包括的エクソームデータ解析によるMarfan症候群および類縁疾患の責任遺伝子探索

2017 Fiscal Year Research-status Report

• Project/Area Number: 17K15630
• Research Institution: Yokohama City University
• Principal Investigator: 水口 剛 横浜市立大学, 医学部, 講師 (90404996)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 遺伝学 / ゲノム / 遺伝子 / 次世代シーケンス / 遺伝子変異 / 全エクソーム解析

Outline of Annual Research Achievements

Exome-wide 相関解析を単一遺伝子病であるマルファン症候群（MFS）および類縁疾患に適用し、従来の家系をベースとした遺伝学解析では同定できなかった遺伝要因の探索を行った。具体的には患者群（既知のMFS責任遺伝子異常を除外した431 例）および正常対照群のWhole Exome Sequencing (WES）データ（481 例）を用い、遺伝子単位で病的意義が高いと推定されるvariantが患者群において有意に集積する遺伝子を検討した（Burden test）。Burden test の結果、既知のMFS責任遺伝子FBN1 が検出されたが、これは遺伝子スクリーニングで見落とされたFBN1変異の検出を示唆し、Burden test が遺伝要因の探索に有用であることが明示された。候補遺伝子群について変異の頻度データ、遺伝子発現のパターン、既知責任遺伝子との機能的関連、機能的変異に関する不寛容性（ExACのPLI スコア、misZ スコアなど）を考慮し、候補遺伝子の絞り込みを行った。候補遺伝子のうち両親検体の協力が得られた家系についてSanger法による変異確認と、de novo の可能性を評価した。また上記WESデータに加えて、新たに本年度１０検体のMFSおよび類縁疾患の症例を集積した。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

Burden test においては頻度の低い稀なvariant を検定するため、遺伝的異質性や集団階層化が検出力に大きな影響を与える。MFS および類縁疾患の原因として頻度の高いFBN1/TGFBR1/TGFBR2 遺伝子変異を除外した日本人コホートは最適の研究対象であり、既に統計解析可能なWESデータを集積することができた。Exome-wide な解析により、バイアスの少ない新たなカテゴリーの疾患関連遺伝子の抽出が期待される

Strategy for Future Research Activity

検出に最適な疾患モデル（遺伝形式、浸透率、遺伝的異質性、変異の効果など）は未知のため、複数のタイプの相関解析が可能な公開ソフトウェア（RVTESTS,https://github.com/zhanxw/rvtests）を使用して今後も統計解析を進める。
統計学的な検出力を上げるため、正常対照群のデータ数を増やすことも検討している。
またWESデータを用いたコピー数異常に関する検討が不十分であるため、Exome Hidden Markov Model (XHMM) 法によるゲノムワイドコピー数解析を行う予定である。

Causes of Carryover

平成29年度は主に研究室のゲノム情報解析リソースを用いた遺伝統計学解析を中心に解析を進めたため次年度使用額が生じた。
この遺伝学解析の結果に基づいて平成30年度に実施を予定するゲノム解析および分子生物実験試薬の支払い等に使用する予定である。

Research Products

• [Journal Article] Loss-of-function and gain-of-function mutations in PPP3CA cause two distinct disorders (2018)
  • Author(s): Mizuguchi T, Nakashima M, Kato M, Okamoto N, Kurahashi H, Ekhilevitch N, Shiina M, Nishimura G, Shibata T, Matsuo M, Ikeda T, Ogata K, Tsuchida N, Mitsuhashi S, Miyatake S, Takata A, Miyake N, Hata K, Kaname T, Matsubara Y, Saitsu H, Matsumoto N.
  • Journal Title: Human Molecular Genetics Volume: 27 Pages: 1421～1433
  • DOI: 10.1093/hmg/ddy052
  • Peer Reviewed
• [Journal Article] A homozygous NOP14 variant is likely to cause recurrent pregnancy loss (2018)
  • Author(s): Suzuki Toshifumi、Behnam Mahdiyeh、Ronasian Firooze、Salehi Mansoor、Shiina Masaaki、Koshimizu Eriko、Fujita Atsushi、Sekiguchi Futoshi、Miyatake Satoko、Mizuguchi Takeshi、Nakashima Mitsuko、Ogata Kazuhiro、Takeda Satoru、Matsumoto Naomichi、Miyake Noriko
  • Journal Title: Journal of Human Genetics Volume: 63 Pages: 425～430
  • DOI: 10.1038/s10038-018-0410-6
  • Peer Reviewed
• [Journal Article] A novel homozygous DPH1 mutation causes intellectual disability and unique craniofacial features (2018)
  • Author(s): Sekiguchi Futoshi、Nasiri Jafar、Sedghi Maryam、Salehi Mansoor、Hosseinzadeh Majid、Okamoto Nobuhiko、Mizuguchi Takeshi、Nakashima Mitsuko、Miyatake Satoko、Takata Atsushi、Miyake Noriko、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 63 Pages: 487～491
  • DOI: 10.1038/s10038-017-0404-9
  • Peer Reviewed
• [Journal Article] De novo hotspot variants in CYFIP2 cause early-onset epileptic encephalopathy (2018)
  • Author(s): Nakashima Mitsuko、Kato Mitsuhiro、Aoto Kazushi、Shiina Masaaki、Belal Hazrat、Mukaida Souichi、Kumada Satoko、Sato Atsushi、Zerem Ayelet、Lerman-Sagie Tally、Lev Dorit、Leong Huey Yin、Tsurusaki Yoshinori、Mizuguchi Takeshi、Miyatake Satoko、Miyake Noriko、Ogata Kazuhiro、Saitsu Hirotomo、Matsumoto Naomichi
  • Journal Title: Annals of Neurology Volume: 83 Pages: 794～806
  • DOI: 10.1002/ana.25208
  • Peer Reviewed
• [Journal Article] Novel recessive mutations in MSTO1 cause cerebellar atrophy with pigmentary retinopathy (2018)
  • Author(s): Iwama Kazuhiro、Takaori Toru、Fukushima Ai、Tohyama Jun、Ishiyama Akihiko、Ohba Chihiro、Mitsuhashi Satomi、Miyatake Satoko、Takata Atsushi、Miyake Noriko、Ito Shuichi、Saitsu Hirotomo、Mizuguchi Takeshi、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 63 Pages: 263～270
  • DOI: 10.1038/s10038-017-0405-8
  • Peer Reviewed
• [Journal Article] A novel missense SNAP25b mutation in two affected siblings from an Israeli family showing seizures and cerebellar ataxia (2018)
  • Author(s): Fukuda Hiroyuki、Imagawa Eri、Hamanaka Kohei、Fujita Atsushi、Mitsuhashi Satomi、Miyatake Satoko、Mizuguchi Takeshi、Takata Atsushi、Miyake Noriko、Kramer Uri、Matsumoto Naomichi、Fattal-Valevski Aviva
  • Journal Title: Journal of Human Genetics Volume: 63 Pages: 673～676
  • DOI: 10.1038/s10038-018-0421-3
  • Peer Reviewed
• [Journal Article] A novel mutation in SLC1A3 causes episodic ataxia (2018)
  • Author(s): Iwama Kazuhiro、Iwata Aya、Shiina Masaaki、Mitsuhashi Satomi、Miyatake Satoko、Takata Atsushi、Miyake Noriko、Ogata Kazuhiro、Ito Shuichi、Mizuguchi Takeshi、Matsumoto Naomichi
  • Journal Title: Journal of Human Genetics Volume: 63 Pages: 207～211
  • DOI: 10.1038/s10038-017-0365-z
  • Peer Reviewed
• [Journal Article] Detection of copy number variations in epilepsy using exome data (2018)
  • Author(s): Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, Watanabe S, Chiyonobu T, Morimoto M, Ohta M, Kumakura A, Kubota M, Kumagai Y, Hamano SI, Mizuguchi T. et al.
  • Journal Title: Clinical Genetics Volume: 93 Pages: 577～587
  • DOI: 10.1111/cge.13144
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Novel biallelic SZT2 mutations in 3 cases of early-onset epileptic encephalopathy (2017)
  • Author(s): Tsuchida N, Nakashima M, Miyauchi A, Yoshitomi S, Kimizu T, Ganesan V, Teik KW, Ch'ng GS, Kato M, Mizuguchi T, Takata A, Miyatake S, Miyake N, Osaka H, Yamagata T, Nakajima H, Saitsu H, Matsumoto N
  • Journal Title: Clinical Genetics Volume: 93 Pages: 266～274
  • DOI: 10.1111/cge.13061
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A familial case of PDE10A-associated childhood-onset chorea with bilateral striatal lesions (2017)
  • Author(s): Miyatake S, Koshimizu E, Shirai I, Kumada S, Nakata Y, Kamemaru A, Nakashima M, Mizuguchi T, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: Movement Disorders Volume: 33 Pages: 177～179
  • DOI: 10.1002/mds.27219
  • Peer Reviewed
• [Journal Article] A novel missense mutation affecting the same amino acid as the recurrent PACS1 mutation in Schuurs-Hoeijmakers syndrome (2017)
  • Author(s): Miyake N, Ozasa S, Mabe H, Kimura S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N
  • Journal Title: Clinical Genetics Volume: 93 Pages: 929～930
  • DOI: 10.1111/cge.13105
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A novel GFI1B mutation at the first zinc finger domain causes congenital macrothrombocytopenia (2017)
  • Author(s): Uchiyama Y, Ogawa Y, Kunishima S, Shiina M, Nakashima M, Yanagisawa K, Yokohama A, Imagawa E, Miyatake S, Mizuguchi T, Takata A, Miyake N, Ogata K, Handa H, Matsumoto N
  • Journal Title: British Journal of Haematology Volume: － Pages: －
  • DOI: 10.1111/bjh.14710
  • Peer Reviewed
• [Journal Article] PARS2 and NARS2 mutations in infantile-onset neurodegenerative disorder (2017)
  • Author(s): Mizuguchi T, Nakashima M, Kato M, Yamada K, Okanishi T, Ekhilevitch N, Mandel H, Eran A, Toyono M, Sawaishi Y, Motoi H, Shiina M, Ogata K, Miyatake S, Miyake N, Saitsu H, Matsumoto N
  • Journal Title: Journal of Human Genetics Volume: 62 Pages: 525～529
  • DOI: 10.1038/jhg.2016.163
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] ANKRD11 variants cause variable clinical features associated with KBG syndrome and Coffin?Siris-like syndrome (2017)
  • Author(s): Miyatake S, Okamoto N, Stark Z, Nabetani M, Tsurusaki Y, Nakashima M, Miyake N, Mizuguchi T, Ohtake A, Saitsu H, Matsumoto N
  • Journal Title: Journal of Human Genetics Volume: 62 Pages: 741～746
  • DOI: 10.1038/jhg.2017.24
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Biallelic Mutations in MYPN , Encoding Myopalladin, Are Associated with Childhood-Onset, Slowly Progressive Nemaline Myopathy (2017)
  • Author(s): Miyatake S, Mitsuhashi S, Hayashi YK, Purevjav E, Nishikawa A, Koshimizu E, Suzuki M, Yatabe K, Tanaka Y, Ogata K, Kuru S, Shiina M, Tsurusaki Y, Nakashima M, Mizuguchi T, Miyake N, Saitsu H, Ogata K, Kawai M, Towbin J, Nonaka I, Nishino I, Matsumoto N
  • Journal Title: The American Journal of Human Genetics Volume: 100 Pages: 169～178
  • DOI: 10.1016/j.ajhg.2016.11.017
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of atypical Kabuki syndrome arising from a novel missense variant in HNRNPK (2017)
  • Author(s): Miyake N, Inaba M, Mizuno S, Shiina M, Imagawa E, Miyatake S, Nakashima M, Mizuguchi T, Takata A, Ogata K, Matsumoto N
  • Journal Title: Clinical Genetics Volume: 92 Pages: 554～555
  • DOI: 10.1111/cge.13023
  • Peer Reviewed
• [Journal Article] An atypical case of SPG56/CYP2U1-related spastic paraplegia presenting with delayed myelination (2017)
  • Author(s): Minase G, Miyatake S, Nabatame S, Arai H, Koshimizu E, Mizuguchi T, Nakashima M, Miyake N, Saitsu H, Miyamoto T, Sengoku K, Matsumoto N
  • Journal Title: Journal of Human Genetics Volume: 62 Pages: 997～1000
  • DOI: 10.1038/jhg.2017.77
  • Peer Reviewed
• [Journal Article] Identification of novel SNORD118 mutations in seven patients with leukoencephalopathy with brain calcifications and cysts (2017)
  • Author(s): Iwama K, Mizuguchi T, Takanashi JI, Shibayama H, Shichiji M, Ito S, Oguni H, Yamamoto T, Sekine A, Nagamine S, Ikeda Y, Nishida H, Kumada S, Yoshida T, Awaya T. et al.
  • Journal Title: Clinical Genetics Volume: 92 Pages: 180～187
  • DOI: 10.1111/cge.12991
  • Peer Reviewed
• [Journal Article] Mutations in genes encoding polycomb repressive complex 2 subunits cause Weaver syndrome (2017)
  • Author(s): Imagawa E, Higashimoto K, Sakai Y, Numakura C, Okamoto N, Matsunaga S, Ryo A, Sato Y, Sanefuji M, Ihara K, Takada Y, Nishimura G, Saitsu H, Mizuguchi T, Miyatake S, Nakashima M, Miyake N, Soejima H, Matsumoto N
  • Journal Title: Human Mutation Volume: 38 Pages: 637～648
  • DOI: 10.1002/humu.23200
  • Peer Reviewed / Int'l Joint Research