Elucidation for genetic basis of infantile epileptic encephalopathy by using comprehensive genetic analysis

• Project/Area Number: 25293085
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Human genetics
• Research Institution: Hamamatsu University School of Medicine (2015); Yokohama City University
• Principal Investigator: Saitsu Hirotomo 浜松医科大学, 医学部, 教授 (40402838)
• Co-Investigator(Renkei-kenkyūsha): KODERA HIROFUMI 横浜市立大学, 博士研究員 (70637884)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2015: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2014: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2013: ¥8,190,000 (Direct Cost: ¥6,300,000、Indirect Cost: ¥1,890,000)
• Keywords: 遺伝子変異 / てんかん性脳症 / エクソーム解析 / 乳児てんかん / 遺伝学 / てんかん / ゲノム

Outline of Final Research Achievements

Target capture analysis against 35 or 50 epilepsy genes and whole exome sequencing was performed in 104 and 623 cases with infantile epileptic encephalopathy, respectively. We identified several new disease causing genes (GNAO1, SLC35A2, PIGA, COG2, KCNB1). With our analysis along with world-wide progress of genetics of infantile epileptic encephalopathy, approximately 45 % of cases could be genetically diagnosed.

Research Products

• [Int'l Joint Research] Sheba Medical Center/Wolfson Medical Center/Schneider's Children Medical Center(イスラエル)
• [Journal Article] High prevalence of genetic alterations in early-onset epileptic encephalopathies associated with infantile movement disorders. (2016)
  • Author(s): Kobayashi Y, Tohyama J, Kato M, Akasaka N, Magara S, Kawashima H, Ohashi T, Shiraishi H, Nakashima M, Saitsu H, Matsumoto N.
  • Journal Title: Brain Dev. Volume: 38 Issue: 7 Pages: 285-92
  • DOI: 10.1038/jhg.2016.27
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia (2016)
  • Author(s): Makrythanasis P, Kato M, Zaki MS, Saitsu H, Nakamura K, Santoni FA, Miyatake S, Nakashima M, Issa MY, Guipponi M, Letourneau A, Logan CV, Roberts N, Parry DA, Johnson CA, Matsumoto N, Hamamy H, Sheridan E, Kinoshita T, Antonarakis SE, Murakami Y.
  • Journal Title: Am J Hum Genet Volume: 98 Issue: 4 Pages: 615-626
  • DOI: 10.1016/j.ajhg.2016.02.007
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay (2016)
  • Author(s): Saitsu H, Fukai R, Ben-Zeev B, Sakai Y, Mimaki M, Okamoto N, Suzuki Y, Monden Y, Saito H, Tziperman B, Torio M, Akamine S, Takahashi N, Osaka H, Yamagata T, Nakamura K, Tsurusaki Y, Nakashima M, Miyake N, Shiina M, Ogata K, Matsumoto N
  • Journal Title: Eur J Hum Genet Volume: 24(1) Issue: 1 Pages: 129-134
  • DOI: 10.1038/ejhg.2015.92
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ineffective quinidine therapy in early onset epileptic encephalopathy with KCNT1 mutation. (2016)
  • Author(s): Chong PF, Nakamura R, Saitsu H, Matsumoto N, Kira R.
  • Journal Title: Ann Neurol. Volume: 79 Issue: 3 Pages: 502-3
  • DOI: 10.1002/ana.24598
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Two cases of early-onset myoclonic seizures with continuous parietal delta activity caused by EEF1A2 mutations. (2016)
  • Author(s): Inui T, Kobayashi S, Ashikari Y, Sato R, Endo W, Uematsu M, Oba H, Saitsu H, Matsumoto N, Kure S, Haginoya K.
  • Journal Title: Brain Dev. Volume: 38 Issue: 5 Pages: 520-4
  • DOI: 10.1016/j.braindev.2015.11.003
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] De novo DNM1 mutations in two cases of epileptic encephalopathy. (2015)
  • Author(s): Nakashima M, Kouga T, Lourenço CM, Shiina M, Goto T, Tsurusaki Y, Miyatake S, Miyake N, Saitsu H, Ogata K, Osaka H, Matsumoto N.
  • Journal Title: Epilepsia Volume: Epub 2015 Nov 27. Issue: 1
  • DOI: 10.1111/epi.13257
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] De novo KCNB1 mutations in infantile epilepsy inhibit repetitive neuronal firing. (2015)
  • Author(s): Saitsu, H., T. Akita, J. Tohyama, H. Goldberg-Stern, Y. Kobayashi, R. Cohen, M. Kato, C. Ohba, S. Miyatake, Y. Tsurusaki, M. Nakashima, N. Miyake, A. Fukuda, and N. Matsumoto
  • Journal Title: Sci Rep Volume: 5 Issue: 1 Pages: 15199-15199
  • DOI: 10.1038/srep15199
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] De novo KCNT1 mutations in early-onset epileptic encephalopathy. (2015)
  • Author(s): Ohba C, Kato M, Takahashi N, Osaka H, Shiihara T, Tohyama J, Nabatame S, Azuma J, Fujii Y, Hara M, Tsurusawa R, Inoue T, Ogata R, Watanabe Y, Togashi N, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Saitsu H, Matsumoto N.
  • Journal Title: Epilepsia Volume: 56(9) Issue: 9
  • DOI: 10.1111/epi.13072
  • Peer Reviewed / Open Access
• [Journal Article] Somatic Mutations in the MTOR gene cause focal cortical dysplasia type IIb (2015)
  • Author(s): Nakashima M, Saitsu H, Takei N, Tohyama J, Kato M, Kitaura H, Shiina M, Shirozu H, Masuda H, Watanabe K, Ohba C, Tsurusaki Y, Miyake N, Zheng Y, Sato T, Takebayashi H, Ogata K, Kameyama S, Kakita A, Matsumoto N
  • Journal Title: Ann. Neurol. Volume: 78 Issue: 3 Pages: 375-386
  • DOI: 10.1002/ana.24444
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] GRIN1 mutations cause encephalopathy with infantile-onset epilepsy, and hyperkinetic and stereotyped movement disorders (2015)
  • Author(s): Ohba C, Shiina M, Tohyama J, Haginoya K, Lerman-Sagie T, Okamoto N, Blumkin L, Lev D, Mukaida S, Nozaki F, Uematsu M, Onuma A, Kodera H, Nakashima M, Tsurusaki Y, Miyake N, Tanaka F, Kato M, Ogata K, Saitsu H, Matsumoto N
  • Journal Title: Epilepsia Volume: 印刷中 Issue: 6 Pages: 841-848
  • DOI: 10.1111/epi.12987
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] SPTAN1 encephalopathy: distinct phenotypes and genotypes (2015)
  • Author(s): Tohyama J, Nakashima M, Nabatame S, Gaik-Siew C, Miyata R, Rener-Primec Z, Kato M, Matsumoto N, Saitsu H
  • Journal Title: Journal of Human Genetics Volume: 60(4) Issue: 4 Pages: 167-173
  • DOI: 10.1038/jhg.2015.5
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Mutations in the glutaminyl-tRNA synthetase gene cause early-onset epileptic encephalopathy. (2015)
  • Author(s): Kodera H, Osaka H, Iai M, Aida N, Yamashita A, Tsurusaki Y, Nakashima M, Miyake N, Saitsu H, Matsumoto N.
  • Journal Title: Journal of Human Genetics Volume: 60 Pages: 97-101
  • NAID: 40020368024
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Compound heterozygous BRAT1 mutations cause familial Ohtahara syndrome with hypertonia and microcephaly. (2014)
  • Author(s): Saitsu H, Yamashita S, Tanaka Y, Tsurusaki Y, Nakashima M, Miyake N, Matsumoto N.
  • Journal Title: Journal of Human Genetics Volume: 59 Issue: 12 Pages: 687-690
  • DOI: 10.1038/jhg.2014.91
  • NAID: 40020308684
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Novel compound heterozygous PIGT mutations caused multiple congenital anomalies-hypotonia-seizures syndrome 3 (2014)
  • Author(s): Nakashima M, Kashii H, Murakami Y, Kato M, Tsurusaki Y, Miyake N, Kubota M, Kinoshita T, Saitsu H, Matsumoto N.
  • Journal Title: Neurogenet Volume: 15（3） Issue: 3 Pages: 193-200
  • DOI: 10.1007/s10048-014-0408-y
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Causative novel PNKP mutations and concomitant PCDH15 mutations in a patient with microcephaly with early-onset seizures and developmental delay syndrome and hearing loss (2014)
  • Author(s): Nakashima M, Takano K, Osaka H, Aida N, Tsurusaki Y, Miyake N, Saitsu H, Matsumoto N.
  • Journal Title: J Hum Genet Volume: 59（8） Issue: 8 Pages: 471-474
  • DOI: 10.1038/jhg.2014.51
  • Peer Reviewed / Acknowledgement Compliant
• [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] PIGA mutations cause early-onset epileptic encephalopathies and distinctive features (2014)
  • Author(s): Kato M, Saitsu H, Murakami Y , Kikuchi K, Watanabe S, Iai M, Miya K, Matsuura R, Takayama R, Ohba C, Nakashima M, Tsurusaki Y, Miyake N, Hamano S, Osaka H, Hayasaka K, Kinoshita T, Matsumoto N.
  • Journal Title: Neurology Volume: 82（18） Issue: 18 Pages: 1587-1596
  • DOI: 10.1212/wnl.0000000000000389
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] De novo EEF1A2 mutations in patients with characteristic facial features, intellectual disability and, autistic behaviors and epilepsy (2014)
  • Author(s): Nakajima J, Okamoto N, Tohyama J, Kato M, Arai H, Funahashi O, Tsurusakia Y, Nakashima M, Kawashima H, Saitsu H, Matsumoto N, Miyake N.
  • Journal Title: Clin Genet Volume: 87(4) Issue: 4 Pages: 356-361
  • DOI: 10.1111/cge.12394
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] PIGO mutations in intractable epilepsy and severe developmental delay with mild elevation of alkaline phosphatase levels. (2014)
  • Author(s): Nakamura, K.Osaka, H.Murakami, Y.Anzai, R.Nishiyama, K.Kodera, H.Nakashima, M.Tsurusaki, Y.Miyake, N.Kinoshita, T.Matsumoto, N. and Saitsu, H
  • Journal Title: Epilepsia Volume: 55 Issue: 2 Pages: 13-17
  • DOI: 10.1111/epi.12508
  • Peer Reviewed
• [Journal Article] RBPJ is disrupted in a case of proximal 4p deletion syndrome with epilepsy (2014)
  • Author(s): Nakayama T, Saitsu H, Endo W, Kikuchi A, Uematsu M, Haginoya K, Hino-Fukuyo N, Kobayashi T, Iwasaki M, T ominaga T, Kure S, Matsumoto N
  • Journal Title: Brain Dev Volume: 36(6) Issue: 6 Pages: 532-6
  • DOI: 10.1016/j.braindev.2013.07.009
  • Peer Reviewed / Open Access
• [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 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 GNAO1, Encoding a Gαo Subunit of Heterotrimeric G Proteins, Cause Epileptic Encephalopathy. (2013)
  • Author(s): Nakamura, K., et al.,
  • Journal Title: Am. J. Hum. Genet. Volume: 93 Issue: 3 Pages: 496-505
  • DOI: 10.1016/j.ajhg.2013.07.014
  • 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] 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
• [Presentation] Somatic mutations in the MTOR gene cause focal cortical dysplasia type IIb (2015)
  • Author(s): Hirotomo Saitsu et al.
  • Organizer: American Epilepsy Society
  • Place of Presentation: Philadelphia
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Presentation] GNAO1変異が引き起こす表現型の広がり：てんかん性脳症から不随意運動を伴う発達遅滞まで (2015)
  • Author(s): 才津浩智等
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2015-10-16
• [Presentation] 次世代シークエンスが切り開く 疾患の原因解明 (2015)
  • Author(s): 才津浩智
  • Organizer: 日本人類遺伝学会
  • Place of Presentation: 京王プラザホテル（東京都）
  • Year and Date: 2015-10-16
  • Invited
• [Presentation] Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay (2015)
  • Author(s): Hirotomo Saitsu et al.
  • Organizer: American Society of Human Genetics
  • Place of Presentation: Baltimore
  • Year and Date: 2015-10-09
  • Int'l Joint Research
• [Presentation] Phenotypic spectrum of GNAO1 variants: epileptic encephalopathy to involuntary movements with severe developmental delay (2015)
  • Author(s): Hirotomo Saitsu et al.
  • Organizer: International Workshop on Advanced Genomics
  • Place of Presentation: 学術総合センター 一橋講堂（東京都）
  • Year and Date: 2015-05-20
  • Int'l Joint Research
• [Presentation] 乳幼児てんかん性脳症の遺伝要因の解明 (2015)
  • Author(s): 才津 浩智
  • Organizer: 第67回大阪小児てんかん研究会
  • Place of Presentation: ホテルグランヴィア大阪、大阪
  • Year and Date: 2015-03-14
  • Invited
• [Presentation] エクソーム解析による包括的遺伝子診断 (2014)
  • Author(s): 才津 浩智
  • 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
  • Place of Presentation: タワーホール船堀、東京
  • Year and Date: 2014-11-20
  • Invited
• [Presentation] 次世代シークエンサーを用いた包括的遺伝子診断 (2014)
  • Author(s): 才津 浩智
  • Organizer: 2014アジレントゲノミックスフォーラム
  • Place of Presentation: 国際ファッションセンター、東京
  • Year and Date: 2014-06-04
  • Invited
• [Presentation] WDR45変異によるオートファジー障害が脳内に鉄沈着を伴う神経変性症を引き起こす (2014)
  • Author(s): 才津 浩智
  • Organizer: 第55回日本神経学会学術大会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2014-05-21
  • Invited
• [Presentation] 次世代シークエンサーによるてんかんを伴う知的障害の網羅的遺伝子解析 (2014)
  • Author(s): 才津 浩智
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋国際会議場、名古屋
  • Year and Date: 2014-04-11
  • Invited
• [Presentation] 加速する発達期脳神経疾患の原因解明 (2013)
  • Author(s): 才津 浩智
  • Organizer: 第58回日本人類遺伝学会
  • Place of Presentation: 江陽グランドホテル、仙台
  • Invited
• [Presentation] 次世代シークエンサーを用いた遺伝子診断 (2013)
  • Author(s): 才津 浩智
  • Organizer: NGS現場の会第3回研究会
  • Place of Presentation: 神戸国際会議場、神戸
  • Invited
• [Presentation] 遺伝子検査と新規遺伝子同定におけるイルミナシークエンサーの運用 (2013)
  • Author(s): 才津 浩智
  • Organizer: イルミナ 次世代シーケンサーユーザーフォーラム
  • Place of Presentation: 東京 ヒューリックホール、東京
  • Invited
• [Presentation] 早期発症てんかん性脳症の遺伝学的解明 ～次世代シークエンサーの活用～ (2013)
  • Author(s): 才津 浩智
  • Organizer: 第55回日本小児神経学会学術集会
  • Place of Presentation: iichiko総合文化センター、大分
  • Invited
• [Book] 増刊号 臨床医が知っておきたい先天異常 「次世代シークエンスによる遺伝子診断の進歩」 (2013)
  • Author(s): 才津 浩智
  • Total Pages: 279
  • Publisher: 日本小児医事出版社
• [Book] 実験医学増刊 ゲノム 医学・生命科学研究 「次世代シークエンサーによるメンデル遺伝性疾患の責任遺伝子解明 (2013)
  • Author(s): 大場 ちひろ、才津 浩智、松本 直通
  • Total Pages: 2543
  • Publisher: 羊土社
• [Remarks] 医学群 遺伝学 才津准教授、松本教授ら研究グループが、小児の難治性てんかんの原因遺伝子を発見
  • URL: http://www.yokohama-cu.ac.jp/univ/pr/press/130827.html
• [Patent(Industrial Property Rights)] 小児期のてんかんおよび不随意運動をきたす疾患の検出方法 (2013)
  • Inventor(s): 松本直通、才津浩智
  • Industrial Property Rights Holder: 公立大学法人横浜市立大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2013-123660
  • Filing Date: 2013-06-12