Elucidation of the mechanism for neurodevelopmental disorder derived from chromosomal microstructural abnormalities

• Project/Area Number: 18K07803
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Tokyo Women's Medical University
• Principal Investigator: Yamamoto Toshiyuki 東京女子医科大学, 医学部, 教授 (20252851)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: ゲノム構造異常 / 次世代シーケンス / ゲノムコピー数変化 / 神経発達障害 / ゲノムコピー数 / 染色体構造異常 / ロングリードシーケンス / マイクロアレイ / マイクロアレイ染色体検査 / デジタルPCR / long sequence / 染色体微細構造異常 / ゲノム

Outline of Final Research Achievements

Advanced technologies in genomic analysis have revealed that previously unknown complex genomic structural abnormalities are responsible for patients with neurodevelopmental disorders. The purpose of this study was to clarify the mechanism of complex structural abnormalities revealed by microarray chromosomal examination. For this purpose, nanopore sequence technology was used for a long sequencing. Consequently, some of the complex structural abnormalities consisted with multiple deletions and duplications were caused by chromothripsis or chromanasynthesis. Furthermore, we analyzed two cases showing complicated abnormalities associated with triplications in both ends of the duplication, and clarified for the first time in the world that it is composed of only two breakpoint-junctions.

Academic Significance and Societal Importance of the Research Achievements

現在の発達したゲノム解析技術により、神経発達障害患者の３割程度は原因を明らかにすることができるようになってきている。しかしながら、半数以上の患者においては未だに原因が明らかでない。このような患者の発症原因の１つとしてコピー数変化のないゲノム構造異常が考えられる。本研究で明らかになったゲノム構造異常の発生メカニズムの理解は、今後ゲノム解析技術の進歩を臨床面に応用する際に大いに参考になると考える。

Research Products

• [Journal Article] Deep intronic deletion in intron 3 of PLP1 is associated with a severe phenotype of Pelizaeus-Merzbacher disease (2021)
  • Author(s): Yamamoto-Shimojima Keiko、Akagawa Hiroyuki、Yanagi Kumiko、Kaname Tadashi、Okamoto Nobuhiko、Yamamoto Toshiyuki
  • Journal Title: Human Genome Variation Volume: 8 Issue: 1 Pages: 14-14
  • DOI: 10.1038/s41439-021-00144-y
  • Peer Reviewed / Open Access
• [Journal Article] Breakpoint junction analysis for complex genomic rearrangements with the caldera volcano‐like pattern (2020)
  • Author(s): Yanagishita Tomoe、Imaizumi Taichi、Yamamoto‐Shimojima Keiko、Yano Tamami、Okamoto Nobuhiko、Nagata Satoru、Yamamoto Toshiyuki
  • Journal Title: Human Mutation Volume: 41 Issue: 12 Pages: 2119-2127
  • DOI: 10.1002/humu.24108
  • Peer Reviewed
• [Journal Article] Complex chromosomal rearrangements of human chromosome 21 in a patient manifesting clinical features partially overlapped with that of Down syndrome (2020)
  • Author(s): Imaizumi Taichi、Yamamoto-Shimojima Keiko、Yanagishita Tomoe、Ondo Yumiko、Nishi Eriko、Okamoto Nobuhiko、Yamamoto Toshiyuki
  • Journal Title: Human Genetics Volume: 139 Issue: 12 Pages: 1555-1563
  • DOI: 10.1007/s00439-020-02196-6
  • Peer Reviewed
• [Journal Article] Analyses of breakpoint junctions of complex genomic rearrangements comprising multiple consecutive microdeletions by nanopore sequencing (2020)
  • Author(s): Imaizumi Taichi、Yamamoto-Shimojima Keiko、Yanagishita Tomoe、Ondo Yumiko、Yamamoto Toshiyuki
  • Journal Title: Journal of Human Genetics Volume: 65 Issue: 9 Pages: 735-741
  • DOI: 10.1038/s10038-020-0762-6
  • Peer Reviewed
• [Journal Article] Induced pluripotent stem cells established from a female patient with Xq22 deletion confirm that BEX2 escapes from X‐chromosome inactivation (2020)
  • Author(s): Yamamoto‐Shimojima Keiko、Osawa Mitsujiro、Saito Megumu K.、Yamamoto Toshiyuki
  • Journal Title: Congenital Anomalies Volume: 61 Issue: 2 Pages: 63-67
  • DOI: 10.1111/cga.12403
• [Journal Article] De novo SMARCA2 variants clustered outside the helicase domain cause a new recognizable syndrome with intellectual disability and blepharophimosis distinct from Nicolaides?Baraitser syndrome (2020)
  • Author(s): Cappuccio Gerarda、Telethon Undiagnosed Diseases Program、Sayou Camille、Tanno Pauline Le、Tisserant Emilie、Bruel Ange-Line、Kennani Sara El、,,,,Yamamoto Toshiyuki、et al.
  • Journal Title: Genetics in Medicine Volume: 22 Issue: 11 Pages: 1838-1850
  • DOI: 10.1038/s41436-020-0898-y
• [Journal Article] Application of induced pluripotent stem cells in epilepsy (2020)
  • Author(s): Hirose Shinichi、Tanaka Yasuyoshi、Shibata Mami、Kimura Yuichi、Ishikawa Mitsuru、Higurashi Norimichi、Yamamoto Toshiyuki、Ichise Eisuke、Chiyonobu Tomohiro、Ishii Atsushi
  • Journal Title: Molecular and Cellular Neuroscience Volume: 108 Pages: 103535-103535
  • DOI: 10.1016/j.mcn.2020.103535
  • Peer Reviewed / Open Access
• [Journal Article] Coffin‐Siris syndrome with bilateral macular dysplasia caused by a novel exonic deletion in ARID1B (2020)
  • Author(s): Fujita Takako、Ihara Yukiko、Hayashi Hitomi、Ishii Atsushi、Ideguchi Hiroshi、Inoue Takahito、Imaizumi Taichi、Yamamoto Toshiyuki、Hirose Shinichi
  • Journal Title: Congenital Anomalies Volume: 60 Issue: 6 Pages: 189-193
  • DOI: 10.1111/cga.12383
  • NAID: 50014626632
  • Peer Reviewed
• [Journal Article] The involvement of U-type dicentric chromosomes in the formation of terminal deletions with or without adjacent inverted duplications. (2020)
  • Author(s): Kato T, Inagaki H, Miyai S, Suzuki F, Naru Y, Shinkai Y, Kato A, Kanyama K, Mizuno S, Muramatsu Y, Yamamoto T, Shinya M, Tazaki Y, Hiwatashi S, Ikeda T, Ozaki M, Kurahashi H.
  • Journal Title: Hum Genet. Volume: 139(11) Issue: 11 Pages: 1417-1427
  • DOI: 10.1007/s00439-020-02186-8
  • Peer Reviewed
• [Journal Article] Analyses of breakpoint-junctions of complex genomic rearrangements comprising multiple consecutive microdeletions by nanopore sequencing. (2020)
  • Author(s): Imaizumi T, Yamamoto-Shimojima K, Yanagishita T, Ondo Y, Yamamoto T.
  • Journal Title: J Hum Genet Volume: in press
  • Peer Reviewed
• [Journal Article] A novel α-spectrin pathogenic variant in trans to α-spectrin LELY causing neonatal jaundice with hemolytic anemia from hereditary pyropoikilocytosis coexisting with Gilbert syndrome. (2020)
  • Author(s): Suzuki T, Togawa T, Kanno H, Ogura H, Yamamoto T, Sugiura T, Kouwaki M, Saitoh S.
  • Journal Title: J Pediatr Hemat/Onc Volume: in press
  • Peer Reviewed
• [Journal Article] Deletion in the cobalamin synthetase W domain-containing protein 1 gene is associated with congenital anomalies of the kidney and urinary tract. (2020)
  • Author(s): Kanda S, Ohmuraya M, Akagawa H, Horita S, Yoshida Y, Kaneko N, Sugawara N, Ishizuka K, Miura K, Harita Y, Yamamoto T, Oka A, Araki K, Furukawa T, Hattori M.
  • Journal Title: J Am Soc Nephrol Volume: 31 Issue: 1 Pages: 139-147
  • DOI: 10.1681/asn.2019040398
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Primrose syndrome associated with unclassified immunodeficiency and a novel ZBTB20 mutation. (2020)
  • Author(s): Yamamoto-Shimojima K, Imaizumi T, Akagawa H, Kanno H, Yamamoto T.
  • Journal Title: Am J Med Genet A Volume: 182 Issue: 3 Pages: 521-526
  • DOI: 10.1002/ajmg.a.61432
  • Peer Reviewed / Open Access
• [Journal Article] Duchenne型筋ジストロフィー患者の母親で認められたモザイク変異と遺伝カウンセリング. (2020)
  • Author(s): 村松みゆき, 白井謙太朗, 今泉太一, 柳下友映, 山本圭子, 山本俊至.
  • Journal Title: 脳と発達 Volume: 52 Pages: 41-44
  • NAID: 130007786531
  • Peer Reviewed
• [Journal Article] Compound Heterozygous <i>ALDH7A1</i> Mutation Causes the Hemi-Allelic Expression in a Patient with Pyridoxine-Dependent Epilepsy (2019)
  • Author(s): Yanagishita T, Yamamoto-Shimojima K, Koike T, Nasu H, Takahashi Y, Akiyama T, Nagata S, Yamamoto T.
  • Journal Title: Tokyo Women's Medical University Journal Volume: 3 Issue: 0 Pages: 73-77
  • DOI: 10.24488/twmuj.2019005
  • NAID: 130007770823
  • ISSN: 2432-6186
  • Year and Date: 2019-12-20
  • Peer Reviewed / Open Access
• [Journal Article] Advantages of ddPCR in detection of <i>PLP1</i> duplications (2019)
  • Author(s): Imaizumi T, Yamamoto-Shimojima K, Yamamoro T.
  • Journal Title: Intractable & Rare Diseases Research Volume: 8 Issue: 3 Pages: 198-202
  • DOI: 10.5582/irdr.2019.01067
  • NAID: 130007709095
  • ISSN: 2186-361X, 2186-3644
  • Year and Date: 2019-08-31
  • Peer Reviewed / Open Access
• [Journal Article] Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders (2019)
  • Author(s): Yamamoto Toshiyuki、Imaizumi Taichi、Yamamoto-Shimojima Keiko、Kurahashi Hirokazuら,
  • Journal Title: Brain and Development Volume: 41 Issue: 9 Pages: 776-782
  • DOI: 10.1016/j.braindev.2019.05.007
  • Peer Reviewed
• [Journal Article] Establishment of a simple and rapid method to detect MECP2 duplications using digital polymerase chain reaction. (2019)
  • Author(s): Yanagishita T, Yamamoto-Shimojima K, Nakano S, Sasaki T, Shigematsu H, Imai K, Yamamoto T.
  • Journal Title: Congenital Anomalies (Kyoto) Volume: 印刷中 Issue: 1 Pages: 10-14
  • DOI: 10.1111/cga.12325
  • Peer Reviewed
• [Journal Article] Preimplantation genetic testing for aneuploidy: a comparison of live birth rates in patients with recurrent pregnancy loss due to embryonic aneuploidy or recurrent implantation failure. (2019)
  • Author(s): Sato T, Sugiura-Ogasawara M, Ozawa F, Yamamoto T, Kato T, Kurahashi H, Kuroda T, Aoyama N, Kato K, Kobayashi R, Fukuda A, Utsunomiya T, Kuwahara A, Saito H, Takeshita T, Irahara M.
  • Journal Title: Hum Reprod. Volume: 34 Issue: 12 Pages: 2340-2348
  • DOI: 10.1093/humrep/dez229
  • Peer Reviewed / Open Access
• [Journal Article] PRRT2 mutations in Japanese patients with benign infantile epilepsy and paroxysmal kinesigenic dyskinesia (2019)
  • Author(s): Okumura Akihisa、Shimojima Keiko、Kurahashi Hirokazuら.
  • Journal Title: Seizure Volume: 71 Pages: 1-5
  • DOI: 10.1016/j.seizure.2019.05.017
  • Peer Reviewed
• [Journal Article] Narrowing down the region responsible for 1q23.3q24.1 microdeletion by identifying the smallest deletion. (2019)
  • Author(s): Hoshina T, Seto T, Shimono T, Sakamoto H, Okuyama T, Hamazaki T, Yamamoto T.
  • Journal Title: Hum Genome Var. Volume: 6 Issue: 1 Pages: 47-47
  • DOI: 10.1038/s41439-019-0079-1
  • Peer Reviewed / Open Access
• [Journal Article] Natural histories of patients with Wolf-Hirschhorn syndrome derived from variable chromosomal abnormalities. (2019)
  • Author(s): Yamamoto-Shimojima K, Kouwaki M, Kawashima Y, Itomi K, Momosaki K, Ozasa S, Okamoto N, Yokochi K, Yamamoto T.
  • Journal Title: Congenit Anom (Kyoto). Volume: 59 Issue: 5 Pages: 169-173
  • DOI: 10.1111/cga.12318
  • Peer Reviewed
• [Journal Article] Sequential radiologic findings in osteopathia striata with cranial sclerosis. (2019)
  • Author(s): Tomita Y, Chong P-F, Yamamoto T, Akaminea S, Imaizumi T, Kira R.
  • Journal Title: Diagn Interv Imaging. Volume: 100 Issue: 9 Pages: 529-531
  • DOI: 10.1016/j.diii.2019.04.001
  • Peer Reviewed
• [Journal Article] Elucidation of the pathogenic mechanism and potential treatment strategy for a female patient with spastic paraplegia derived from a single-nucleotide deletion in PLP1 (2019)
  • Author(s): Yamamoto-Shimojima Keiko、Imaizumi Taichi、Aoki Yusuke、Inoue Ken、Kaname Tadashi、Okuno Yusuke、Muramatsu Hideki、Kato Kohji、Yamamoto Toshiyuki
  • Journal Title: Journal of Human Genetics Volume: 未定 Issue: 7 Pages: 665-671
  • DOI: 10.1038/s10038-019-0600-x
  • Peer Reviewed
• [Journal Article] A case of de novo splice site variant in SLC35A2 showing developmental delays, spastic paraplegia, and delayed myelination. (2019)
  • Author(s): Miyamoto S, Nakashima M, Ohashi T, Hiraide T, Kurosawa K, Yamamoto T, Takanashi J, Osaka H, Inoue K, Miyazaki T, Wada Y, Okamoto N, Saitsu H.
  • Journal Title: Mol Genet Genomic Med. Volume: 7 Issue: 8
  • DOI: 10.1002/mgg3.814
  • Peer Reviewed / Open Access
• [Journal Article] Phenotypic features of 1q41q42 microdeletion including WDR26 and FBXO28 are clinically recognizable: The first case from Japan. (2019)
  • Author(s): Yanagishita T, Yamamoto-Shimojima K, Nakano S, Sasaki T, Shigematsu H, Imai K, Yamamoto T.
  • Journal Title: Brain Dev. Volume: 41 Issue: 5 Pages: 452-455
  • DOI: 10.1016/j.braindev.2018.12.006
  • Peer Reviewed
• [Journal Article] De novo 1p35.2 microdeletion including PUM1 identified in a patient with sporadic west syndrome. (2019)
  • Author(s): Imaizumi T, Mogami Y, Okamoto N, Yamamoto-Shimojima K, Yamamoto T.
  • Journal Title: Congenital Anomalies (Kyoto) Volume: 印刷中 Issue: 6 Pages: 193-194
  • DOI: 10.1111/cga.12322
  • Peer Reviewed
• [Journal Article] Identification of a rare homozygous <i>SZT2</i> variant due to uniparental disomy in a patient with a neurodevelopmental disorder (2018)
  • Author(s): Imaizumi Taichi、Kumakura Akira、Yamamoto-Shimojima Keiko、Ondo Yumko
  • Journal Title: Intractable & Rare Diseases Research Volume: 7 Issue: 4 Pages: 245-250
  • DOI: 10.5582/irdr.2018.01117
  • NAID: 130007533901
  • ISSN: 2186-361X, 2186-3644
  • Year and Date: 2018-11-30
  • Peer Reviewed / Open Access
• [Journal Article] Novel compound heterozygous EPG5 mutations consisted with a missense mutation and a microduplication in the exon 1 region identified in a Japanese patient with Vici syndrome (2018)
  • Author(s): Shimada Shino、Hirasawa Kyoko、Takeshita Akiko、Nakatsukasa Hidetsugu、Yamamoto-Shimojima Keiko、Imaizumi Taichi、Nagata Satoru、Yamamoto Toshiyuki
  • Journal Title: American Journal of Medical Genetics Part A Volume: 176 Issue: 12 Pages: 2803-2807
  • DOI: 10.1002/ajmg.a.40500
  • Peer Reviewed
• [Journal Article] An episode of acute encephalopathy with biphasic seizures and late reduced diffusion followed by hemiplegia and intractable epilepsy observed in a patient with a novel frameshift mutation in HNRNPU (2018)
  • Author(s): Shimada Shino、Oguni Hirokazu、Otani Yui、Nishikawa Aiko、Ito Susumu、Eto Kaoru、Nakazawa Tomoyuki、Yamamoto-Shimojima Keiko、Takanashi Jun-ichi、Nagata Satoru、Yamamoto Toshiyuki
  • Journal Title: Brain and Development Volume: 40 Issue: 9 Pages: 813-818
  • DOI: 10.1016/j.braindev.2018.05.010
  • Peer Reviewed
• [Journal Article] Early-Onset Diabetes Mellitus in a Patient With a Chromosome 13q34qter Microdeletion Including IRS2. (2018)
  • Author(s): Babaya N, Noso S, Hiromine Y, Ito H, Taketomo Y, Yamamoto T, Kawabata Y, Ikegami H.
  • Journal Title: J Endocr Soc. Volume: 11 Issue: 10 Pages: 1207-1213
  • DOI: 10.1210/js.2018-00175
  • Peer Reviewed / Open Access
• [Journal Article] Independent occurrence of de novo HSPD1 and HIP1 variants in brothers with different neurological disorders ? leukodystrophy and autism (2018)
  • Author(s): Yamamoto Toshiyuki、Yamamoto-Shimojima Keiko、Ueda Yuki、Imai Katsumi、Takahashi Yukitoshi、Imagawa Eri、Miyake Noriko、Matsumoto Naomichi
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 18-18
  • DOI: 10.1038/s41439-018-0020-z
  • Peer Reviewed / Open Access
• [Journal Article] Interstitial deletion within 7q31.1q31.3 in a woman with mild intellectual disability and schizophrenia (2018)
  • Author(s): Akahoshi Keiko、Yamamoto Toshiyuki
  • Journal Title: Neuropsychiatric Disease and Treatment Volume: Volume 14 Pages: 1773-1778
  • DOI: 10.2147/ndt.s168469
• [Journal Article] A novel MLH1 mutation in a Japanese family with Lynch syndrome associated with small bowel cancer (2018)
  • Author(s): Akizawa Yoshika、Yamamoto Toshiyuki、Tamura Kazuo、Kanno Toshiyuki、Takahashi Nobuko、Ohki Takeshi、Omori Teppei、Tokushige Katsutoshi、Yamamoto Masakazu、Saito Kayoko
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 13-13
  • DOI: 10.1038/s41439-018-0013-y
• [Journal Article] Infantile spasms related to a 5q31.2-q31.3 microdeletion including PURA (2018)
  • Author(s): Shimojima Keiko、Okamoto Nobuhiko、Ohmura Kayo、Nagase Hiroaki、Yamamoto Toshiyuki
  • Journal Title: Human Genome Variation Volume: 5 Issue: 1 Pages: 18007-18007
  • DOI: 10.1038/hgv.2018.7
  • Peer Reviewed
• [Journal Article] Somatic mosaic deletions involving SCN1A cause Dravet syndrome (2018)
  • Author(s): Nakayama Tojo、Ishii Atsushi、Yoshida Takeshi、Nasu Hirosato、Shimojima Keiko、Yamamoto Toshiyuki、Kure Shigeo、Hirose Shinichi
  • Journal Title: American Journal of Medical Genetics Part A Volume: 176 Issue: 3 Pages: 657-662
  • DOI: 10.1002/ajmg.a.38596
  • Peer Reviewed
• [Presentation] 小児神経科医が知っておくべき臨床遺伝学的検査. (2020)
  • Author(s): 山本俊至
  • Organizer: 第20回常総セミナー
  • Invited
• [Presentation] Genomic backgrounds of Japanese patients with undiagnosed neurodevelopmental disorders. (2019)
  • Author(s): Yamamoto T, Imaizumi T, Yamamoto-Shimojima K, Yanagishita T, Seto T, Okamoto N.
  • Organizer: The 59th Annual Meeting of the Japanese Teratology Society/ The 13th World Congress of the International Cleftlip and Palate Foundation -CLEFT 2019-
  • Int'l Joint Research
• [Presentation] 着床前染色体異数性診断(PGT-A)に用いる染色体数的異常の診断方法の検討. (2019)
  • Author(s): 山本俊至, 山本圭子, 恩藤由美子, 青山直樹, 黒田知子, 加藤恵一.
  • Organizer: 臨床遺伝2019 in Sapporo/第26回日本遺伝子診療学会大会・第43回日本遺伝カウンセリング学会学術集会合同学術集会
• [Presentation] 神経発達障害に対するクリニカルシーケンスの診断効率. (2019)
  • Author(s): 山本俊至, 今泉太一, 山本圭子, 柳下友映, 瀬戸俊之, 岡本伸彦.
  • Organizer: 日本人類遺伝学会第64回大会
• [Presentation] 小児神経科医が知っておくべきゲノム医療 (2019)
  • Author(s): 山本俊至
  • Organizer: 第69回日本小児神経学会関東地方会
  • Invited
• [Presentation] 着床前染色体異数性診断の現状と課題 (2019)
  • Author(s): 山本俊至
  • Organizer: 日本人類遺伝学会第63回大会
• [Presentation] 4pモノソミー症候群10例における遺伝子型・表現型相関解析 (2019)
  • Author(s): 山本俊至, 山本-下島圭子, 幸脇正典, 鞁嶋有紀, 糸見和也, 百崎謙, 小篠史郎, 岡本伸彦, 横地健治
  • Organizer: 第60回日本小児神経学会学術集会
• [Book] 症例でわかる小児神経疾患の遺伝学的アプローチ (2019)
  • Author(s): 山本俊至
  • Total Pages: 212
  • Publisher: 診断と治療社
  • ISBN: 4787824376