Discovery of the Molecular Pathogenesis of Tetralogy of Fallot Based on Personal Genomics

• Project/Area Number: 26860784
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: The University of Tokyo
• Principal Investigator: Inuzuka Ryo 東京大学, 医学部附属病院, 講師 (00597560)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2015: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2014: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 円錐動脈幹異常 / エクソーム解析 / 機能解析 / ファロー四徴症 / 先天性心疾患 / 網羅的遺伝子解析

Outline of Final Research Achievements

We performed whole exome analyses of 53 isolated cases with conotruncal anolies (including 3 cases with patent trucus arteriosus, 31 with tetralogy of Fallot and 21 cases with transposition of great arteries) and two families with tetralogy of Fallot. Exome analysis of the first family revealed JAG1 mutaion which has been reported to be related to Alagille syndrome. Asyptomatic mother of the proband had the same mutation, suggesting the low penetrance of the mutation. Six candidate genes were found from the analysis of the second family. We are now perfoming functional analysis using zebrafish for the one of the candidate genes, LZTR1, which is located at 22q11.2 lesion know to be related to pathogenesis of tetralogy of Fallot.

Research Products

• [Journal Article] Report from the Japanese Society of Pediatric Cardiology and Cardiac Surgery Research Committee on Cardio-Vascular Function in Adult Patients with Congenital Heart Disease: Mechanism of Aortic Root Dilation and Cardio-Vascular Function in Patients with Tetralogy of Fallot. (2016)
  • Author(s): Seki M, Kuwata S, Kurishima C, Nakagawa R, Inuzuka R, Sugimoto M, Saiki H, Iwamoto Y, Ishido H, Masutani S, Senzaki H
  • Journal Title: Pediatr Int Volume: 未定 Issue: 5 Pages: 323-330
  • DOI: 10.1111/ped.12932
  • NAID: 130004879037
  • Peer Reviewed
• [Journal Article] Influence of Cardiac Function and Loading Conditions on the Myocardial Performance Index – Theoretical Analysis Based on a Mathematical Model – (2016)
  • Author(s): Inuzuka R, Kuwata S, Kurishima C, Liang F, Sughimoto K, Senzaki H.
  • Journal Title: Circulation Journal Volume: 80 Issue: 1 Pages: 148-156
  • DOI: 10.1253/circj.CJ-15-0598
  • NAID: 130005116979
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Peak oxygen uptake, ventilatory efficiency and QRS-duration predict event free survival in patients late after surgical repair of tetralogy of Fallot (2015)
  • Author(s): Müller J, Hager A, Diller GP, Derrick G, Buys R, Dubowy KO, Takken T, Orwat S, Inuzuka R, Vanhees L, Gatzoulis M, Giardini A
  • Journal Title: Int J Cardiol Volume: 196 Pages: 158-64
  • DOI: 10.1016/j.ijcard.2015.05.174
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Influence of Left Ventricular Stiffness on Hemodynamics in Patients With Untreated Atrial Septal Defects (2015)
  • Author(s): Kurishima, C.Inuzuka, R.Kuwata, S.Iwamoto, Y.Sugimoto, M.Saiki, H.Ishido, H.Masutani, S.Senzaki, H.
  • Journal Title: Circulation Journal Volume: 79 Issue: 8 Pages: 1823-1827
  • DOI: 10.1253/circj.CJ-14-1351
  • NAID: 130005089353
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed
• [Presentation] Whole exome sequencing of a monozygotic twin pair discordant for congenital heart defects (2015)
  • Author(s): Yu Nakagama, Ryo Inuzuka, Katsutoshi Nakano, Yu Tanaka, Takahira Kasagami, Takahiro Shindo, Yoichiro Hirata, Nobutaka Shimizu, Akira Oka
  • Organizer: The 32nd International Society for Heart Research Congress
  • Place of Presentation: 神戸国際会議場（神戸市・中央区）
  • Year and Date: 2015-12-10
  • Int'l Joint Research
• [Presentation] 収縮末期圧距離関係（ESPDR）と前負荷動員一回仕事量（PRSW）の生理学的関係についての検討 (2015)
  • Author(s): 犬塚 亮、先崎 秀明
  • Organizer: 第35回日本小児循環動態研究会
  • Place of Presentation: 千葉市文化センター（千葉市・中央区）
  • Year and Date: 2015-10-24
• [Presentation] Preload recruitable stroke workのsingle-beatからの予測(Single-beat Estimation of Preload Recruitable Stroke Work) (2015)
  • Author(s): 犬塚 亮, 先崎 秀明
  • Organizer: 第51回日本小児循環器学会学術総会
  • Place of Presentation: ホテル日航東京（東京・港区）
  • Year and Date: 2015-07-16