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 Geus; Suzanna G.M. 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

doi:10.1038/ejhg.2016.182

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 José H. Van Den Boogaard, Hans Scheffer, Marcel Nelen, Hannie Kremer, Lies Hoefsloot, Margit Schraders, Helger G. Yntema

Onderzoeksoutput: Bijdrage aan tijdschrift › Artikel › peer review

98 Citaten (Scopus)

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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.

Originele taal-2	Engels
Pagina's (van-tot)	308-314
Aantal pagina's	7
Tijdschrift	European Journal of Human Genetics
Volume	25
Nummer van het tijdschrift	3
DOI's	https://doi.org/10.1038/ejhg.2016.182
Status	Gepubliceerd - 1 feb. 2017
Extern gepubliceerd	Ja

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10.1038/ejhg.2016.182

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Seco, C. Z., Wesdorp, M., Feenstra, I., Pfundt, R., Hehir-Kwa, J. Y., Lelieveld, S. H., Castelein, S., Gilissen, C., De Wijs, I. J., Admiraal, R. J. C., Pennings, R. J. E., Kunst, H. P. M., Van De Kamp, J. M., Tamminga, S., Houweling, A. C., Plomp, A. S., Maas, S. M., De Koning Gans, P. A. M., Kant, S. G., ... Yntema, H. G. (2017). The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands. European Journal of Human Genetics, 25(3), 308-314. https://doi.org/10.1038/ejhg.2016.182

@article{77e2028e5fb74fa7907764446091ac46,

title = "The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands",

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.",

author = "Seco, {Celia Zazo} and Mieke Wesdorp and Ilse Feenstra and Rolph Pfundt and Hehir-Kwa, {Jayne Y.} and Lelieveld, {Stefan H.} and Steven Castelein and Christian Gilissen and {De Wijs}, {Ilse J.} and Admiraal, {Ronald J.C.} and Pennings, {Ronald J.E.} and Kunst, {Henricus P.M.} and {Van De Kamp}, {Jiddeke M.} and Saskia Tamminga and Houweling, {Arjan C.} and Plomp, {Astrid S.} and Maas, {Saskia M.} and {De Koning Gans}, {Pia A.M.} and Kant, {Sarina G.} and {De Geus}, {Christa M.} and Frints, {Suzanna G.M.} and Vanhoutte, {Els K.} and {Van Dooren}, {Marieke F.} and {Van Den Boogaard}, {Marie Jos{\'e} H.} and Hans Scheffer and Marcel Nelen and Hannie Kremer and Lies Hoefsloot and Margit Schraders and Yntema, {Helger G.}",

year = "2017",

month = feb,

day = "1",

doi = "10.1038/ejhg.2016.182",

language = "English",

volume = "25",

pages = "308--314",

journal = "European Journal of Human Genetics",

issn = "1018-4813",

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Seco, CZ, Wesdorp, M, Feenstra, I, Pfundt, R, Hehir-Kwa, JY, Lelieveld, SH, Castelein, S, Gilissen, C, De Wijs, IJ, Admiraal, RJC, Pennings, RJE, Kunst, HPM, Van De Kamp, JM, Tamminga, S, Houweling, AC, Plomp, AS, Maas, SM, De Koning Gans, PAM, Kant, SG, De Geus, CM, Frints, SGM, Vanhoutte, EK, Van Dooren, MF, Van Den Boogaard, MJH, Scheffer, H, Nelen, M, Kremer, H, Hoefsloot, L, Schraders, M & Yntema, HG 2017, 'The diagnostic yield of whole-exome sequencing targeting a gene panel for hearing impairment in the Netherlands', European Journal of Human Genetics, vol. 25, nr. 3, blz. 308-314. https://doi.org/10.1038/ejhg.2016.182

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.

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U2 - 10.1038/ejhg.2016.182

DO - 10.1038/ejhg.2016.182

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AN - SCOPUS:85007275576

SN - 1018-4813

VL - 25

SP - 308

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JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

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ER -

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

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