TY - JOUR
T1 - The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands
AU - Seco, Celia Zazo
AU - Wesdorp, Mieke
AU - Feenstra, Ilse
AU - Pfundt, Rolph
AU - Hehir-Kwa, Jayne Y.
AU - Lelieveld, Stefan H.
AU - Castelein, Steven
AU - Gilissen, Christian
AU - De Wijs, Ilse J.
AU - Admiraal, Ronald J.C.
AU - Pennings, Ronald J.E.
AU - Kunst, Henricus P.M.
AU - Van De Kamp, Jiddeke M.
AU - Tamminga, Saskia
AU - Houweling, Arjan C.
AU - Plomp, Astrid S.
AU - Maas, Saskia M.
AU - De Koning Gans, Pia A.M.
AU - Kant, Sarina G.
AU - De Geus, Christa M.
AU - Frints, Suzanna G.M.
AU - Vanhoutte, Els K.
AU - Van Dooren, Marieke F.
AU - Van Den Boogaard, Marie José H.
AU - Scheffer, Hans
AU - Nelen, Marcel
AU - Kremer, Hannie
AU - Hoefsloot, Lies
AU - Schraders, Margit
AU - Yntema, Helger G.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85007275576&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/ejhg.2016.182
DO - https://doi.org/10.1038/ejhg.2016.182
M3 - Article
C2 - 28000701
SN - 1018-4813
VL - 25
SP - 308
EP - 314
JO - European journal of human genetics
JF - European journal of human genetics
IS - 3
ER -