Identification of novel causative genes for early-onset epileptic encephalopathies using HRM analysis and next-generation sequencer

• Project/Area Number: 24591500
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Yamagata University
• Principal Investigator: KATO Mitsuhiro 山形大学, 医学部, 講師 (10292434)
• Co-Investigator(Kenkyū-buntansha): TAKAHASHI Nobuya 山形大学, 医学部, 医員 (20536958) ; KIKUCHI Takahiro 山形大学, 医学部, 医員 (00594300) ; NAKAMURA Kazuyuki 山形大学, 医学部, 医員 (20436215)
• Co-Investigator(Renkei-kenkyūsha): MATSUMOTO Naomichi 横浜市立大学, 医学(系)研究科(研究院), 教授 (80325638) ; SAITSU Hirotomo 横浜市立大学, 医学(系)研究科(研究院), 准教授 (40402838)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2014: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2013: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2012: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000)
• Keywords: てんかん / 大田原症候群 / 遺伝子解析 / KCNQ2 / SCN2A / SCN8A / イオンチャネル / 全エクソーム解析 / 次世代シーケンサー / 遺伝子

Outline of Final Research Achievements

To clarify the genetic background of early-onset epileptic encephalopathies (EOEE), we performed high-resolution melting (HRM) analysis as a high-throughput mutation screening method and whole exome sequencing (WES) analysis using next-generation sequencer (NGS). We identified KCNQ2 mutations in 3 of 12 patients with Ohtahara syndrome, SCN2A mutations in 15 of 328 patients with EOEE, and SCN8A mutations in 7 patients with EOEE. A combination of HRM analysis and WES analysis using NGS can efficiently detect the genetic cause of EOEE.

Research Products

• [Journal Article] Early onset epileptic encephalopathy caused by de novo SCN8A mutations (2014)
  • Author(s): Ohba C, Kato M, Takahashi S, Lerman-Sagie T, Lev D, Terashima H, Kubota M, Kawawaki H, Matsufuji M, Kojima Y, Tateno A, Goldberg-Stern H, Straussberg R, Marom D, Leshinsky-Silver E, Nakashima M, Nishiyama K, Tsurusaki Y, Miyake N, Tanaka F, Matsumoto N, Saitsu H:
  • Journal Title: Epilepsia Volume: 55 Issue: 7 Pages: 994-1000
  • DOI: 10.1111/epi.12668
  • Peer Reviewed
• [Journal Article] Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome. (2013)
  • Author(s): Nakamura K, et al., Miyake N, et al., *Matsumoto N, *Saitsu H (* denotes co-corresponding).
  • Journal Title: Neurology Volume: 81 Issue: 11 Pages: 992-998
  • DOI: 10.1212/wnl.0b013e3182a43e57
  • Peer Reviewed
• [Journal Article] De novo mutations in SLC35A2 encoding a UDP-galactose transporter cause early-onset epileptic encephalopathy (2013)
  • Author(s): Kodera H, Nakamura K, Osaka H, Maegaki Y, Haginoya K, Mizumoto S, Kato M, Okamoto N, Iai M, Kondo Y, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Hayasaka K, Sugahara K, Yuasa I, Wada Y, Matsumoto N, Saitsu H.
  • Journal Title: Hum Mutat Volume: 34 Issue: 12 Pages: 1708-1714
  • DOI: 10.1002/humu.22446
  • Peer Reviewed
• [Journal Article] Clinical spectrum of early onset epileptic encephalopathies caused by KCNQ2 mutation (2013)
  • Author(s): Kato M, …Saitsu H.
  • Journal Title: Epilepsia Volume: in press Issue: 7 Pages: 1282-7
  • DOI: 10.1111/epi.12200
  • Peer Reviewed
• [Journal Article] Target capture sequencing for detection of mutations and copy number changes causing early-onset epileptic encephalopathy. (2013)
  • Author(s): Kodera H, Kato M, Nord AS, Walsh T, Lee M, Yamanaka G, Tohyama J, Nakamura K, Nakagawa E, Ikeda T, Ben-Zeev B, Lev D, Lerman-Sagie T, Straussberg R, Tanabe S, Ueda K, Amamoto M, Ohta S, Nododa Y, Nishiyama K, Tsurusaki Y, Nakashima M, Miyake N, Hayasaka K, King M-C, Matsumoto N, *Saitsu H.
  • Journal Title: Epilepsia Volume: 54 Issue: 7 Pages: 1262-1269
  • DOI: 10.1111/epi.12203
  • Peer Reviewed
• [Journal Article] Whole exome sequencing identifies KCNQ2 mutations in Ohtahara syndrome (2012)
  • Author(s): *Saitsu H et al.
  • Journal Title: Ann Neurol Volume: 72(2):298-300 Issue: 2 Pages: 298-300
  • DOI: 10.1002/ana.23620
  • Peer Reviewed
• [Journal Article] CASK aberrations in male patients with Ohtahara syndrome and cerebellar hypoplasia (2012)
  • Author(s): *Saitsu H et al.
  • Journal Title: Epilepsia Volume: 53(8):1441-1449 Issue: 8 Pages: 1441-1449
  • DOI: 10.1111/j.1528-1167.2012.03548.x
  • Peer Reviewed
• [Journal Article] Association of genomic deletions in the STXBP1 gene with Ohtahara syndrome (2012)
  • Author(s): *Saitsu H et al.
  • Journal Title: Clinical Genetics Volume: 81(4):399-402 Issue: 4 Pages: 86-90
  • DOI: 10.1111/j.1399-0004.2011.01733.x
  • Peer Reviewed
• [Journal Article] Mutations affecting components of the SWI/SNF complex cause Coffin-Siris syndrome (2012)
  • Author(s): Tsurusaki Y, Okamoto N, Ohashi H, Kosho T, Imai Y, Hibi-Ko Y, Kaname T, Naritomi K, Kawame H, Wakui K, Fukushima Y, Homma T, Kato M, Hiraki Y, Yamagata T, Yano S, Mizuno S, Sakazume S, Ishii T, Nagai T, Shiina M, Ogata K, Ohta T, Niikawa N, Miyatake S, Okada I, Mizuguchi T, Doi H, Saitsu H, Miyake N, Matsumoto N
  • Journal Title: Nat Genet Volume: 44 Issue: 4 Pages: 376-378
  • DOI: 10.1038/ng.2219
  • Peer Reviewed
• [Journal Article] Congenital dysplastic microcephaly and hypoplasia of the brainstem and cerebellum with diffuse intracranial calcification (2012)
  • Author(s): Nakamura K, Hayasaka K, et al
  • Journal Title: J Child Neurol Volume: 27 Issue: 2 Pages: 218-221
  • DOI: 10.1177/0883073811416239
  • Peer Reviewed
• [Journal Article] Respiratory syncytial virus-associated encephalopathy complicated by congenital myopathy. (2012)
  • Author(s): Nakamura K, Kato M, Sasaki A, Shiihara T, Hayasaka K
  • Journal Title: Pediatr Int Volume: 54 Issue: 5 Pages: 709-711
  • DOI: 10.1111/j.1442-200x.2012.03594.x
  • Peer Reviewed
• [Journal Article] The incidence of hypoplasia of the corpus callosum in patients with dup (X)(q28) involving MECP2 is associated with the location of distal breakpoints. (2012)
  • Author(s): Honda S, et al.
  • Journal Title: Am J Med Genet Volume: 158A Issue: 6 Pages: 1292-1303
  • DOI: 10.1002/ajmg.a.35321
  • Peer Reviewed
• [Journal Article] De Novo and Inherited Mutations in COL4A2, Encoding the Type IV Collagen alpha2 Chain Cause Porencephaly (2011)
  • Author(s): Yoneda Y, et al.
  • Journal Title: Am J Hum Genet Volume: 90 Issue: 1 Pages: 86-90
  • DOI: 10.1016/j.ajhg.2011.11.016
  • Peer Reviewed
• [Journal Article] Early infantile epileptic encephalopathy associated with the disrupted gene encoding Slit-Robo Rho GTPase activating protein 2 (SRGAP2) (2011)
  • Author(s): Saitsu H, Osaka H, Sugiyama S, Kurosawa K, Mizuguchi T, Nishiyama K, Nishimura A, Tsurusaki Y, Doi H, Miyake N, Harada N, Kato M, Matsumoto N
  • Journal Title: Am J Med Genet A Volume: (in press) Issue: 1 Pages: 2879-84
  • DOI: 10.1002/ajmg.a.34363
  • Peer Reviewed
• [Presentation] SCN8Aのde novo変異が原因となる乳児期早期発症の難治性てんかんについての検討． (2014)
  • Author(s): 大場ちひろ、加藤光広、高橋悟、寺嶋宙、久保田雅也、川脇壽、松藤まゆみ、小島泰子、舘野昭彦、中島光子、西山精視、鶴崎美徳、三宅紀子、田中章景、才津浩智、松本直通
  • Organizer: 日本人類遺伝学会第59回大会・日本遺伝子診療学会第21回大会合同大会
  • Place of Presentation: タワーホール船堀（東京都江戸川区）
  • Year and Date: 2014-11-20 – 2014-11-22
• [Presentation] Interneuronopathies and genetics of the epileptic encephalopathies. (2014)
  • Author(s): Kato M
  • Organizer: 10th Asian & Oceanian Epilepsy Congress
  • Place of Presentation: The Grand copthorne Waterfront，Singapore
  • Year and Date: 2014-08-07 – 2014-08-10
  • Invited
• [Presentation] Clinical spectrum of SCN2A mutations expanding to Ohtahara syndrome: Involvement of chromosomal aberrations in patients with early epileptic encephalopathy. (2013)
  • Author(s): Nakamura K, Saitsu H, Kato M, Osaka H, Yamashita S, Nakagawa E, et al.
  • Organizer: 30th International Epilepsy Congress
  • Place of Presentation: Palais des congres de Montreal, Montreal, Canada
• [Presentation] Phenotypic spectrum of SPTAN1 encephalopathy. (2013)
  • Author(s): Tohyama J, Akasaka N, Writzl K, Nonoda Y, Hamdan FF, Michaud JL, Osaka H, Shimono M, Kato M, Matsumoto N, Saitsu H.
  • Organizer: 30th International Epilepsy Congress
  • Place of Presentation: Palais des congres de Montreal, Montreal, Canada
• [Presentation] Early-onset epileptic encephalopathies caused by PIGA gene mutation. (2013)
  • Author(s): Kato M, Saitsu H, Murakami Y, Kikuchi K, Watanabe S, Matsuura R, Takayama R, Hamano S, Kinoshita T, Hayasaka K, Matsumoto N
  • Organizer: American Epilepsy Society Annual Meeting 2013
  • Place of Presentation: Walter E. Washington Convention Center, Washington, D.C., USA
• [Presentation] Inherited GPI-anchor deficiencies caused by the hypomorphic mutations in PIGA gene: comparison to paroxysmal nocturnal hemogrobinuria. (2013)
  • Author(s): Murakami Y, Kato M, Saitsu H, Kikuchi K, Watanabe S, Iai M, Matsuura R, Takayama R, Ohba C, Hamano S, Osaka H, Hayasaka K, Matsumoto N, Kinoshita T
  • Organizer: 55th American Society of Hematology Annual Meeting and Exposition
  • Place of Presentation: Ernest N. Morial Convention Center, New Orleans, USA
• [Presentation] The Genetic Background of Cortical Dysplasias (2013)
  • Author(s): Mitsuhiro Kato
  • Organizer: 2013 Cortical Dysplasia Symposium
  • Place of Presentation: Zenda Suites, Tainan, Taiwan
  • Invited
• [Presentation] Lissencephaly and related disorders. (2012)
  • Author(s): Mitsuhiro Kato
  • Organizer: International Child Neurology Congress (ICNC) Pre Congress Symposium Malformations of Cortical Development
  • Place of Presentation: Brisbane Convention and Exhibition Centre, Brisbane, Australia
  • Invited
• [Presentation] New genetic discoveries in malignant forms of neonatal seizures. (2012)
  • Author(s): Mitsuhiro Kato
  • Organizer: The conjoined congresses of the 12th International Child Neurology Congress and the 11th Asian and Oceanian Congress of Child Neurology (ICNC⁄AOCCN 2012)
  • Place of Presentation: Brisbane Convention and Exhibition Centre, Brisbane, Australia
  • Invited
• [Presentation] Genetics in Epilepsy, update. (2012)
  • Author(s): Mitsuhiro Kato
  • Organizer: Annual Autumn Meeting of the Korean Child Neurology Society
  • Place of Presentation: Novotel Busan Ambassador hotel, Busan, Korea
  • Invited
• [Presentation] Ohtahara syndrome and other neonatal-onset epileptic encephalopathies caused by missense mutations of the KCNQ2 gene. (2012)
  • Author(s): Kato M, Saitsu H, Yamagata T, Arai H, Fujii T, Hirata Y, Kusama Y, Yamashita S, Nakagawa T, Koide A, Goto T, Kubota M, Fujita T, Ihara Y, Sugai K, Saito K, Hayasaka K, Matsumoto N
  • Organizer: American Epilepsy Society 2012 Annual meeting
  • Place of Presentation: San Diego Convention Center, San Diego, USA
• [Book] Jasper's Basic Mechanisms of the Epilepsies. (2012)
  • Author(s): Saitsu H, Kato M, Matsumoto N
  • Total Pages: 11
  • Publisher: Oxford
• [Remarks] 山形大学医学部小児科学講座 神経グループ研究紹介
  • URL: http://www.id.yamagata-u.ac.jp/Ped/medical/neurology_03.html