Exploratory research of causal genes by whole-exome sequencing in patients with familial WPW syndrome

• Project/Area Number: 19K08319
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya University
• Principal Investigator: FUKASAWA YOSHIE 名古屋大学, 医学部附属病院, 病院助教 (00612764)
• Co-Investigator(Kenkyū-buntansha): 加藤 太一 名古屋大学, 医学系研究科, 准教授 (20422777)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: WPW症候群 / PRKAG2遺伝子 / エクソーム解析 / PRKAG2 / 次世代シークエンサー

Outline of Research at the Start

WPW症候群は頻度が高い不整脈疾患であり、時に突然死を起こす。多くは孤発例だが、一部は家族性に発症する。家族性WPW症候群の原因遺伝子解析はSanger法を中心に行われていて、多くはPRKAG2遺伝子変異である。一方、この遺伝子に変異を認めない例も多く、未知の原因遺伝子が存在する可能性が高い。また、次世代シークエンサーによる遺伝子解析も一報の報告があるのみである。本研究はこれまでの報告で最大の7家系の家族性WPW症候群を対象に、原因遺伝子を次世代シークエンサーによる全エクソーム解析で同定する。本研究によって、家族性WPW症候群の発症機序や病態が明らかになり、適切な管理につながると考えられる。

Outline of Final Research Achievements

We conducted search for causal genes in 8 families with familial WPW syndrome by whole-exome sequencing. Only one family identified a pathogenic variant of PRKAG2 gene, already known as the causal gene of familial WPW syndrome. A missense mutation in a causal gene(gene X) of hypertrophic cardiomyopathy was confirmed in one family with WPW syndrome for more than 3 generations. There was no report of WPW syndrome caused by this gene variant, it was considered to be a novel phenotype. The causal gene couldn't detect in the other 6 families.
We planned an experimental functional analysis to prove that the pathogenic variant of gene X presents with WPW syndrome. We planned to create a model mouse using CRISPER-Cas9 and detect supraventricullar tachycardia caused by WPW syndrome with an implantable electrocardiograph, but we couldn't realize due to equipment and financial problems.

Academic Significance and Societal Importance of the Research Achievements

「家族性WPW症候群の原因遺伝子＝PRKAG2」として知られているが、意外にもPRKAG2遺伝子の病的バリアントを有する確率は低いことが示された。また、PRKAG2遺伝子変異でもWPW症候群と肥大型心筋症と合併することが多いと報告されているが、この度確認された遺伝子Xについても肥大型心筋症の原因遺伝子であり、両疾患の発症には共通する分子メカニズムが存在する可能性が示唆された。

Research Products

• [Journal Article] Conception by assisted reproductive technology in infants with critical congenital heart disease in Japan (2022)
  • Author(s): Morimoto Yoshihito、Go Kiyotaka、Yamamoto Hidenori、Fukasawa Yoshie、Nakai Michikazu、Morihana Eiji、Yasuda Kazushi、Nishikawa Hiroshi、Ohashi Naoki、Takahashi Yoshiyuki、Kato Taichi
  • Journal Title: Reproductive BioMedicine Online Volume: 44 Issue: 1 Pages: 163-170
  • DOI: 10.1016/j.rbmo.2021.10.005
  • Peer Reviewed / Open Access
• [Journal Article] Echocardiography Monitoring of Pulmonary Hypertension after Pediatric Hematopoietic Stem Cell Transplantation: Pediatric Pulmonary Arterial Hypertension and Pulmonary Veno-Occlusive Disease after Hematopoietic Stem Cell Transplantation (2021)
  • Author(s): Kawashima Nozomu、Fukasawa Yoshie、Nishikawa Eri、Ohta-Ogo Keiko、Ishibashi-Ueda Hatsue、Hamada Motoharu、Ichikawa Daisuke、Narita Atsushi、Okuno Yusuke、Muramatsu Hideki、Nishio Nobuhiro、Kojima Seiji、Kato Taichi、Takahashi Yoshiyuki
  • Journal Title: Transplantation and Cellular Therapy Volume: 27 Issue: 9 Pages: 786.e1-786.e8
  • DOI: 10.1016/j.jtct.2021.05.017
  • Peer Reviewed
• [Journal Article] Successful treatment of a novel type I interferonopathy due to a de novo PSMB9 gene mutation with a Janus kinase inhibitor (2021)
  • Author(s): Kataoka S, Kawashima N, Okuno Y, Muramatsu H, Miwata S, Narita K, Hamada M, Murakami N, Taniguchi R, Ichikawa D, Kitazawa H, Suzuki K, Nishikawa E, Narita A, Nishio N, Yamamoto H, Fukasawa Y, Kato T, Yamamoto H, Natsume J, Kojima S, Nishio I, Taketani T, Ohnishi H, Tahakashi Y.
  • Journal Title: Journal of Allergy and Clinical Immunology Volume: - Issue: 2 Pages: 639-644
  • DOI: 10.1016/j.jaci.2021.03.010
  • NAID: 120007192018
  • Peer Reviewed
• [Journal Article] Phosphorylated proteome analysis of a novel germline ABL1 mutation causing an autosomal dominant syndrome with ventricular septal defect (2021)
  • Author(s): Yamamoto Hidenori、Hayano Satoshi、Okuno Yusuke、Onoda Atsuto、Kato Kohji、Nagai Noriko、Fukasawa Yoshie、Saitoh Shinji、Takahashi Yoshiyuki、Kato Taichi
  • Journal Title: International Journal of Cardiology Volume: 326 Pages: 81-87
  • DOI: 10.1016/j.ijcard.2020.10.032
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prediction of postnatal clinical course in primary congenital dilated cardiomyopathy (2019)
  • Author(s): Yamamoto Hidenori、Fukasawa Yoshie、Ohashi Naoki、Yokoyama Takehiko、Suzuki Kazutaka、Ota Takaya、Yasuda Kazushi、Omoya Kentaro、Takahashi Yoshiyuki、Kato Taichi
  • Journal Title: Pediatrics International Volume: 61 Issue: 12 Pages: 1196-1201
  • DOI: 10.1111/ped.14029
  • Peer Reviewed
• [Journal Article] Severe fetal cardiomegaly caused by multiple non-giant placental chorioangiomas (2019)
  • Author(s): Yamamoto Hidenori、Fukasawa Yoshie、Kato Taichi
  • Journal Title: Cardiology in the Young Volume: 29 Issue: 12 Pages: 1559-1560
  • DOI: 10.1017/s1047951119002567
  • NAID: 120006847449
  • Peer Reviewed
• [Journal Article] Ventricular tachycardia and chest pain due to foreign body in the pericardium caused by self-injurious behaviour (2019)
  • Author(s): Yamamoto Hidenori、Fukasawa Yoshie、Kato Taichi
  • Journal Title: Cardiology in the Young Volume: 29 Issue: 09 Pages: 1217-1218
  • DOI: 10.1017/s1047951119001744
  • NAID: 120006847450
  • Peer Reviewed