Establishment of comprehensive gene analysis of Noonan syndrome and related disorders

• Project/Area Number: 26461520
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Tohoku University
• Principal Investigator: Niihori Tetsuya 東北大学, 医学系研究科, 准教授 (40436134)
• Co-Investigator(Kenkyū-buntansha): 松原 洋一 国立研究開発法人国立成育医療研究センター, 所長室, 研究所長 (00209602) ; 青木 洋子 東北大学, 医学系研究科, 教授 (80332500)
• Research Collaborator: Umeki Ikumi
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: ヌーナン症候群 / コステロ症候群 / CFC症候群 / 遺伝子解析 / 次世代シークエンサー / NGS

Outline of Final Research Achievements

NGS enables comprehensive gene analysis of Noonan syndrome and related disorders. However, there are problems about cost and flexibility of target design. To solve these problems, we established a gene analysis system using multiplex PCR and NGS. We analyzed total 48 samples including positive controls. The results were acceptable, though minor modifications were needed.

Research Products

• [Journal Article] A patient with a novel purine-rich element binding protein A (PURA) mutation. (2017)
  • Author(s): Okamoto N, Nakao H, Niihori T, Aoki Y.
  • Journal Title: Congenit Anom (Kyoto) Volume: 印刷中 Issue: 6 Pages: 201-204
  • DOI: 10.1111/cga.12214
  • Peer Reviewed
• [Journal Article] Human genetic variation database, a reference database of genetic variations in the Japanese population. (2016)
  • Author(s): Higasa K, Miyake N, Yoshimura J, Okamura K, Niihori T, Saitsu H, Doi K, Shimizu M, Nakabayashi K, Aoki Y, Tsurusaki Y, Morishita S, Kawaguchi T, Migita O, (中略), Matsumoto N, Matsuda F.
  • Journal Title: J Hum Genet. Volume: advance online publication Issue: 6 Pages: 547-553
  • DOI: 10.1038/jhg.2016.12
  • Peer Reviewed / Open Access
• [Journal Article] Spectrum of mutations and genotype-phenotype analysis in Noonan syndrome patients with RIT1 mutations. (2016)
  • Author(s): Yaoita M, Niihori T, Mizuno S, Okamoto N, Hayashi S, Watanabe A, Yokozawa M, Suzumura H, Nakahara A, Nakano Y, Hokosaki T, Ohmori A, Sawada H, Migita O, Mima A, Lapunzina P, Santos-Simarro F, García-Miñaúr S, Ogata T, Kawame H, Kurosawa K, Ohashi H, Inoue S, Matsubara Y, Kure S, Aoki Y.
  • Journal Title: Hum Genet. Volume: 135 Issue: 2 Pages: 209-222
  • DOI: 10.1007/s00439-015-1627-5
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Recent advances in RASopathies. (2016)
  • Author(s): Aoki Y, Niihori T, Inoue S, Matsubara Y.
  • Journal Title: J Hum Genet. Volume: 61 Issue: 1 Pages: 33-39
  • DOI: 10.1038/jhg.2015.114
  • NAID: 40020859216
  • Peer Reviewed
• [Journal Article] Mutations in MECOM, Encoding Oncoprotein EVI1, Cause Radioulnar Synostosis with Amegakaryocytic Thrombocytopenia. (2015)
  • Author(s): Niihori T, Ouchi-Uchiyama M, Sasahara Y, Kaneko T, Hashii Y, Irie M, Sato A, Saito-Nanjo Y, Funayama R, Nagashima T, Inoue S, Nakayama K, Ozono K, Kure S, Matsubara Y, Imaizumi M, Aoki Y.
  • Journal Title: Am J Hum Genet. Volume: 97 Issue: 6 Pages: 848-854
  • DOI: 10.1016/j.ajhg.2015.10.010
  • Peer Reviewed / Open Access
• [Journal Article] Adult mice expressing a Braf Q241R mutation on an ICR/CD-1 background exhibit a cardio-facio-cutaneous syndrome phenotype. (2015)
  • Author(s): Moriya M, Inoue S, Miyagawa-Tomita S, Nakashima Y, Oba D, Niihori T, Hashi M, Ohnishi H, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Hum Mol Genet. Volume: 24 Issue: 25 Pages: 7349-7360
  • DOI: 10.1093/hmg/ddv435
  • Peer Reviewed
• [Journal Article] Somatic BRAF c.1799T>A p.V600E Mosaicism syndrome characterized by a linear syringocystadenoma papilliferum, anaplastic astrocytoma, and ocular abnormalities. (2015)
  • Author(s): Watanabe Y, Shido K, Niihori T, Niizuma H, Katata Y, Iizuka C, Oba D, Moriya K, Saito-Nanjo Y, Onuma M, Rikiishi T, Sasahara Y, Watanabe M, Aiba S, Saito R, Sonoda Y, Tominaga T, Aoki Y, Kure S.
  • Journal Title: Am J Med Genet A. Volume: 170 Issue: 1 Pages: 189-194
  • DOI: 10.1002/ajmg.a.37376
  • Peer Reviewed
• [Journal Article] A postzygotic NRAS mutation in a patient with Schimmelpenning syndrome. (2015)
  • Author(s): Kuroda Y, Ohashi I, Enomoto Y, Naruto T, Baba N, Tanaka Y, Aida N, Okamoto N, Niihori T, Aoki Y, Kurosawa K.
  • Journal Title: Am J Med Genet A. Volume: 167A Issue: 9 Pages: 2223-2225
  • DOI: 10.1002/ajmg.a.37135
  • Peer Reviewed
• [Journal Article] Genomic analysis identifies candidate pathogenic variants in 9 of 18 patients with unexplained West syndrome. (2015)
  • Author(s): Hino-Fukuyo N, Kikuchi A, Arai-Ichinoi N, Niihori T, Sato R, Suzuki T, Kudo H, Sato Y, Nakayama T, Kakisaka Y, Kubota Y, Kobayashi T, Funayama R, Nakayama K, Uematsu M, Aoki Y, Haginoya K, Kure S.
  • Journal Title: Hum Genet. Volume: 134 Issue: 6 Pages: 649-658
  • DOI: 10.1007/s00439-015-1553-6
  • Peer Reviewed / Open Access
• [Journal Article] Mutations in PIGL in a patient with Mabry syndrome. (2015)
  • Author(s): Fujiwara I, Murakami Y, Niihori T, Kanno J, Hakoda A, Sakamoto O, Okamoto N, Funayama R, Nagashima T, Nakayama K, Kinoshita T, Kure S, Matsubara Y, Aoki Y.
  • Journal Title: Am J Med Genet A. Volume: in press Issue: 4 Pages: 777-785
  • DOI: 10.1002/ajmg.a.36987
  • Peer Reviewed / Open Access
• [Journal Article] Targeted Next-Generation Sequencing Effectively Analyzed the Cystic Fibrosis Transmembrane Conductance Regulator Gene in Pancreatitis. (2015)
  • Author(s): Nakano E, Masamune A, Niihori T, Kume K, Hamada S, Aoki Y, Matsubara Y, Shimosegawa T.
  • Journal Title: Dig Dis Sci. Volume: - Issue: 5 Pages: 1297-1307
  • DOI: 10.1007/s10620-014-3476-9
  • Peer Reviewed
• [Journal Article] A novel heterozygous MAP2K1 mutation in a patient with Noonan syndrome with multiple lentigines. (2015)
  • Author(s): Nishi E, Mizuno S, Nanjo Y, Niihori T, Fukushima Y, Matsubara Y, Aoki Y, Kosho T.
  • Journal Title: Am J Med Genet A. Volume: 167 Issue: 2 Pages: 407-411
  • DOI: 10.1002/ajmg.a.36842
  • Peer Reviewed
• [Journal Article] GNE myopathy associated with congenital thrombocytopenia: a report of two siblings. (2014)
  • Author(s): Izumi R, Niihori T, Suzuki N, Sasahara Y, Nishiyama A, Nishiyama S, Endo K, Kato M, Warita H, Konno H, Tateyama M, Nagashima T, Funayama R, Nakayama K, Kure S, Matsubara Y, Aoki Y, Aoki M.
  • Journal Title: Neuromuscul. Disord. Volume: 24(12) Issue: 12 Pages: 1068-1072
  • DOI: 10.1016/j.nmd.2014.07.008
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] New BRAF knockin mice provide a pathogenetic mechanism of developmental defects and a therapeutic approach in cardio-facio-cutaneous syndrome. (2014)
  • Author(s): Inoue S. I. et al.
  • Journal Title: Hum. Mol. Genet. Volume: 23 Issue: 24 Pages: 6553-6566
  • DOI: 10.1093/hmg/ddu376
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Mutations in MECOM, encoding oncoprotein EVI1, cause radioulnar synostosis with amegakaryocytic thrombocytopenia (2016)
  • Author(s): Niihori T, Ouchi-Uchiyama M, Sasahara Y, Kaneko T, Hashii Y, Irie M, Sato A, Saito-Nanjo Y, Funayama R, Nagashima T, Inoue S, Nakayama K, Ozono K, Kure S, Matsubara Y, Imaizumi M, Aoki Y
  • Organizer: 13th ICHG
  • Place of Presentation: 国立京都国際会館（京都市）
  • Year and Date: 2016-04-03
  • Int'l Joint Research
• [Presentation] 次世代シークエンサーを用いた希少遺伝性難病病因遺伝子の探索 (2014)
  • Author(s): 新堀哲也、井泉瑠美子、西山亜由美、矢尾板全子、大場大樹、守谷充司、井上晋一、舟山亮、城田松之、中山啓子、松原洋一、青木洋子
  • Organizer: 第３回生命医薬情報学連合大会
  • Place of Presentation: 仙台国際センター（仙台市）
  • Year and Date: 2014-10-02 – 2014-10-04