomp, Saskia M Maas, Pia AM de Koning Gans, Sarina G Kant, Christa M de Geus, Suzanna GM Frints, Els K Vanhoutte, Marieke F van Dooren, Marie- José H van den Boogaard, Hans Scheffer, Marcel Nelen, Hannie Kremer, Lies Hoefsloot, Margit Schraders, Helger G Yntema

Hearing impairment (HI) is genetically heterogeneous which hampers genetic counseling and molecular diagnosis. Testing of several single HI-related genes is laborious and expensive. In this study, we evaluate the diagnostic utility of whole-exome sequencing (WES) targeting a panel of HI-related genes. Two hundred index patients, mostly of Dutch origin, with presumed hereditary HI underwent WES followed by targeted analysis of an HI gene panel of 120 genes. We found causative variants underlying the HI in 67 of 200 patients (33.5%). Eight of these patients have a large homozygous deletion involving STRC, OTOA or USH2A, which could only be identified by copy number variation detection. Variants of uncertain significance were found in 10 patients (5.0%). In the remaining 123 cases, no potentially causative variants were detected (61.5%). In our patient cohort, causative variants in GJB2, USH2A, MYO15A and STRC, and in MYO6 were the leading causes for autosomal recessive and dominant HI, respectively. Segregation analysis and functional analyses of variants of uncertain significance will probably further increase the diagnostic yield of WES.European Journal of Human Genetics advance online publication, 21 December 2016; doi:10.1038/ejhg.2016.182.