限局性皮質異形成における体細胞変異、コピー数異常検出による遺伝的原因の解明

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K17936
• Research Institution: Yokohama City University
• Principal Investigator: 藤田 京志 横浜市立大学, 医学部, 助教 (20805113)
• Project Period (FY): 2020-04-01 – 2023-03-31
• 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 Annual Research Achievements

限局性皮質異形成や片側巨脳症等を認める64症例に対して、病変部脳組織と血液由来DNAを用いた解析により遺伝的原因の同定を行った。原因が判明したのは37症例でそのバリアントは生殖細胞系列バリアントが4個、病変部脳組織特異的な体細胞バリアントが35個であった。これらのバリアントのうち、３個は遺伝子コピー数の変化、36個は一塩基置換や小さいサイズの挿入欠失であった。
今回検出されたバリアントのうち、これまでに報告の少ないまたは新規の原因遺伝子としてPTPN11またはMAP2K1のバリアント、MTORのインフレームバリアントがある。これらについては培養細胞と発現ベクターを用いた実験により、以前より限局性皮質異形成や片側巨脳症の原因として考えられているｍTORパスウェイの活性化を確認することができたため、疾患の発症に関与していることが考えられた。
脳組織由来DNAでの遺伝子コピー数の変化を認めた2症例では、その領域に限局性皮質異形成の原因として知られている遺伝子であるTSC1またはDEPDC5が含まれていた。DEPDC5遺伝子を含むCNVを有する症例は同遺伝子に体細胞バリアントも有しており、以前より少数の症例で報告されている2ヒットであることが示唆された。
限局性皮質異形成や片側巨脳症はmTORパスウェイ上に位置する遺伝子の一塩基置換や小さいサイズの挿入欠失が解析対象とされていることが多いが、本研究において検出されたRAS/MAPKパスウェイ上にある遺伝子（PTPN11、MAP2K1）や体細胞CNVにも着目していく必要がある。

Research Products

• [Journal Article] An integrated genetic analysis of epileptogenic brain malformed lesions (2023)
  • Author(s): A. Fujita, et al.
  • Journal Title: Acta Neuropathol Commun Volume: 11 Pages: 33
  • DOI: 10.1186/s40478-023-01532-x
  • Peer Reviewed / Open Access
• [Journal Article] Incomplete hippocampal inversion in patients with mutations in genes involved in sonic hedgehog signaling (2023)
  • Author(s): T. Higashijima, H. Shirozu, H. Saitsu, M. Sonoda, A. Fujita, H. Masuda, T. Yamamoto, N. Matsumoto and S. Kameyama
  • Journal Title: Heliyon Volume: 9 Pages: e14712
  • DOI: 10.1016/j.heliyon.2023.e14712
  • Peer Reviewed
• [Journal Article] Three KINSSHIP syndrome patients with mosaic and germline AFF3 variants (2023)
  • Author(s): Y. Inoue, N. Tsuchida, N. Okamoto, S. Shuichi, K. Ohashi, S. Saitoh, A. Ogawa, K. Hamada, M. Sakamoto, N. Miyake, K. Hamanaka, A. Fujita, E. Koshimizu, S. Miyatake, T. Mizuguchi, K. Ogata, Y. Uchiyama and N. Matsumoto
  • Journal Title: Clin Genet Volume: 103 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): T. Itai, A. Sugie, Y. Nitta, R. Maki, T. Suzuki, Y. Shinkai, Y. Watanabe, Y. Nakano, K. Ichikawa, N. Okamoto, Y. Utsuno, E. Koshimizu, A. Fujita, K. Hamanaka, Y. Uchiyama, N. Tsuchida, N. Miyake, K. Misawa, T. Mizuguchi, S. Miyatake and N. Matsumoto
  • Journal Title: Sci Rep Volume: 13 Pages: 975
  • DOI: 10.1038/s41598-023-27770-6
  • Peer Reviewed
• [Journal Article] ATP1A3-related early childhood onset developmental and epileptic encephalopathy responding to corpus callosotomy: A case report (2023)
  • Author(s): K. Moriyama, T. Mizuno, T. Suzuki, M. Inaji, T. Maehara, A. Fujita, M. Kato and N. Matsumoto
  • Journal Title: Brain Dev Volume: 45 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): K. Saida, others , A. Fujita, Y. Uchiyama, T. Mizuguchi, S. Miyatake, N. Miyake, R. M. Elshafie, K. Salayev, U. Guliyeva, F. S. Alkuraya, J. G. Gleeson, K. G. Monaghan, K. G. Langley, H. Yang, M. Motavaf, S. Safari, M. Alipour, K. Ogata, A. E. X. Brown, J. R. Lupski, H. Houlden and N. Matsumoto
  • Journal Title: Genet Med Volume: 25 Pages: 90-102
  • DOI: 10.1016/j.gim.2022.09.010
  • Peer Reviewed
• [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 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 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): K. Hamanaka, N. Miyake, T. Mizuguchi, S. Miyatake, others, E. Koshimizu, A. Fujita, B. Erturk, Y. Hiraki, G. S. Ch'ng, M. Kato, N. Okamoto, A. Takata and N. Matsumoto
  • Journal Title: Genome Medicine Volume: 14 Pages: 40
  • DOI: 10.1186/s13073-022-01042-w
  • Peer Reviewed / Open Access
• [Journal Article] Amelioration of a neurodevelopmental disorder by carbamazepine in a case having a gain-of-function GRIA3 variant (2022)
  • Author(s): K. Hamanaka, K. Miyoshi, J. H. Sun, K. Hamada, T. Komatsubara, K. Saida, N. Tsuchida, Y. Uchiyama, A. Fujita, T. Mizuguchi, B. Gerard, A. Bayat, B. Rinaldi, M. Kato, J. Tohyama, K. Ogata, Y. S. Shi, K. Saito, S. Miyatake and N. Matsumoto
  • Journal Title: Hum Genet Volume: 141 Pages: 283-293
  • DOI: 10.1007/s00439-021-02416-7
  • Peer Reviewed
• [Journal Article] De novo heterozygous variants in KIF5B cause kyphomelic dysplasia (2022)
  • Author(s): T. Itai, Z. Wang, G. Nishimura, H. Ohashi, L. Guo, Y. Wakano, T. Sugiura, H. Hayakawa, M. Okada, T. Saisu, A. Kitta, H. Doi, K. Kurosawa, Y. Hotta, K. Hosono, M. Sato, K. Shimizu, K. Takikawa, S. Watanabe, N. Ikeda, M. Suzuki, A. Fujita, Y. Uchiyama, N. Tsuchida, S. Miyatake, N. Miyake, N. Matsumoto and S. Ikegawa
  • Journal Title: Clin Genet Volume: 102 Pages: 3-11
  • DOI: 10.1111/cge.14133
  • Peer Reviewed
• [Journal Article] Patients with biallelic GGC repeat expansions in NOTCH2NLC exhibiting a typical neuronal intranuclear inclusion disease phenotype (2022)
  • Author(s): S. Kameyama, T. Mizuguchi, H. Doi, S. Koyano, M. Okubo, M. Tada, H. Shimizu, H. Fukuda, N. Tsuchida, Y. Uchiyama, E. Koshimizu, K. Hamanaka, A. Fujita, K. Misawa, S. Miyatake, K. Kanai, F. Tanaka and N. Matsumoto
  • Journal Title: Genomics Volume: 114 Pages: 110469
  • DOI: 10.1016/j.ygeno.2022.110469
  • Peer Reviewed
• [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): H. Kimura, M. Nakatochi, B. Aleksic, J. Guevara, M. Toyama, Y. Hayashi, H. Kato, I. Kushima, M. Morikawa, K. Ishizuka, T. Okada, Y. Tsurusaki, A. Fujita, N. Miyake, T. Ogi, A. Takata, N. Matsumoto, J. Buxbaum, N. Ozaki and J. Sebat
  • Journal Title: Transl Psychiatry Volume: 12 Pages: 265
  • DOI: 10.1038/s41398-022-02033-6
  • Peer Reviewed
• [Journal Article] Rapid and comprehensive diagnostic method for repeat expansion diseases using nanopore sequencing (2022)
  • Author(s): S. Miyatake, E. Koshimizu, A. Fujita, et al.
  • Journal Title: NPJ Genom Med Volume: 7 Pages: 62
  • DOI: 10.1038/s41525-022-00331-y
  • Peer Reviewed / Open Access
• [Journal Article] Monogenic causes of pigmentary mosaicism (2022)
  • Author(s): K. Saida, P. F. Chong, A. Yamaguchi, N. Saito, H. Ikehara, E. Koshimizu, R. Miyata, A. Ishiko, K. Nakamura, H. Ohnishi, K. Fujioka, T. Sakakibara, H. Asada, K. Ogawa, K. Kudo, E. Ohashi, M. Kawai, Y. Abe, N. Tsuchida, Y. Uchiyama, K. Hamanaka, A. Fujita, et al.
  • Journal Title: Hum Genet Volume: 141 Pages: 1771-1784
  • DOI: 10.1007/s00439-022-02437-w
  • Peer Reviewed
• [Journal Article] Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy (2022)
  • Author(s): M. Sakamoto, K. Iwama, others, C. Ohba, S. Ito, H. Saitsu, K. Saida, N. Tsuchida, Y. Uchiyama, E. Koshimizu, A. Fujita, K. Hamanaka, K. Misawa, S. Miyatake, T. Mizuguchi, N. Miyake and N. Matsumoto
  • Journal Title: Genet Med Volume: 24 Pages: 2453-2463
  • DOI: 10.1016/j.gim.2022.08.007
  • Peer Reviewed
• [Journal Article] Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome (2022)
  • Author(s): R. Seyama, Y. Uchiyama, J. R. M. Ceroni, V. E. H. Kim, I. Furquim, R. S. Honjo, M. A. A. Castro, L. V. L. Pires, H. Aoi, K. Iwama, K. Hamanaka, A. Fujita, N. Tsuchida, E. Koshimizu, K. Misawa, S. Miyatake, T. Mizuguchi, S. Makino, A. Itakura, D. R. Bertola, C. A. Kim and N. Matsumoto
  • Journal Title: Genomics Volume: 114 Pages: 110468
  • DOI: 10.1016/j.ygeno.2022.110468
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distal 2q duplication in a patient with intellectual disability (2022)
  • Author(s): T. Suzuki, H. Osaka, N. Miyake, A. Fujita, Y. Uchiyama, R. Seyama, E. Koshimizu, S. Miyatake, T. Mizuguchi, S. Takeda and N. Matsumoto
  • Journal Title: Hum Genome Var Volume: 9 Pages: 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