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Human Genetics

, Volume 134, Issue 6, pp 649–658 | Cite as

Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome

  • Naomi Hino-Fukuyo
  • Atsuo Kikuchi
  • Natsuko Arai-Ichinoi
  • Tetsuya Niihori
  • Ryo Sato
  • Tasuku Suzuki
  • Hiroki Kudo
  • Yuko Sato
  • Tojo Nakayama
  • Yosuke Kakisaka
  • Yuki Kubota
  • Tomoko Kobayashi
  • Ryo Funayama
  • Keiko Nakayama
  • Mitsugu Uematsu
  • Yoko Aoki
  • Kazuhiro Haginoya
  • Shigeo Kure
Original Investigation

Abstract

West syndrome, which is narrowly defined as infantile spasms that occur in clusters and hypsarrhythmia on EEG, is the most common early-onset epileptic encephalopathy (EOEE). Patients with West syndrome may have clear etiologies, including perinatal events, infections, gross chromosomal abnormalities, or cases followed by other EOEEs. However, the genetic etiology of most cases of West syndrome remains unexplained. DNA from 18 patients with unexplained West syndrome was subjected to microarray-based comparative genomic hybridization (array CGH), followed by trio-based whole-exome sequencing in 14 unsolved families. We identified candidate pathogenic variants in 50 % of the patients (n = 9/18). The array CGH revealed candidate pathogenic copy number variations in four cases (22 %, 4/18), including an Xq28 duplication, a 16p11.2 deletion, a 16p13.1 deletion and a 19p13.2 deletion disrupting CACNA1A. Whole-exome sequencing identified candidate mutations in known epilepsy genes in five cases (36 %, 5/14). Three candidate de novo mutations were identified in three cases, with two mutations occurring in two new candidate genes (NR2F1 and CACNA2D1) (21 %, 3/14). Hemizygous candidate mutations in ALG13 and BRWD3 were identified in the other two cases (14 %, 2/14). Evaluating a panel of 67 known EOEE genes failed to identify significant mutations. Despite the heterogeneity of unexplained West syndrome, the combination of array CGH and whole-exome sequencing is an effective means of evaluating the genetic background in unexplained West syndrome. We provide additional evidence for NR2F1 as a causative gene and for CACNA2D1 and BRWD3 as candidate genes for West syndrome.

Keywords

Intellectual Disability Infantile Spasm Familial Hemiplegic Migraine Epileptic Encephalopathy West Syndrome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

The authors thank the patients, families, and doctors who participated in this study. We thank Yoko Chiba and Kumi Ito, Miyuki Tsuda, Mami Kikuchi, Makiko Nakagawa, and Kiyotaka Kuroda for technical assistance. We also acknowledge the support of the Biomedical Research Core of Tohoku University Graduate School of Medicine. This work was supported by grant from the Ministry of Health labor and Welfare, Japan (to SK) and JSPS KAKENHI Grant Number 25461536.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Written informed consent was obtained from all participants or their guardians.

Supplementary material

439_2015_1553_MOESM1_ESM.docx (521 kb)
Supplementary material 1 (DOCX 520 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Naomi Hino-Fukuyo
    • 1
  • Atsuo Kikuchi
    • 1
  • Natsuko Arai-Ichinoi
    • 1
  • Tetsuya Niihori
    • 2
  • Ryo Sato
    • 1
  • Tasuku Suzuki
    • 1
  • Hiroki Kudo
    • 1
  • Yuko Sato
    • 1
  • Tojo Nakayama
    • 1
  • Yosuke Kakisaka
    • 1
    • 3
  • Yuki Kubota
    • 1
  • Tomoko Kobayashi
    • 1
    • 4
  • Ryo Funayama
    • 5
  • Keiko Nakayama
    • 5
  • Mitsugu Uematsu
    • 1
  • Yoko Aoki
    • 2
  • Kazuhiro Haginoya
    • 6
  • Shigeo Kure
    • 1
  1. 1.Department of PediatricsTohoku University School of MedicineSendaiJapan
  2. 2.Department of Medical GeneticsTohoku University School of MedicineSendaiJapan
  3. 3.Department of EpileptologyTohoku University School of MedicineSendaiJapan
  4. 4.Division of Genomic Medicine Support and Genetic Counseling, Department of Education and TrainingTohoku Medical Megabank Organization (ToMMo), Tohoku UniversitySendaiJapan
  5. 5.Division of Cell ProliferationUnited Centers for Advanced Research and Translational Medicine, Tohoku University Graduate School of MedicineSendaiJapan
  6. 6.Department of Pediatric NeurologyTakuto Rehabilitation Center for ChildrenSendaiJapan

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