Elucidation of the genetic causes of focal cortical dysplasia by detection of somatic variants and copy number variants

• Project/Area Number: 20K17936
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56010:Neurosurgery-related
• Research Institution: Yokohama City University
• Principal Investigator: FUJITA Atsushi 横浜市立大学, 医学部, 助教 (20805113)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2021: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000); Fiscal Year 2020: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 難治性てんかん / 体細胞変異 / 次世代シークエンス / mTOR / 単一遺伝子疾患

Outline of Research at the Start

難治性てんかんの原因となる限局性皮質異形成（Focal cortical dysplasia, FCD）の遺伝学的原因として、mTOR関連遺伝子の脳病変部組織に限局した変異が報告されている。これまでにFCD症例に対して次世代シークエンサーを用いた変異解析を実施したが、69％の症例において原因を見いだせていない。脳組織に認められる遺伝子コピー数異常（Copy number variation, CNV）はFCDにおいてこれまでに報告されていないため、変異未同定症例のCNVの関与が示唆される。本研究ではFCDにおいて脳組織特異的な変異・CNVの検出を行い、新規原因遺伝子の同定を目指す。

Outline of Final Research Achievements

Genetic analysis using DNA from brain lesion tissues identified causal variants in 37 of 64 cases with focal cortical dysplasia (FCD) or other abnormalities of cortical development. Of these, somatic variants of PTPN11 and MAP2K1 and in-frame deletion in MTOR have rarely or never been reported in FCD. This study indicates that genetic analysis for FCD and other types of cortical developmental malformations should also focus on the RAS/MAPK pathway genes, in addition to mTOR pathway genes which are often responsible for FCD.

Academic Significance and Societal Importance of the Research Achievements

限局性皮質異形成（FCD）では原因バリアントの大部分がmTORパスウェイの遺伝子であるため、これらに着目した遺伝子解析が行われていることが多い。また、FCDの治療は抗てんかん薬や外科的治療の他にmTOR阻害薬の治験が実施されている。本研究ではmTORパスウェイにつながるRAS/MAPKパスウェイの遺伝子のバリアントを検出した。今後、mTORパスウェイの異常の有無が治療薬選択の情報となる可能性もあるため、RAS/MAPKパスウェイの遺伝子を含む遺伝子解析も原因バリアント検出に貢献できると考えられる。

Research Products

• [Journal Article] An integrated genetic analysis of epileptogenic brain malformed lesions (2023)
  • Author(s): Atsushi Fujita et al.
  • Journal Title: Acta Neuropathologica Communications Volume: 11 Issue: 1 Pages: 33-33
  • DOI: 10.1186/s40478-023-01532-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Incomplete hippocampal inversion in patients with mutations in genes involved in sonic hedgehog signaling (2023)
  • Author(s): Higashijima Takefumi、Shirozu Hiroshi、Saitsu Hirotomo、Sonoda Masaki、Fujita Atsushi、Masuda Hiroshi、Yamamoto Tetsuya、Matsumoto Naomichi、Kameyama Shigeki
  • Journal Title: Heliyon Volume: 9 Issue: 4 Pages: e14712-e14712
  • DOI: 10.1016/j.heliyon.2023.e14712
  • Peer Reviewed / Open Access
• [Journal Article] Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants (2023)
  • Author(s): Inoue Yuta、Tsuchida Naomi、Okamoto Nobuhiko、Shuichi Shimakawa、Ohashi Kei、Saitoh Shinji、Ogawa Atsushi、Hamada Keisuke、Sakamoto Masamune、Miyake Noriko、Hamanaka Kohei、Fujita Atsushi、Koshimizu Eriko、Miyatake Satoko、Mizuguchi Takeshi、Ogata Kazuhiro、Uchiyama Yuri、Matsumoto Naomichi
  • Journal Title: Clinical Genetics Volume: 103 Issue: 5 Pages: 590-595
  • DOI: 10.1111/cge.14292
  • Peer Reviewed
• [Journal Article] A novel NONO variant that causes developmental delay and cardiac phenotypes (2023)
  • Author(s): Itai T、Sugie A、Nitta Y、Maki R、Suzuki T、Shinkai Y、Watanabe Y、Nakano Y、Ichikawa K、Okamoto N、Utsuno Y、Koshimizu E、Fujita A、Hamanaka K、Uchiyama Y、Tsuchida N、Miyake N、Misawa K、Mizuguchi T、Miyatake S、Matsumoto N
  • Journal Title: Scientific Reports Volume: 13 Issue: 1 Pages: 975-975
  • DOI: 10.1038/s41598-023-27770-6
  • Peer Reviewed / Open Access
• [Journal Article] ATP1A3-related early childhood onset developmental and epileptic encephalopathy responding to corpus callosotomy: A case report (2023)
  • Author(s): Moriyama Kengo、Mizuno Tomoko、Suzuki Tomonori、Inaji Motoki、Maehara Taketoshi、Fujita Atsushi、Kato Mitsuhiro、Matsumoto Naomichi
  • Journal Title: Brain and Development Volume: 45 Issue: 1 Pages: 77-81
  • DOI: 10.1016/j.braindev.2022.08.009
  • Peer Reviewed
• [Journal Article] Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals (2023)
  • Author(s): Saida K, Maroofian R, Sengoku T, Mitani T, Pagnamenta AT, Marafi D, Miyatake S, Lupski JR, Houlden H, Matsumoto N.
  • Journal Title: Genet Med Volume: Jan;25(1) Issue: 1 Pages: 90-102
  • DOI: 10.1016/j.gim.2022.09.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A novel homozygous CHMP1A variant arising from segmental uniparental disomy causes pontocerebellar hypoplasia type 8 (2023)
  • Author(s): M. Sakamoto, T. Shiiki, S. Matsui, N. Okamoto, E. Koshimizu, N. Tsuchida, Y. Uchiyama, K. Hamanaka, A. Fujita, S. Miyatake, K. Misawa, T. Mizuguchi and N. Matsumoto
  • Journal Title: J Hum Genet Volume: 68 Issue: 4 Pages: 247-253
  • DOI: 10.1038/s10038-022-01098-x
  • Peer Reviewed
• [Journal Article] Distal arthrogryposis in a girl arising from a novel TNNI2 variant inherited from paternal somatic mosaicism (2023)
  • Author(s): R. Seyama, Y. Uchiyama, Y. Kaneshi, K. Hamanaka, A. Fujita, N. Tsuchida, E. Koshimizu, K. Misawa, S. Miyatake, T. Mizuguchi, S. Makino, A. Itakura, N. Okamoto and N. Matsumoto
  • Journal Title: J Hum Genet Volume: 68 Issue: 5 Pages: 363-367
  • DOI: 10.1038/s10038-022-01117-x
  • Peer Reviewed
• [Journal Article] Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants. (2022)
  • Author(s): Hamanaka K, Miyake N, Mizuguchi T, Miyatake S, Uchiyama Y, Tsuchida N, Sekiguchi F, Mitsuhashi S, Tsurusaki Y, Nakashima M, Saitsu H, Yamada K, Sakamoto M, Fukuda H, Ohori S, Saida K, Itai T, Azuma Y, Koshimizu E, Fujita A, Erturk B, Hiraki Y, Ch'ng GS, Kato M, Okamoto N, Takata A, Matsumoto N.
  • Journal Title: Genome Med Volume: 14 Issue: 1 Pages: 40-40
  • DOI: 10.1186/s13073-022-01042-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant (2022)
  • Author(s): Hamanaka Kohei、Miyoshi Keita、Sun Jia-Hui、Hamada Keisuke、Komatsubara Takao、Saida Ken、Tsuchida Naomi、Uchiyama Yuri、Fujita Atsushi、Mizuguchi Takeshi、Gerard Benedicte、Bayat Allan、Rinaldi Berardo、Kato Mitsuhiro、Tohyama Jun、Ogata Kazuhiro、Shi Yun Stone、Saito Kuniaki、Miyatake Satoko、Matsumoto Naomichi
  • Journal Title: Human Genetics Volume: 141 Issue: 2 Pages: 283-293
  • DOI: 10.1007/s00439-021-02416-7
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] De novo heterozygous variants in <i>KIF5B</i> cause kyphomelic dysplasia (2022)
  • Author(s): Itai Toshiyuki、Wang Zheng、Nishimura Gen、Ohashi Hirofumi、Guo Long、Wakano Yasuhiro、Sugiura Takahiro、Hayakawa Hiromi、Okada Mayumi、Saisu Takashi、Kitta Ayana、Doi Hiroshi、Kurosawa Kenji、Hotta Yoshihiro、Hosono Katsuhiro、Sato Miho、他
  • Journal Title: Clinical Genetics Volume: 102 Issue: 1 Pages: 3-11
  • DOI: 10.1111/cge.14133
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Patients with biallelic GGC repeat expansions in NOTCH2NLC exhibiting a typical neuronal intranuclear inclusion disease phenotype (2022)
  • Author(s): Shinichi Kameyama, Takeshi Mizuguchi, Hiroshi Doi, et al.
  • Journal Title: Genomics Volume: 114 Issue: 5 Pages: 110469-110469
  • DOI: 10.1016/j.ygeno.2022.110469
  • Peer Reviewed / Open Access
• [Journal Article] Exome sequencing analysis of Japanese autism spectrum disorder case-control sample supports an increased burden of synaptic function-related genes (2022)
  • Author(s): Kimura H, Okada T, Sebat J, et al.
  • Journal Title: Translational Psychiatry Volume: 12 Issue: 1 Pages: 265-265
  • DOI: 10.1038/s41398-022-02033-6
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid and comprehensive diagnostic method for repeat expansion diseases using nanopore sequencing (2022)
  • Author(s): Satoko Miyatake, Eriko Koshimizu, Atsushi Fujita, Hiroshi Doi, et al.
  • Journal Title: npj Genomic Medicine Volume: 7 Issue: 1 Pages: 62-62
  • DOI: 10.1038/s41525-022-00331-y
  • Peer Reviewed / Open Access
• [Journal Article] Monogenic causes of pigmentary mosaicism (2022)
  • Author(s): Saida Ken、Chong Pin Fee、Yamaguchi Asuka、...Mitsuhiro Kato, et al.
  • Journal Title: Human Genetics Volume: 141 Issue: 11 Pages: 1771-1784
  • DOI: 10.1007/s00439-022-02437-w
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy (2022)
  • Author(s): Sakamoto M et al, Saitoh Sは30番目
  • Journal Title: Genetics in Medicine Volume: 24 Issue: 12 Pages: 2453-2463
  • DOI: 10.1016/j.gim.2022.08.007
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome (2022)
  • Author(s): Seyama R, Uchiyama Y, Ceroni JRM, Kim VEH, Furquim I, Honjo RS, Castro MAA, Pires LVL, Aoi H, Iwama K, Hamanaka K, Fujita A, Tsuchida N, Koshimizu E, Misawa K, Miyatake S, Mizuguchi T, Makino S, Itakura A, Bertola DR, Kim CA, Matsumoto N.
  • Journal Title: Genomics Volume: Sep;114(5) Issue: 5 Pages: 110468-110468
  • DOI: 10.1016/j.ygeno.2022.110468
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Distal 2q duplication in a patient with intellectual disability (2022)
  • Author(s): Suzuki T, Osaka H, Miyake N, Fujita A, Uchiyama Y, Seyama R, Koshimizu E, Miyatake S, Mizuguchi T, Takeda S, Matsumoto N.
  • Journal Title: Hum Genome Var Volume: Nov 10;9(1) Issue: 1 Pages: 39-39
  • DOI: 10.1038/s41439-022-00215-8
  • Peer Reviewed / Open Access
• [Journal Article] Detecting the NOTCH2NLC Repeat Expansion in Neuronal Intranuclear Inclusion Disease (2022)
  • Author(s): S. Mitsuhashi, A. Fujita, N. Matsumoto
  • Journal Title: Genomic Structural Variants in Nervous System Disorders (Part of the Neuromethods book series) Volume: 182 Pages: 121-138
  • DOI: 10.1007/978-1-0716-2357-2_7
  • ISBN: 9781071623565, 9781071623572