Comprehensive analysis of causative gene in familial congenital heart disease by whole exome analysis

• Project/Area Number: 19K17357
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 52050:Embryonic medicine and pediatrics-related
• Research Institution: Nagoya University
• Principal Investigator: YAMAMOTO Hidenori 名古屋大学, 医学部附属病院, 医員 (80801662)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 先天性心疾患 / 全エクソーム解析 / プロテオーム解析 / チロシンキナーゼ / 22q11.2欠失症候群 / リン酸化プロテオーム解析 / エクソーム解析 / 心室中隔欠損症 / 房室中隔欠損症 / 次世代シークエンサー

Outline of Research at the Start

先天性心疾患は頻度が高く、生命予後に大きな影響を与えるが、多くは多因子遺伝である一方で、一部家族性に発症する例がある。家族性の先天性心疾患では、家系内で心疾患の種類が異なる場合も多く、候補遺伝子の特定を困難にする要因の一つであると考えられる。本研究の目的は家系内で同一の先天性心疾患の家系（心室中隔欠損症家系と房室中隔欠損症家系）の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ことである。本研究の成果は、心臓の中隔が欠損する心室中隔欠損症、房室中隔欠損症の発症機序や病態の解明と、疾患の適切な管理と遺伝カウンセリングにつながると考えられる。

Outline of Final Research Achievements

The causative genes were searched for in 3 families with hereditary congenital heart disease, which were revealed in all families.
One of them was a novel mutation in ABL1. The onset mechanism of congenital heart disease due to abnormal ABL1 has not been elucidated at all, and experiments using cultured cells revealed increased phosphorylation of UFD1. We reported this as the first study to examine the onset mechanism of congenital heart disease associated with ABL1 abnormalities.
In the other two families, new gene abnormalities of TBX20 (submitting) and gene Y (preparing for functional analysis experiment) were found, respectively.

Academic Significance and Societal Importance of the Research Achievements

先天性心疾患の約10%が単一遺伝子異常に由来すると考えられているが、本研究で対象としたような多数の発症者を含む大家系では、網羅的遺伝子解析を行うことで、非常に高率に原因遺伝子が判明することが示された。
単一遺伝子異常に由来する先天性心疾患は、原因遺伝子によって発症しうる心疾患がある程度予測可能であるため、原因遺伝子を判明させることは、次子・次世代の発症リスクの予測や、将来的には出生前診断、着床前診断に有用となる可能性が示唆される。

Research Products

• [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] 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] Influence of Percutaneous Occlusion of Atrial Septal Defect on Left Atrial Function Evaluated Using 2D Speckle Tracking Echocardiography (2020)
  • Author(s): Suzuki Kazutaka、Kato Taichi、Koyama Satoshi、Shinohara Tsutomu、Inukai Sachiko、Sato Jun、Yamamoto Hidenori、Omori Daisuke、Yoshida Shuichiro、Takeda Sho、Nishikawa Hiroshi、Ohashi Naoki、Sakurai Hajime、Saitoh Shinji
  • Journal Title: International Heart Journal Volume: 61 Issue: 1 Pages: 83-88
  • DOI: 10.1536/ihj.19-173
  • NAID: 130007792792
  • ISSN: 1349-2365, 1349-3299
  • Year and Date: 2020-01-31
  • Peer Reviewed
• [Journal Article] Mesenchymal stem/stromal cells stably transduced with an inhibitor of CC chemokine ligand 2 ameliorate bronchopulmonary dysplasia and pulmonary hypertension (2020)
  • Author(s): Suzuki Toshihiko、Sato Yoshiaki、Yamamoto Hidenori、Kato Taichi、Kitase Yuma、Ueda Kazuto、Mimatsu Haruka、Sugiyama Yuichiro、Onoda Atsuto、Saito Shigeki、Takahashi Yoshiyuki、Nakayama Takayuki、Hayakawa Masahiro
  • Journal Title: Cytotherapy Volume: - Issue: 4 Pages: 180-192
  • DOI: 10.1016/j.jcyt.2020.01.009
  • Peer Reviewed
• [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] 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
• [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
• [Presentation] TBX20新規9塩基欠失が確認された遺伝性心中隔欠損の1家系 (2021)
  • Author(s): 山本英範、早野聡、森本美仁、郷清貴、深澤佳絵、加藤太一
  • Organizer: 第130回東海小児循環器談話会
• [Presentation] ABL1変異は先天性心疾患を伴う症候群の原因となる～エクソーム解析と質量分析法を応用した遺伝性心室中隔欠損症の網羅的病態解明～ (2020)
  • Author(s): 山本英範、早野聡、奥野友介、小野田淳人、加藤耕治、長井典子、深澤佳絵、齋藤伸治、高橋義行、加藤太一
  • Organizer: 第56回日本小児循環器学会総会・学術集会
• [Presentation] 早産児慢性肺疾患に合併する肺高血圧症のモデルラット作成および網羅的病態解明 (2019)
  • Author(s): 山本英範、深澤佳絵、小野田淳人、三浦良介、呉尚治、沼口敦、佐藤義朗、加藤太一
  • Organizer: 第55回日本小児循環器学会