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2022 Fiscal Year Annual Research Report

ロングリードシーケンサーを用いた神経筋疾患の原因探索と病態解明

Research Project

Project/Area Number 20K07907
Research InstitutionYokohama City University

Principal Investigator

宮武 聡子  横浜市立大学, 附属病院, 准教授 (50637890)

Project Period (FY) 2020-04-01 – 2023-03-31
Keywordsロングリードシーケンサー / 神経筋疾患 / 脊髄小脳変性症 / リピート伸長病 / CANVAS / RFC1 / ナノポアシーケンス / ターゲットロングリードシーケンス法
Outline of Annual Research Achievements

本研究は、ショートリード次世代シーケンサーの“次の世代”と位置付けられるロングリードシーケンサーを用いて、ショートリードシーケンサーの弱点を補完する全ゲノム解析系を構築し、全エクソーム解析で未解決の神経筋疾患症例の遺伝学的原因を同定することを目的とした。
研究全体の成果として、①脊髄小脳変性症の1つの病型である、小脳性運動失調、ニューロパチー、前庭機能障害を主徴とする小脳性運動失調・ニューロパチー・前庭反射消失症候群(Cerebellar ataxia, neuropathy, vestibular areflexia syndrome; CANVAS)の原因変異である、RFC1遺伝子のイントロン領域に存在する両アレル性リピート異常伸長の全配列(約2-8kb)を決定し、リピートユニットの組み合わせの多様性があることを発見、さらに配列パターンの組み合わせと臨床症状の関連について観察、報告したこと[Miyatake et al., Brain. Apr 29;145(3):1139-1150 (2022)]、②リピート伸長病の原因となる病的リピート伸長を、網羅的に一括スクリーニングできる迅速ロングリードシーケンス系を確立したこと[Miyatake et al., npj Genom. Med. 7, 62 (2022)]、が挙げられる。
前者は、長いリピート伸長の完全配列決定はこれまでほとんど行われてこなかったところ、ロングリードシーケンサーを用いて、リピート配列の全長を解読できたことが既存のゲノム手法の限界を打ち破る新たな知見であり、後者は、ナノポアシーケンサーのターゲットロングリードシーケンス法を利用したもので、従来のPCRを主体としたゲノム手法ではスクリーニングが困難であったリピート伸長病の簡便・迅速・正確な診断が可能となったことが有意義であった。

  • Research Products

    (24 results)

All 2023 2022

All Journal Article (20 results) (of which Int'l Joint Research: 7 results,  Peer Reviewed: 20 results,  Open Access: 13 results) Presentation (4 results) (of which Invited: 2 results)

  • [Journal Article] Molecular diagnosis of 405 individuals with autism spectrum disorder2023

    • Author(s)
      Miyake N, Tsurusaki Y, Fukai R, Kushima I, Okamoto N, Ohashi K, Nakamura K, Miyatake S, Matsumoto N.
    • Journal Title

      Eur J Hum Genet

      Volume: 27-Mar Pages: -

    • DOI

      10.1038/s41431-023-01335-7

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Publisher Correction: A novel NONO variant that causes developmental delay and cardiac phenotypes2023

    • 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

      Sci Rep

      Volume: Mar 9;13(1) Pages: 3954

    • DOI

      10.1038/s41598-023-30968-3

    • Peer Reviewed / Open Access
  • [Journal Article] An integrated genetic analysis of epileptogenic brain malformed lesions2023

    • Author(s)
      Fujita A, Kato M, Sugano H, Iimura Y, Suzuki H, Tohyama J, Fukuda M, Miyatake S, Mizuguchi T, Nakashima M, Saitsu H, Miyake N, Kakita A, Matsumoto N.
    • Journal Title

      Acta Neuropathol Commun

      Volume: Mar 2;11(1) Pages: 33

    • DOI

      10.1186/s40478-023-01532-x

    • Peer Reviewed / Open Access
  • [Journal Article] A case of early-infantile onset, rapidly progressive leukoencephalopathy with calcifications and cysts caused by biallelic SNORD118 variants2023

    • Author(s)
      Kodama K, Aoyama H, Murakami Y, Takanashi JI, Koshimizu E, Miyatake S, Iwama K, Mizuguchi T, Matsumoto N, Omata T.
    • Journal Title

      Radiol Case Rep

      Volume: Jan 12;18(3) Pages: 1217-1220

    • DOI

      10.1016/j.radcr.2022.11.033

    • Peer Reviewed / Open Access
  • [Journal Article] A novel NONO variant that causes developmental delay and cardiac phenotypes2023

    • 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

      Sci Rep

      Volume: Jan 18;13(1) Pages: 975

    • DOI

      10.1038/s41598-023-27770-6

    • Peer Reviewed / Open Access
  • [Journal Article] Brain monoamine vesicular transport disease caused by homozygous SLC18A2 variants: A study in 42 affected individuals2023

    • 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) Pages: 90-102

    • DOI

      10.1016/j.gim.2022.09.010

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Genetic and clinical landscape of childhood cerebellar hypoplasia and atrophy2022

    • Author(s)
      Sakamoto M, Iwama K, Sasaki M, Ishiyama A, Komaki H, Saito T, Miyatake S, Mizuguchi T, Miyake N, Matsumoto N.
    • Journal Title

      Genet Med

      Volume: Dec;24(12) Pages: 2453-2463

    • DOI

      10.1016/j.gim.2022.08.007

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] A case of generalized dystonia DYT28 with a novel de novo mutation in the KMT2B gene2022

    • Author(s)
      Hara K, Ouchi H, Hamanaka K, Miyatake S, Matsumoto N.
    • Journal Title

      Rinsho Shinkeigaku

      Volume: Nov 26;62(11) Pages: 856-859

    • DOI

      10.5692/clinicalneurol.cn-001773

    • Peer Reviewed
  • [Journal Article] Distal 2q duplication in a patient with intellectual disability2022

    • 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) Pages: 39

    • DOI

      10.1038/s41439-022-00215-8

    • Peer Reviewed / Open Access
  • [Journal Article] A case of ALG11-congenital disorders of glycosylation diagnosed by post-mortem whole exome sequencing2022

    • Author(s)
      Arai Y, Okanishi T, Kanai S, Okazaki T, Koshimizu E, Miyatake S, Maeoka Y, Fujimoto A, Matsumoto N, Maegaki Y.
    • Journal Title

      Brain Dev

      Volume: Nov;44(10) Pages: 732-736

    • DOI

      10.1016/j.braindev.2022.07.005

    • Peer Reviewed
  • [Journal Article] Monogenic causes of pigmentary mosaicism2022

    • Author(s)
      Saida K, Chong PF, Yamaguchi A, Saito N, Ikehara H, Koshimizu E, Miyata R, Ishiko A, Nakamura K, Ohnishi H, Fujioka K, Sakakibara T, Asada H, Ogawa K, Kudo K, Ohashi E, Kawai M, Abe Y, Tsuchida N, Uchiyama Y, Hamanaka K, Fujita A, Mizuguchi T, Miyatake S, Miyake N, Kato M, Kira R, Matsumoto N.
    • Journal Title

      Hum Genet

      Volume: Nov;141(11) Pages: 1771-1784

    • DOI

      10.1007/s00439-022-02437-w

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Rapid and comprehensive diagnostic method for repeat expansion diseases using nanopore sequencing2022

    • Author(s)
      Miyatake S, Koshimizu E, Fujita A, Doi H, Okubo M, Wada T, Hamanaka K, Ueda N, Kishida H, Minase G, Matsuno A, Kodaira M, Ogata K, Kato R, Sugiyama A, Sasaki A, Miyama T, Satoh M, Uchiyama Y, Tsuchida N, Hamanoue H, Misawa K, Hayasaka K, Sekijima Y, Adachi H, Yoshida K, Tanaka F, Mizuguchi T, Matsumoto N.
    • Journal Title

      NPJ Genom Med

      Volume: Oct 26;7(1) Pages: 62

    • DOI

      10.1038/s41525-022-00331-y

    • Peer Reviewed / Open Access
  • [Journal Article] Pathogenic variants detected by RNA sequencing in Cornelia de Lange syndrome2022

    • 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) Pages: 110468

    • DOI

      10.1016/j.ygeno.2022.110468

    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Patients with biallelic GGC repeat expansions in NOTCH2NLC exhibiting a typical neuronal intranuclear inclusion disease phenotype2022

    • Author(s)
      Kameyama S, Mizuguchi T, Doi H, Koyano S, Okubo M, Tada M, Shimizu H, Fukuda H, Tsuchida N, Uchiyama Y, Koshimizu E, Hamanaka K, Fujita A, Misawa K, Miyatake S, Kanai K, Tanaka F, Matsumoto N.
    • Journal Title

      Genomics

      Volume: Sep;114(5) Pages: 110469

    • DOI

      10.1016/j.ygeno.2022.110469

    • Peer Reviewed / Open Access
  • [Journal Article] A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode2022

    • Author(s)
      Marafi D, Kozar N, Duan R, Bradley S, Yokochi K, Kato M, Arai H, Miyatake S, Matsumoto N, Wagner M.
    • Journal Title

      Am J Hum Genet

      Volume: Sep 1;109(9) Pages: 1713-1723

    • DOI

      10.1016/j.ajhg.2022.07.006

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] De novo heterozygous variants in KIF5B cause kyphomelic dysplasia2022

    • Author(s)
      Itai T, Wang Z, Nishimura G, Ohashi H, Guo L, Wakano Y, Sugiura T, Hayakawa H, Okada M, Saisu T, Kitta A, Doi H, Kurosawa K, Hotta Y, Hosono K, Sato M, Shimizu K, Takikawa K, Watanabe S, Ikeda N, Suzuki M, Fujita A, Uchiyama Y, Tsuchida N, Miyatake S, Miyake N, Matsumoto N, Ikegawa S.
    • Journal Title

      Clin Genet

      Volume: Jul;102(1) Pages: 3-11

    • DOI

      10.1111/cge.14133

    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Actin-binding protein filamin-A drives tau aggregation and contributes to progressive supranuclear palsy pathology2022

    • Author(s)
      Tsujikawa K, Hamanaka K, Riku Y, Miyatake S, Japanese Longitudinal Biomarker Study in PSP and CBD (JALPAC) Consortium; Sobue G, Matsumoto N, Sahashi K, Katsuno M.
    • Journal Title

      Sci Adv

      Volume: May 27;8(21) Pages: eabm5029

    • DOI

      10.1126/sciadv.abm5029

    • Peer Reviewed / Open Access
  • [Journal Article] Repeat conformation heterogeneity in cerebellar ataxia, neuropathy, vestibular areflexia syndrome2022

    • Author(s)
      Miyatake S, Yoshida K, Koshimizu E, Doi H, Tanaka F, Mizuguchi T, Matsumoto N.
    • Journal Title

      Brain

      Volume: Apr 29;145(3) Pages: 1139-1150

    • DOI

      10.1093/brain/awab363

    • Peer Reviewed
  • [Journal Article] Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants2022

    • 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: Apr 26;14(1) Pages: 40

    • DOI

      10.1186/s13073-022-01042-w

    • Peer Reviewed / Open Access
  • [Journal Article] Long-term course of early onset developmental and epileptic encephalopathy associated with 2q24.3 microduplication2022

    • Author(s)
      Masuda T, Osaka H, Tsuchida N, Miyatake S, Nishimura K, Takenouchi T, Takahashi T, Matsumoto N, Yamagata T.
    • Journal Title

      Epilepsy Behav Rep

      Volume: Apr 25;19 Pages: 100547

    • DOI

      10.1016/j.ebr.2022.100547

    • Peer Reviewed / Open Access
  • [Presentation] CANVASはrepeat conformation heterogeneityを有する2022

    • Author(s)
      宮武聡子
    • Organizer
      日本人類遺伝学会第67回大会
  • [Presentation] ホットトピックス06: 小児神経疾患の分子機構最前線~成人との懸け橋2022

    • Author(s)
      宮武聡子
    • Organizer
      第63回日本神経学会学術大会
    • Invited
  • [Presentation] 教育コース08: 神経内科医が知っておきたい小児神経2022

    • Author(s)
      宮武聡子
    • Organizer
      第63回日本神経学会学術大会
    • Invited
  • [Presentation] Cerebellar ataxia, neuropathy, vestibular areflexia syndrome has repeat conformation heterogeneity2022

    • Author(s)
      宮武聡子
    • Organizer
      第63回日本神経学会学術大会

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Published: 2023-12-25  

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