Detection of copy number variations in epilepsy using exome data

N. Tsuchida; M. Nakashima; M. Kato; E. Heyman; T. Inui; K. Haginoya; S. Watanabe; T. Chiyonobu; M. Morimoto; M. Ohta; A. Kumakura; M. Kubota; Y. Kumagai; S. I. Hamano; C. M. Lourenco; N. A. Yahaya; G. S. Ch'ng; L. H. Ngu; A. Fattal-Valevski; M. Weisz Hubshman; N. Orenstein; D. Marom; L. Cohen; H. Goldberg-Stern; Y. Uchiyama; E. Imagawa; T. Mizuguchi; A. Takata; N. Miyake; H. Nakajima; H. Saitsu; S. Miyatake; N. Matsumoto

doi:10.1111/cge.13144

Detection of copy number variations in epilepsy using exome data

N. Tsuchida
, M. Nakashima
, M. Kato
, E. Heyman
, T. Inui
, K. Haginoya
, S. Watanabe
, T. Chiyonobu
, M. Morimoto
, M. Ohta
, A. Kumakura
, M. Kubota
, Y. Kumagai
, S. I. Hamano
, C. M. Lourenco
, N. A. Yahaya
, G. S. Ch'ng
, L. H. Ngu
, A. Fattal-Valevski
, M. Weisz Hubshman

N. Orenstein, D. Marom, L. Cohen, H. Goldberg-Stern, Y. Uchiyama, E. Imagawa, T. Mizuguchi, A. Takata, N. Miyake, H. Nakajima, H. Saitsu, S. Miyatake, N. Matsumoto

Yokohama City University
Hamamatsu University School of Medicine
Yamagata University
Showa Medical University
Assaf Harofeh Medical Center
Miyagi Children's Hospital
Kyoto Prefectural University of Medicine
JA Toride General Hospital
Tazuke Kofukai, Medical Research Institute, Kitano Hospital
National Center for Child Health and Development
Saitama Children's Medical Center
Universidade de São Paulo
Hospital Raja Perempuan Zainab II
Kuala Lumpur Hospital
Tel Aviv University
Tel Aviv Sourasky Medical Center
Schneider Childrens Medical Center Israel
Rabin Medical Center Israel

Research output: Contribution to journal › Article › peer-review

40 Scopus citations

Abstract

Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

Original language	English
Pages (from-to)	577-587
Number of pages	11
Journal	Clinical Genetics
Volume	93
Issue number	3
DOIs	https://doi.org/10.1111/cge.13144
State	Published - Mar 2018
Externally published	Yes

Bibliographical note

Publisher Copyright:
© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Funding

Technology Agency (JST); Japan Society for the Promotion of Science (JSPS); Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); Japan Agency for Medical Research and Development (AMED); Strategic Research Program for Brain Science; Comprehensive Research on Disability Health and Welfare grant; Research on Measures for Intractable Diseases grant We would like to thank the patients and their families for their participation in this study. We are also grateful to Ms. Mai Sato, Ms. Nobuko Watanabe, Ms. Sayaka Sugimoto, Ms. Kaori Takabe, Mr. Syohei Nakamura, and Mr. Takafumi Miyama from Department of Human Genetics, Yokohama City University Graduate School of Medicine for their excellent technical assistance. This work is supported by the grants for Research on Measures for Intractable Diseases grant; the Comprehensive Research on Disability Health and Welfare grant; the Strategic Research Program for Brain Science; the Practical Research Project for Rare/Intractable Diseases, from the Japan Agency for Medical Research and Development (AMED); a grant-in-aid for Scientific Research on Innovative Areas (Transcription Cycle) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (MEXT); grants-in-aid for Scientific Research (A, B and C); Challenging Exploratory Research and Young Scientists (B) from the Japan Society for the Promotion of Science (JSPS); the Creation of Innovation Centers for Advanced Interdisciplinary Research Areas Program in the Project for Developing Innovation Systems from the Japan Science and Technology Agency (JST); and grants from the Ministry of Health, Labor and Welfare and the Takeda Science Foundation. Wendy Brooks, PhD, from Edanz Group (www.edanzediting.com/ac) provided English language editing services for a draft of this manuscript.

Funders	Funder number
Takeda Science Foundation
Japan Agency for Medical Research and Development
Japan Society for the Promotion of Science	16H05160, 16H05357, 16K09975, 17K15630
Ministry of Education, Culture, Sports, Science and Technology
Japan Science and Technology Agency
Ministry of Health, Labour and Welfare

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

copy number variation
epilepsy
microdeletion
whole-exome sequencing

Access to Document

10.1111/cge.13144

Cite this

Tsuchida, N., Nakashima, M., Kato, M., Heyman, E., Inui, T., Haginoya, K., Watanabe, S., Chiyonobu, T., Morimoto, M., Ohta, M., Kumakura, A., Kubota, M., Kumagai, Y., Hamano, S. I., Lourenco, C. M., Yahaya, N. A., Ch'ng, G. S., Ngu, L. H., Fattal-Valevski, A., ... Matsumoto, N. (2018). Detection of copy number variations in epilepsy using exome data. Clinical Genetics, 93(3), 577-587. https://doi.org/10.1111/cge.13144

@article{5b339490c20e45408bee6609d02b5c78,

title = "Detection of copy number variations in epilepsy using exome data",

abstract = "Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7\%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.",

keywords = "copy number variation, epilepsy, microdeletion, whole-exome sequencing",

author = "N. Tsuchida and M. Nakashima and M. Kato and E. Heyman and T. Inui and K. Haginoya and S. Watanabe and T. Chiyonobu and M. Morimoto and M. Ohta and A. Kumakura and M. Kubota and Y. Kumagai and Hamano, \{S. I.\} and Lourenco, \{C. M.\} and Yahaya, \{N. A.\} and Ch'ng, \{G. S.\} and Ngu, \{L. H.\} and A. Fattal-Valevski and \{Weisz Hubshman\}, M. and N. Orenstein and D. Marom and L. Cohen and H. Goldberg-Stern and Y. Uchiyama and E. Imagawa and T. Mizuguchi and A. Takata and N. Miyake and H. Nakajima and H. Saitsu and S. Miyatake and N. Matsumoto",

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year = "2018",

month = mar,

doi = "10.1111/cge.13144",

language = "אנגלית",

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Tsuchida, N, Nakashima, M, Kato, M, Heyman, E, Inui, T, Haginoya, K, Watanabe, S, Chiyonobu, T, Morimoto, M, Ohta, M, Kumakura, A, Kubota, M, Kumagai, Y, Hamano, SI, Lourenco, CM, Yahaya, NA, Ch'ng, GS, Ngu, LH, Fattal-Valevski, A, Weisz Hubshman, M, Orenstein, N, Marom, D, Cohen, L, Goldberg-Stern, H, Uchiyama, Y, Imagawa, E, Mizuguchi, T, Takata, A, Miyake, N, Nakajima, H, Saitsu, H, Miyatake, S & Matsumoto, N 2018, 'Detection of copy number variations in epilepsy using exome data', Clinical Genetics, vol. 93, no. 3, pp. 577-587. https://doi.org/10.1111/cge.13144

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T1 - Detection of copy number variations in epilepsy using exome data

AU - Tsuchida, N.

AU - Nakashima, M.

AU - Kato, M.

AU - Heyman, E.

AU - Inui, T.

AU - Haginoya, K.

AU - Watanabe, S.

AU - Chiyonobu, T.

AU - Morimoto, M.

AU - Ohta, M.

AU - Kumakura, A.

AU - Kubota, M.

AU - Kumagai, Y.

AU - Hamano, S. I.

AU - Lourenco, C. M.

AU - Yahaya, N. A.

AU - Ch'ng, G. S.

AU - Ngu, L. H.

AU - Fattal-Valevski, A.

AU - Weisz Hubshman, M.

AU - Orenstein, N.

AU - Marom, D.

AU - Cohen, L.

AU - Goldberg-Stern, H.

AU - Uchiyama, Y.

AU - Imagawa, E.

AU - Mizuguchi, T.

AU - Takata, A.

AU - Miyake, N.

AU - Nakajima, H.

AU - Saitsu, H.

AU - Miyatake, S.

AU - Matsumoto, N.

PY - 2018/3

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N2 - Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

AB - Epilepsies are common neurological disorders and genetic factors contribute to their pathogenesis. Copy number variations (CNVs) are increasingly recognized as an important etiology of many human diseases including epilepsy. Whole-exome sequencing (WES) is becoming a standard tool for detecting pathogenic mutations and has recently been applied to detecting CNVs. Here, we analyzed 294 families with epilepsy using WES, and focused on 168 families with no causative single nucleotide variants in known epilepsy-associated genes to further validate CNVs using 2 different CNV detection tools using WES data. We confirmed 18 pathogenic CNVs, and 2 deletions and 2 duplications at chr15q11.2 of clinically unknown significance. Of note, we were able to identify small CNVs less than 10 kb in size, which might be difficult to detect by conventional microarray. We revealed 2 cases with pathogenic CNVs that one of the 2 CNV detection tools failed to find, suggesting that using different CNV tools is recommended to increase diagnostic yield. Considering a relatively high discovery rate of CNVs (18 out of 168 families, 10.7%) and successful detection of CNV with <10 kb in size, CNV detection by WES may be able to surrogate, or at least complement, conventional microarray analysis.

KW - copy number variation

KW - epilepsy

KW - microdeletion

KW - whole-exome sequencing

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DO - 10.1111/cge.13144

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ER -

Detection of copy number variations in epilepsy using exome data

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

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