Elucidation of the onset mechanism of human imprinting disorders using the method of methylation analysis with high-density DNA methylation arrays

• Project/Area Number: 15K15096
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Human genetics
• Research Institution: National Center for Child Health and Development
• Principal Investigator: Kagami Masayo 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 室長 (70399484)
• Co-Investigator(Kenkyū-buntansha): 中林 一彦 国立研究開発法人国立成育医療研究センター, 周産期病態研究部, 室長 (10415557) ; 松原 圭子 国立研究開発法人国立成育医療研究センター, 分子内分泌研究部, 研究員 (90542952)
• Co-Investigator(Renkei-kenkyūsha): TAKADA SHUJI (20382856)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2015: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: エピジェネティクス / インプリンティング / DNAメチル化 / MLID / インプリンティング異常症 / メチル化解析 / アレイ / 網羅的 / 網羅的メチル化解析

Outline of Final Research Achievements

Patients with multiple imprinting disturbance (MLID) show abnormal methylation levels in the multiple differentially methylated regions (DMRs), however, the frequencies, onset mechanism, and clinical features of MLID remain to be clarified. We screened 1300 patients with imprinting disorders by methylation analysis using pyrosequencing and detected 38 patients with MLID. Furthermore, we examined methylation levels of 43 DMRs using high-density DNA methylation arrays in 5 patients with Kagami-Ogata syndrome caused by epimutation and 4 patients with Temple syndrome (TS14) caused by epimutation. We detected first TS14 patients with MLID.

Research Products

• [Int'l Joint Research] St Olav's Hospital (Norway)
• [Int'l Joint Research] Department of Health, Hong Kong(中国)
• [Journal Article] Maternal uniparental disomy for chromosome 20: physical and endocrinological characteristics of five patient. (2018)
  • Author(s): Kawasima S, Nakmura A, Inoue T, Matsubara K, Horikawa R, Wakui K, Takano K, Fikushima Y, Tatematsu T, Mizuno S. Tsubaki J, Kure S, Matsubara Y, Ogata T, Fukami M, Kagami M
  • Journal Title: J Clin Endocrinol Metab. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of parent-of-origin methylation using the Illumina Infinium MethylationEPIC array platform. (2018)
  • Author(s): Mora JRH, Tayama C, Sanchez-Delgado M, Monteagudo-Sanchez A, Hata K, Ogata T, Medrano J, Eugenia Poo-Llanill M, Simón C, Moran S, Esteller M, Tenorio J, Lapunzina P, Kagami M, Monk D, Nakabayashi K
  • Journal Title: Epigenomics Volume: 印刷中
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A case of paternal uniparental isodisomy for chromosome 7 associated with overgrowth (2018)
  • Author(s): Nakamura Akie、Muroya Koji、Ogata-Kawata Hiroko、Nakabayashi Kazuhiko、Matsubara Keiko、Ogata Tsutomu、Kurosawa Kenji、Fukami Maki、Kagami Masayo
  • Journal Title: J Med Genet Volume: 55 Issue: 8 Pages: 2017-104986
  • DOI: 10.1136/jmedgenet-2017-104986
  • Peer Reviewed
• [Journal Article] Effectiveness of Sodium-Glucose Cotransporter-2 Inhibitor as an Add-on Drug to GLP-1 Receptor Agonists for Glycemic Control of a Patient with Prader-Willi Syndrome: A Case Report. (2018)
  • Author(s): Horikawa Y, Enya M, Komagata M, Hashimotoi KI, Kagami M, Fukami M, Takeda J.
  • Journal Title: Diabetes Ther. Volume: 9 Issue: 1 Pages: 421-426
  • DOI: 10.1007/s13300-018-0369-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A 3-year-old girl with 46,XX,upd(14)mat/47,XX,+14 mosaicism. (2018)
  • Author(s): Ushijima K, Yatsuga S, Nakamura A, Fukami M, Kagami M.
  • Journal Title: J Hum Genet. Volume: 63 Issue: 3 Pages: 377-381
  • DOI: 10.1038/s10038-017-0381-z
  • Peer Reviewed
• [Journal Article] (Epi)genotype-Phenotype Analysis in 69 Japanese Patients With Pseudohypoparathyroidism Type I (2017)
  • Author(s): Sano Shinichiro、Nakamura Akie、Matsubara Keiko、Nagasaki Keisuke、Fukami Maki、Kagami Masayo、Ogata Tsutomu
  • Journal Title: J Endocr Soc Volume: 2 Issue: 1 Pages: 9-23
  • DOI: 10.1210/js.2017-00293
  • Peer Reviewed / Open Access
• [Journal Article] Mosaic upd(14)pat in a patient with mild features of Kagami-Ogata syndrome (2017)
  • Author(s): Haug Marte G.、Brendehaug Atle、Houge Gunnar、Kagami Masayo、Ogata Tsutomu
  • Journal Title: Clin Case Rep Volume: 6 Issue: 1 Pages: 91-95
  • DOI: 10.1002/ccr3.1300
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A de novo 50-bp <b><i>GNAS</i></b> Intragenic Duplication in a Patient with Pseudohypoparathyroidism Type 1a (2017)
  • Author(s): Suzuki Erina、Bo Ryosuke、Sue Kaori、Awano Hiroyuki、Ogata Tsutomu、Narumi Satoshi、Kagami Masayo、Sano Shinichiro、Fukami Maki
  • Journal Title: Cytogenetic and Genome Research Volume: 153 Issue: 3 Pages: 125-130
  • DOI: 10.1159/000485644
  • Peer Reviewed
• [Journal Article] Sustained endocrine profiles of a girl with WAGR syndrome (2017)
  • Author(s): Takada Yui、Sakai Yasunari、Matsushita Yuki、Ohkubo Kazuhiro、Koga Yuhki、Akamine Satoshi、Torio Michiko、Ishizaki Yoshito、Sanefuji Masafumi、Torisu Hiroyuki、Shaw Chad A.、Kagami Masayo、Hara Toshiro、Ohga Shouichi
  • Journal Title: BMC Medical Genetics Volume: 18 Issue: 1 Pages: 117-117
  • DOI: 10.1186/s12881-017-0477-5
  • Peer Reviewed / Open Access
• [Journal Article] Continuous hypomethylation of the KCNQ1OT1:TSS-DMR in monochorionic twins discordant for Beckwith-Wiedemann syndrome (2017)
  • Author(s): Inoue Takanobu、Nakamura Akie、Matsubara Keiko、Nyuzuki Hiromi、Nagasaki Keisuke、Oka Akira、Fukami Maki、Kagami Masayo
  • Journal Title: American Journal of Medical Genetics Part A Volume: 173 Issue: 10 Pages: 2847-2850
  • DOI: 10.1002/ajmg.a.38419
  • Peer Reviewed
• [Journal Article] Maternally derived 15q11.2-q13.1 duplication and H19-DMR hypomethylation in a patient with Silver?Russell syndrome (2017)
  • Author(s): Dateki Sumito、Kagami Masayo、Matsubara Keiko、Izumi Kei、Watanabe Satoshi、Nakatomi Akiko、Kondoh Tatsuro、Fukami Maki、Moriuchi Hiroyuki
  • Journal Title: Journal of Human Genetics Volume: 62 Issue: 10 Pages: 919-922
  • DOI: 10.1038/jhg.2017.62
  • NAID: 120006987395
  • Peer Reviewed
• [Journal Article] Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients (2017)
  • Author(s): Kagami Masayo、Nagasaki Keisuke、Kosaki Rika、Horikawa Reiko、Naiki Yasuhiro、Saitoh Shinji、Tajima Toshihiro、Yorifuji Tohru、Numakura Chikahiko、Mizuno Seiji、Nakamura Akie、Matsubara Keiko、Fukami Maki、Ogata Tsutomu
  • Journal Title: Genet Med Volume: 19 Issue: 12 Pages: 1356-1366
  • DOI: 10.1038/gim.2017.53
  • Peer Reviewed / Open Access
• [Journal Article] Genetic heterogeneity of patients with suspected Silver-Russell syndrome: genome-wide copy number analysis in 82 patients without imprinting defects. (2017)
  • Author(s): Inoue T, Nakamura A, Fuke T, Yamazawa K, Sano S, Matsubara K, Mizuno S, Matsukura Y, Harashima C, Hasegawa T, Nakajima H, Tsumura K, Kizaki Z, Oka A, Ogata T, Fukami M, Kagami M.
  • Journal Title: Clin Epigenetics Volume: 9 Issue: 1 Pages: 52-52
  • DOI: 10.1186/s13148-017-0350-6
  • Peer Reviewed / Open Access
• [Journal Article] De novo IGF2 mutation on the paternal allele in a patient with Silver-Russell syndrome and ectrodactyly (2017)
  • Author(s): Yamoto Kaori、Saitsu Hirotomo、Nakagawa Norio、Nakajima Hisakazu、Hasegawa Tatsuji、Fujisawa Yasuko、Kagami Masayo、Fukami Maki、Ogata Tsutomu
  • Journal Title: Human mutation Volume: 38 Issue: 8 Pages: 953-958
  • DOI: 10.1002/humu.23253
  • Peer Reviewed
• [Journal Article] Genome-wide multilocus imprinting disturbance analysis in Temple syndrome and Kagami-Ogata syndrome. (2017)
  • Author(s): Kagami M, Matsubara K, Nakabayashi K, Nakamura A, Sano S, Okamura K, Hata K, Fukami M, Ogata T.
  • Journal Title: Genet Med. Volume: 19 Issue: 4 Pages: 476-482
  • DOI: 10.1038/gim.2016.123
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosis and management of Silver?Russell syndrome: first international consensus statement (2017)
  • Author(s): Wakeling Emma L、Brioude Frdric、Lokulo-Sodipe Oluwakemi、O'Connell Susan M.、Salem Jennifer、Bliek Jet、Canton Ana P. M.、Chrzanowska Krystyna H.、Davies Justin H.、Dias Renuka P.、Tsutomu Ogata
  • Journal Title: Nat Rev Endocrinol Volume: 13 Issue: 2 Pages: 105-124
  • DOI: 10.1038/nrendo.2016.138
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Silver-Russell syndrome in a patient with somatic mosaicism for upd(11)mat identified by buccal cell analysis (2017)
  • Author(s): Luk HM, Ivan Lo FM, Sano S, Matsubara K, Nakamura A, Ogata T, Kagami M.
  • Journal Title: Am J Med Genet A Volume: 170(7) Issue: 7 Pages: 1938-41
  • DOI: 10.1002/ajmg.a.37679
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A patient with Temple syndrome satisfying the clinical diagnostic criteria of Silver-Russell syndrome. (2016)
  • Author(s): Goto M, Kagami M, Nishimura G, Yamagata T
  • Journal Title: Am J Med Genet A. Volume: 170 Issue: 9 Pages: 2483-2485
  • DOI: 10.1002/ajmg.a.37827
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Complex Genomic Rearrangement Within the GNAS Region Associated With Familial Pseudohypoparathyroidism Type 1b. (2016)
  • Author(s): Nakamura A, Hamaguchi E, Horikawa R, Nishimura Y, Matsubara K, Sano S, Nagasaki K, Matsubara Y, Umezawa A, Tajima T, Ogata T, Kagami M, Okamura K, Fukami M.
  • Journal Title: J Clin Endocrinol Metab Volume: 101(7) Issue: 7 Pages: 2623-7
  • DOI: 10.1210/jc.2016-1725
  • Peer Reviewed / Open Access
• [Journal Article] Beckwith-Wiedemann syndrome and pseudohypoparathyroidism type Ib in a patient with multilocus methylation defects: a female-dominant phenomenon? (2016)
  • Author(s): Ｓｈｉｎｉｃｈｉｒｏ Ｓａｎｏ
  • Journal Title: Journal of Human Genetics Volume: 未定 Issue: 8 Pages: 765-9
  • DOI: 10.1038/jhg.2016.45
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sporadic pseudohypoparathyroidism type-1b with asymptomatic hypocalcemia. (2016)
  • Author(s): Goto M, Sano S, et al
  • Journal Title: Pediatr Int Volume: 58 Issue: 11 Pages: 1229-1231
  • DOI: 10.1111/ped.13096
  • Peer Reviewed
• [Journal Article] Chromosome 6q24 methylation defects are uncommon in childhood-onset non-autoimmune diabetes mellitus patients born appropriate- or large-for-gestational age (2016)
  • Author(s): Okuno M, Yorifuji T, Kagami M, Ayabe T, Urakami T, Kawamura T, Kikuchi N, Yokota I, Kikuchi T, Amemiya S, Suzuki J, Ogata T, Sugihara S, Fukami M, The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes (JSGIT)
  • Journal Title: Clinical Pediatric Endocrinology Volume: 25 Issue: 3 Pages: 99-102
  • DOI: 10.1297/cpe.25.99
  • NAID: 130005165826
  • ISSN: 0918-5739, 1347-7358
  • Peer Reviewed / Open Access
• [Journal Article] Combined steroidogenic characters of fetal adrenal and Leydig cells in childhood adrenocortical carcinoma. (2016)
  • Author(s): Fujisawa Y, Sakaguchi K, Ono H, Yamaguchi R, Kato F, Kagami M, Fukami M, Ogata T.
  • Journal Title: J Steroid Biochem Mol Biol. Volume: 159 Pages: 86-93
  • DOI: 10.1016/j.jsbmb.2016.02.031
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Risk assessment of medically assisted reproduction and advanced maternal ages in the development of Prader-Willi syndrome due to UPD(15)mat. (2016)
  • Author(s): Matsubara K, Murakami N, Fukami M, Kagami M, Nagai T, Ogata T
  • Journal Title: Clin Genet. Volume: 89(5) Issue: 5 Pages: 614-619
  • DOI: 10.1111/cge.12691
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome). (2015)
  • Author(s): Kagami M, Kurosawa K, Miyazaki O, Ishino F, Matsuoka K, Ogata T
  • Journal Title: Eur J Hum Genet. Volume: 23(11) Issue: 2 Pages: 1488-1498
  • DOI: 10.1038/jhg.2015.113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Comprehensive clinical studies in 34 patients with molecularly defined UPD(14)pat and related conditions (Kagami-Ogata syndrome) (2015)
  • Author(s): Kagami M, Kurosawa K, Miyazaki O, Ishino F, Matsuoka K, Ogata T
  • Journal Title: Eur J Hum Genet Volume: 2 Issue: 11 Pages: 1-8
  • DOI: 10.1038/ejhg.2015.13
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exploration of hydroxymethylation in Kagami-Ogata syndrome caused by hypermethylation of imprinting control regions. (2015)
  • Author(s): Matsubara K, Kagami M, Nakabayashi K, Hata K, Fukami M, Ogata T, Yamazawa K.
  • Journal Title: Clin Epigenetics Volume: 28;7(1) Issue: 1 Pages: 90-90
  • DOI: 10.1186/s13148-015-0124-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Epimutations of the IG-DMR and the MEG3-DMR at the 14q32.2 imprinted region in two patients with Silver-Russell syndrome-compatible phenotype. (2015)
  • Author(s): Kagami M, Mizuno S, Matsubara K, Nakabayashi K, Sano S, Fuke T, Fukami M, Ogata T.
  • Journal Title: Eur J Hum Genet. Volume: 23(8) Pages: 1062-1067
  • Peer Reviewed / Open Access
• [Journal Article] Prenatal findings and epimutations for paternal uniparental disomy for chromosome 14 syndrome. (2015)
  • Author(s): Watanabe T, Go H, Kagami M, Yasuda S, Nomura Y, Fujimori K.
  • Journal Title: J Obstet Gynaecol Res. Volume: 41(7): Issue: 7 Pages: 1133-1136
  • DOI: 10.1111/jog.12665
  • Peer Reviewed
• [Journal Article] Growth hormone deficiency in monozygotic twins with autosomal dominant pseudohypoparathyroidism type Ib (2015)
  • Author(s): Sano S, Iwata H, Matsubara K, Fukami M, Kagami M, Ogata T.
  • Journal Title: Endocrine Journal Volume: 62 Issue: 6 Pages: 523-529
  • DOI: 10.1507/endocrj.EJ15-0033
  • NAID: 130005085768
  • ISSN: 0918-8959, 1348-4540
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Abnormalities in chromosome 6q24 as a cause of early-onset, non-obese, non-autoimmune diabetes mellitus without history of neonatal diabetes. (2014)
  • Author(s): Yorifuji T, Matsubara K, Sakakibara A, Hashimoto Y, Kawakita R, Hosokawa Y, Fujimaru R, Murakami A, Tamagawa N, Hatake K, Nagasaka H, Suzuki J, Urakami T, Izawa M, Kagami M.
  • Journal Title: Diabet Med. Volume: ? Issue: 7 Pages: 963-967
  • DOI: 10.1111/dme.12758
  • Peer Reviewed
• [Presentation] 片親性ダイソミー：両親の年齢と生殖補助医療 (2017)
  • Author(s): 鏡雅代
  • Organizer: 第40回日本分子生物学会
  • Invited
• [Presentation] Kagami-Ogata症候群 (2017)
  • Author(s): 鏡雅代
  • Organizer: 第62回日本人類遺伝学会
  • Invited
• [Presentation] Kagami-Ogata症候群 (2017)
  • Author(s): 鏡雅代
  • Organizer: nordiscience forum 2017
  • Invited
• [Presentation] Temple syndrome: comprehensive molecular and clinical findings in 32 Japanese patients (2017)
  • Author(s): Masayo Kagami et al.
  • Organizer: ESHG 2017
  • Int'l Joint Research
• [Presentation] Kagami-Ogata 症候群: 疾患概念の確立とその病態 (2016)
  • Author(s): 鏡 雅代
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-09
  • Invited
• [Presentation] 当研究室で同定した132 名の片親性ダイソミーにおける両親の年齢および生殖補助医療についての検討 (2016)
  • Author(s): 鏡 雅代、松原 圭子、中村 明枝、井上 毅信、佐野 伸一朗、緒方 勤、深見 真紀
  • Organizer: 第39回日本小児遺伝学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-12-09
  • Int'l Joint Research
• [Presentation] Comprehensive clinical studies in 30 patients molecularly diagnosed with Temple syndrome (2016)
  • Author(s): Masayo Kagami, Keisuke Nagasaki, Rika Kosaki, Horikawa Reiko, Yasuhiro Naiki, Shinji Saitoh, Toshihiro Tajima, Akie Nakamura, Keiko Matsubara, Maki Fukami, Tsutomu Ogata
  • Organizer: 第50回日本小児内分泌学会学術集会・第9回アジア太平洋小児内分泌学会
  • Place of Presentation: 東京
  • Year and Date: 2016-11-19
  • Int'l Joint Research
• [Presentation] シルバーラッセル症候群 診療ガイドライン. (2016)
  • Author(s): 鏡雅代
  • Organizer: 第50回日本小児内分泌学会学術集会・第9回アジア太平洋小児内分泌学会
  • Place of Presentation: 東京
  • Year and Date: 2016-11-16
  • Int'l Joint Research / Invited
• [Presentation] 胎児期発育異常を示すインプリンティング異常症 (2016)
  • Author(s): 鏡雅代
  • Organizer: 新生児科指導医養成事業 第5回教育セミナー
  • Place of Presentation: 仙台
  • Year and Date: 2016-05-02
  • Invited
• [Presentation] Kagami-Ogata syndrome: Clinically recognizable imprinting disorder caused by upd(14)pat and related condition (2016)
  • Author(s): Masayo Kagami
  • Organizer: The 13th International Congress of Human Genetics
  • Place of Presentation: 京都
  • Year and Date: 2016-04-06
  • Int'l Joint Research / Invited
• [Presentation] Kagami-Ogata syndrome: Clinically recognizable imprinting disorder caused by upd(14) pat and related condition (2016)
  • Author(s): Kagami M
  • Organizer: 2016 ICHG (The 13th International Congress of Human Genetics)
  • Place of Presentation: 京都
  • Year and Date: 2016-04-04
  • Int'l Joint Research / Invited
• [Presentation] ヒト 14 番染色体インプリンティング異常症患者における 14 番染色体インプリンティング領域のメチローム解析 (2015)
  • Author(s): 鏡雅代、早野崇英、細道一善、深見真紀、緒方勤、井ノ上逸朗
  • Organizer: 日本人類遺伝学会第60回大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-15
• [Presentation] Year book 4 臨床遺伝、橋渡し研究 (2015)
  • Author(s): 鏡雅代
  • Organizer: 第49回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
  • Invited
• [Presentation] 14番染色体インプリンティング異常症エピ変異例に対する網羅的DMRメチル化解析および臨床像についての検討 (2015)
  • Author(s): 鏡雅代、松原圭子、中林一彦、嘉村浩美、中村明枝、深見真紀、緒方勤
  • Organizer: 第49回日本小児内分泌学会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] Various imprinting disorders underlying Silver-Russell Syndrome-compatible phenotype (2015)
  • Author(s): Kagami M, Matsubara K, Sano S, Nakamura A, Mizuno S, Hamajima N, Yanagisawa A, Hashimoto M, Yukote A, Fukami M, Ogata T
  • Organizer: 54th European for Paediatric Endocrinolgy Annual Meeting
  • Place of Presentation: バルセロナ
  • Year and Date: 2015-10-01
  • Int'l Joint Research
• [Presentation] インプリンティング異常症 (2015)
  • Author(s): 鏡雅代
  • Organizer: 第35回日本小児病理研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2015-08-29
  • Invited