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

被引：92

作者：

Seco, Celia Zazo ^{[1
,2
]}

Wesdorp, Mieke ^{[1
,2
]}

Feenstra, Ilse ^{[3
]}

Pfundt, Rolph ^{[2
,3
]}

Hehir-Kwa, Jayne Y. ^{[2
,3
]}

Lelieveld, Stefan H. ^{[3
]}

Castelein, Steven ^{[3
]}

Gilissen, Christian ^{[3
]}

de Wijs, Ilse J. ^{[3
]}

Admiraal, Ronald J. C. ^{[1
,2
]}

Pennings, Ronald J. E. ^{[1
,4
]}

Kunst, Henricus P. M. ^{[1
,4
]}

van de Kamp, Jiddeke M. ^{[5
]}

Tamminga, Saskia ^{[5
]}

Houweling, Arjan C. ^{[5
]}

Plomp, Astrid S. ^{[6
]}

Maas, Saskia M. ^{[6
,7
]}

Gans, Pia A. M. de Koning ^{[8
]}

Kant, Sarina G. ^{[8
]}

de Geus, Christa M. ^{[9
]}

Frints, Suzanna G. M. ^{[10
]}

Vanhoutte, Els K. ^{[10
]}

van Dooren, Marieke F. ^{[11
]}

van den Boogaard, Marie-Jose H. ^{[12
]}

Scheffer, Hans ^{[2
,3
]}

Nelen, Marcel ^{[3
]}

Kremer, Hannie ^{[1
,2
,3
]}

Hoefsloot, Lies ^{[3
,11
]}

Schraders, Margit ^{[1
,2
]}

Yntema, Helger G. ^{[2
,3
]}

机构：

[1] Radboud Univ Nijmegen, Med Ctr, Dept Otorhinolaryngol Hearing & Genes, Nijmegen, Netherlands

[2] Radboud Univ Nijmegen, Med Ctr, Radboud Inst Mol Life Sci, Nijmegen, Netherlands

[3] Radboud Univ Nijmegen, Med Ctr, Dept Human Genet, POB 9101, NL-6500 HB Nijmegen, Netherlands

[4] Radboud Inst Hlth Sci, Nijmegen, Netherlands

[5] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[6] Univ Amsterdam, Acad Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[7] Univ Amsterdam, Acad Med Ctr, Dept Pediat, Amsterdam, Netherlands

[8] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands

[9] Univ Groningen, Univ Med Ctr Groningen, Dept Genet, Groningen, Netherlands

[10] Maastricht Univ, Med Ctr, Dept Clin Genet, Maastricht, Netherlands

[11] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands

[12] Wilhelmina Childrens Hosp, Utrecht Med Ctr, Dept Clin Genet, Utrecht, Netherlands

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2017年 / 25卷 / 03期

关键词：

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

D O I：

10.1038/ejhg.2016.182

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：308 / 314

页数：7

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