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 J C Admiraal, Ronald J. E. Pennings, Henricus P. M. Kunst, Jiddeke M. van de Kamp, Saskia Tamminga, Arjan C. Houweling, Astrid S. Plomp, Saskia M. Maas, Pia A. M. de Koning Gans, Sarina G. Kant, Christa M. de GeusSuzanna G. M. Frints, Els K. Vanhoutte, Marieke F. van Dooren, Marie-Jose H. van den Boogaard, Hans Scheffer, Marcel Nelen, Hannie Kremer, Lies Hoefsloot, Margit Schraders, Helger G. Yntema*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    47 Citations (Scopus)

    Abstract

    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.

    Original languageEnglish
    Pages (from-to)308-314
    Number of pages7
    JournalEuropean Journal of Human Genetics
    Volume25
    Issue number3
    DOIs
    Publication statusPublished - Feb-2017

    Keywords

    • COPY NUMBER VARIANTS
    • MUTATION
    • DEAFNESS
    • IDENTIFICATION
    • FREQUENCY
    • OTOGELIN
    • SPECTRUM
    • EAR

    Cite this