Gene analysis for novel causative mutations in an inherited arrhythmia and determination of the underlying mechanism of arrhythmia

• Project/Area Number: 18K08100
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Kanazawa University
• Principal Investigator: Hayashi Kenshi 金沢大学, 保健学系, 准教授 (00422642)
• Co-Investigator(Kenkyū-buntansha): 野村 章洋 金沢大学, 附属病院, 特任准教授 (30707542) ; 藤野 陽 金沢大学, 保健学系, 准教授 (40361993)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: 遺伝性不整脈 / 次世代シーケンサー / 機能解析 / ゼブラフィッシュ / 網羅的遺伝子解析 / 全エクソーム解析 / 細胞電気生理

Outline of Final Research Achievements

Inherited arrhythmia can cause sudden cardiac death. It is important to determine the underlying mechanism and prevent the sudden cardiac death. We performed candidate gene analysis or whole exome sequence for inherited arrhythmia including long QT syndrome (n=66) Brugada syndrome (n=32), inherited bradyarrhythmia (n=32), arrhythmogenic right ventricular cardiomyopathy (n=17), and lone atrial fibrillation (n=6) using a next generation sequencer. We performed whole exome sequence of 23 probands diagnosed with early-onset (<65 years) inherited bradyarrhythmia and analysed 117 genes linked to arrhythmogenic diseases or cardiomyopathies. Of 23 inherited bradyarrhythmia probands, we successfully identified pathogenic or likely pathogenic variants in 11 probands (48%).

Academic Significance and Societal Importance of the Research Achievements

次世代シーケンサ－による網羅的遺伝子解析により、従来の方法で見逃されていた数多くの遺伝子変異を見出すことができた。これまで機能解析が困難だった非イオンチャネル遺伝子に対し、CRISPR/Cas9システムを用いてゼブラフィッシュの遺伝子改変を行い、ゼブラフィッシュ胚の心臓の光学マッピング、活動電位測定、体表面心電図測定といった画期的な方法で数日間以内に遺伝子変異の病的意義を明らかにすることができた。

Research Products

• [Int'l Joint Research] Brigham and Women's Hospital/Harvard Medical School(米国)
• [Journal Article] Association of proteinuria with incident atrial fibrillation in the general Japanese population (2021)
  • Author(s): Tanaka Y, Tada H, Hara S, Hayashi K, Patel RB, Nishikawa T, Hashiba A, Takamura M, Greenland P, Kawashiri MA.
  • Journal Title: J Cardiol. Volume: 77 Issue: 1 Pages: 100-105
  • DOI: 10.1016/j.jjcc.2020.08.001
  • Peer Reviewed
• [Journal Article] Myocyte-specific enhancer factor 2c triggers transdifferentiation of adipose tissue-derived stromal cells into spontaneously beating cardiomyocyte-like cells (2021)
  • Author(s): Takashima Shinichiro、Usui Soichiro、Inoue Oto、Goten Chiaki、Yamaguchi Kosei、Takeda Yusuke、Cui Shihe、Sakai Yoshio、Hayashi Kenshi、Sakata Kenji、Kawashiri Masa-aki、Takamura Masayuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1520-1520
  • DOI: 10.1038/s41598-020-80848-3
  • NAID: 120006957801
  • Peer Reviewed
• [Journal Article] Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. (2020)
  • Author(s): Hayashi K, et al.
  • Journal Title: Cardiovasc Res. Volume: 0 Issue: 13 Pages: 0-0
  • DOI: 10.1093/cvr/cvaa010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Risk Factors associated with ischemic stroke in Japanese patients with nonvalvular atrial fibrillation. (2020)
  • Author(s): Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, Hayashi K, Sawano S, Goya M, Yamashita T, Fukuda K, Ogawa H, Tsuda T, Isobe M, Toyoda K, Miyamoto Y, Miyata H, Okamura T, Sasahara Y for the J-RISK AF Research Group.
  • Journal Title: JAMA Network Open. Volume: 3 Issue: 4 Pages: e202881-e202881
  • DOI: 10.1001/jamanetworkopen.2020.2881
  • Peer Reviewed / Open Access
• [Journal Article] Serum sitosterol level predicting ABCG5 or ABCG8 genetic mutations (2020)
  • Author(s): Kojima Nobuko、Tada Hayato、Usui Soichiro、Sakata Kenji、Hayashi Kenshi、Nohara Atsushi、Inazu Akihiro、Takamura Masayuki、Kawashiri Masa-aki
  • Journal Title: Clinica Chimica Acta Volume: 507 Pages: 11-16
  • DOI: 10.1016/j.cca.2020.04.003
  • Peer Reviewed
• [Journal Article] Fulminant myocarditis and pulmonary cavity lesion induced by disseminated mucormycosis in a chronic hemodialysis patient: Report of an autopsied case. (2020)
  • Author(s): Fujisawa Y, Hara S, Zoshima T, Maekawa N, Inoue D, Sasaki M, Gamou T, Nagata Y, Hayashi K, Takeji A, Ito K, Mizushima I, Fujii H, Kawano M.
  • Journal Title: Pathol Int. Volume: Aug;70(8) Issue: 8 Pages: 557-562
  • DOI: 10.1111/pin.12943
  • Peer Reviewed
• [Journal Article] Transient swallowing‐induced atrial tachycardia in a patient with genotyped hypertrophic cardiomyopathy (2020)
  • Author(s): Fujino Noboru、Hayashi Kenshi、Sakata Kenji、Tada Hayato、Nakanishi Chiaki、Tsuda Toyonobu、Nomura Akihiro、Yoshida Shohei、Sakamoto Yuichiro、Kato Takeshi、Furusho Hiroshi、Kawashiri Masa‐aki、Takamura Masayuki
  • Journal Title: Clinical Case Reports Volume: 8 Issue: 9 Pages: 1809-1813
  • DOI: 10.1002/ccr3.3015
  • Peer Reviewed / Open Access
• [Journal Article] Prolongation of QT interval after pulmonary vein isolation for paroxysmal atrial fibrillation (2020)
  • Author(s): Chikata Akio、Kato Takeshi、Usuda Kazuo、Fujita Shuhei、Maruyama Michiro、Otowa Kan‐ichi、Usuda Keisuke、Niwa Satoru、Tsuda Toyonobu、Hayashi Kenshi、Takamura Masayuki
  • Journal Title: Journal of Cardiovascular Electrophysiology Volume: 31 Issue: 9 Pages: 2371-2379
  • DOI: 10.1111/jce.14625
  • Peer Reviewed
• [Journal Article] Personalized medicine for cardiovascular diseases (2020)
  • Author(s): Tada H, Fujino N, Nomura A, Nakanishi C, Hayashi K, Takamura M, Kawashiri MA.
  • Journal Title: J Hum Genet. Volume: 66 Issue: 1 Pages: 67-74
  • DOI: 10.1038/s10038-020-0818-7
  • Peer Reviewed
• [Journal Article] Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of consortium disease cohorts and population controls (2020)
  • Author(s): 2.Walsh R, Lahrouchi N, Tadros R, Kyndt F, Glinge C, Postema PG, et al.
  • Journal Title: Genetics in Medicine Volume: 23 Issue: 1 Pages: 47-58
  • DOI: 10.1038/s41436-020-00946-5
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Hokuriku-plus familial hypercholesterolaemia registry study: rationale and study design (2020)
  • Author(s): Tada Hayato、Kajinami Kouji、et al.
  • Journal Title: BMJ Open Volume: 10 Issue: 9 Pages: e038623-e038623
  • DOI: 10.1136/bmjopen-2020-038623
  • Peer Reviewed / Open Access
• [Journal Article] One Single Nucleotide Polymorphism of the TRPM2 Channel Gene Identified as a Risk Factor in Bipolar Disorder Associates With Autism Spectrum Disorder in a Japanese Population (2020)
  • Author(s): Mahmuda Naila Al、Yokoyama Shigeru、Munesue Toshio、Hayashi Kenshi、Yagi Kunimasa、Tsuji Chiharu、Higashida Haruhiro
  • Journal Title: Diseases Volume: 8 Issue: 1 Pages: 4-4
  • DOI: 10.3390/diseases8010004
  • Peer Reviewed / Open Access
• [Journal Article] Multiple Dynamical Mechanisms of Phase-2 Early Afterdepolarizations in a Human Ventricular Myocyte Model: Involvement of Spontaneous SR Ca (2+) Release. (2020)
  • Author(s): Kurata Y, Tsumoto K, Hayashi K, Hisatome I, Kuda Y, Tanida M.
  • Journal Title: Front Physiol. Volume: 10 Pages: 1545-1545
  • DOI: 10.3389/fphys.2019.01545
  • Peer Reviewed / Open Access
• [Journal Article] Optimization of the hot balloon ablation strategy using real-time pulmonary vein potential monitoring. (2020)
  • Author(s): Chikata A, Kato T, Usuda K, Fujita S, Takaoka M, Tsuda T, Hayashi K, Furusho H, Takamura M.
  • Journal Title: J Cardiovasc Electrophysiol. Volume: 31 Issue: 1 Pages: 163-173
  • DOI: 10.1111/jce.14313
  • Peer Reviewed
• [Journal Article] Mutant KCNJ3 and KCNJ5 potassium channels as novel molecular targets in bradyarrhythmias and atrial fibrillation. (2019)
  • Author(s): Yamada N, Asano Y, Fujita M, Yamazaki S, Inanobe A, Matsuura N, Kobayashi H, Ohno S, Ebana Y, Tsukamoto O, Ishino S, Takuwa A, Kioka H, Yamashita T, Hashimoto N, Zankov DP, Shimizu A, Asakura M, Asanuma H, Kato H, Nishida Y, Miyashita Y, Shinomiya H, Naiki N, Hayashi K, Makiyama T, Ogita H, et al.
  • Journal Title: Circulation Volume: In press Issue: 18 Pages: 2157-2169
  • DOI: 10.1161/circulationaha.118.036761
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of cardiac myosin light chain kinase gene mutation on development of dilated cardiomyopathy (2019)
  • Author(s): Hodatsu A, Fujino N, Uyama Y, Tsukamoto O, Imai-Okazaki A, Yamazaki S, Seguchi O, Konno T, Hayashi K, Kawashiri MA, Asano Y, Kitakaze M, Takashima S, Yamagishi M
  • Journal Title: ESC Heart Fail Volume: 6 Issue: 2 Pages: 06-415
  • DOI: 10.1002/ehf2.12410
  • Peer Reviewed / Open Access
• [Journal Article] Reply to the Editor- Patients with atrial fibrillation with hypertrophic cardiomyopathy: Do we need new stroke risk stratification? (2019)
  • Author(s): Tsuda T, Nomura A, Hayashi K
  • Journal Title: Heart Rhythm. Volume: 16 Issue: 8 Pages: e56-e57
  • DOI: 10.1016/j.hrthm.2019.04.001
  • Peer Reviewed
• [Journal Article] Cost-effectiveness for prevention of thromboembolism by anticoagulants in non-valvular atrial fibrillation: additional analysis from the Hokuriku-Plus AF Registry. (2019)
  • Author(s): Yamagishi M, Tsuda T, Kato T, Furusho H, Hayashi K; Hokuriku?plus AF Registry Research Group.
  • Journal Title: Heart Vessels. Volume: 34 Issue: 6 Pages: 1024-1030
  • DOI: 10.1007/s00380-018-01333-6
  • Peer Reviewed
• [Journal Article] QT間隔の測定法とQT延長症候群の診断の流れ (2019)
  • Author(s): 林 研至
  • Journal Title: 日本医事新報 Volume: 4992 Pages: 20-9
• [Journal Article] Association of Genetic and Clinical Aspects of Congenital Long QT Syndrome With Life-Threatening Arrhythmias in Japanese Patients (2019)
  • Author(s): Shimizu Wataru、Makimoto Hisaki、Yamagata Kenichiro、Kamakura Tsukasa、Wada Mitsuru、Miyamoto Koji、Inoue-Yamada Yuko、Okamura Hideo、Ishibashi Kohei、Noda Takashi、Nagase Satoshi、Miyazaki Aya、Sakaguchi Heima、Shiraishi Isao、Makiyama Takeru、Ohno Seiko、Itoh Hideki、et al
  • Journal Title: JAMA Cardiology Volume: in press Issue: 3 Pages: 246-254
  • DOI: 10.1001/jamacardio.2018.4925
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effect of hypertrophic cardiomyopathy on the prediction of thromboembolism in patients with nonvalvular atrial fibrillation (2018)
  • Author(s): Tsuda T, Hayashi K, Fujino N, Konno T, Tada H, Nomura A, Tanaka Y, Sakata K, Furusho H, Takamura M, Kawashiri MA, Yamagishi M; Hokuriku-Plus AF Registry Investigators.
  • Journal Title: Heart Rhythm Volume: 印刷中 Issue: 6 Pages: 829-837
  • DOI: 10.1016/j.hrthm.2018.11.029
  • Peer Reviewed
• [Journal Article] Functional analysis of KCNH2 gene mutations of type 2 long QT syndrome in larval zebrafish using microscopy and electrocardiography (2018)
  • Author(s): Tanaka Yoshihiro、Hayashi Kenshi、Fujino Noboru、Konno Tetsuo、Tada Hayato、Nakanishi Chiaki、Hodatsu Akihiko、Tsuda Toyonobu、Nagata Yoji、Teramoto Ryota、Yoshida Shohei、Nomura Akihiro、Kawashiri Masa-aki、Yamagishi Masakazu
  • Journal Title: Heart and Vessels Volume: 34 Issue: 1 Pages: 159-166
  • DOI: 10.1007/s00380-018-1231-4
  • Peer Reviewed
• [Journal Article] Author Correction: Heart Failure Phenotypes Induced by Knockdown of DAPIT in Zebrafish: A New Insight into Mechanism of Dilated Cardiomyopathy (2018)
  • Author(s): Nagata Yoji、Yamagishi Masakazu、Konno Tetsuo、Nakanishi Chiaki、Asano Yoshihiro、Ito Shin、Nakajima Yuri、Seguchi Osamu、Fujino Noboru、Kawashiri Masa-aki、Takashima Seiji、Kitakaze Masafumi、Hayashi Kenshi
  • Journal Title: Scientific Reports Volume: 8 Issue: 1 Pages: 7768-7768
  • DOI: 10.1038/s41598-018-26012-4
  • Peer Reviewed / Open Access
• [Presentation] 遺伝情報を考慮した不整脈診療 (2021)
  • Author(s): 林 研至
  • Organizer: 不整脈心電学会東海北陸地方会
  • Invited
• [Presentation] Rare variant of the Glycerol-3-Phosphate Dehydrogenase-1 Like (GPD1-L) Gene in Japanese Patients with Brugada Syndrome (2021)
  • Author(s): Keisuke Usuda, Kenshi Hayashi, et al.
  • Organizer: JCS2021
• [Presentation] Clinical Characteristics and Outcomes in Elderly Japanese Patients With Nonvalvular Atrial Fibrillation -Insights From the Results of Japanese AF Registry- (2021)
  • Author(s): Toyonobu Tsuda, Kenshi Hayashi, et al.
  • Organizer: JCS2021
• [Presentation] Atrial fibrillation as an independent predictor for developing renal dysfunction (2021)
  • Author(s): Yoshihiro Tanaka, Kenshi Hayashi, et al.
  • Organizer: JCS2021
• [Presentation] Rare SCN10A variants associated with cardiac conduction system diseases (2020)
  • Author(s): Kenshi Hayashi, Noboru Fujino, Hiroshi Furusho, Soichiro Usui, Kenji Sakata, Takeshi Kato, Toyonobu Tsuda, Satoru Niwa, Keisuke Usuda, Kazutaka Takeuchi, Masa-aki Kawahiri, and Masayuki Takamura.
  • Organizer: ESC2020
  • Int'l Joint Research
• [Presentation] Lamin A Deficiency Leads to Electrophysiological and Nuclear Abnormalities Reminiscent of Atrial Cardiomyopathy in Zebrafish (2020)
  • Author(s): Teramoto, Hayashi K, Beerens M, Chiang D, Kiviniemi T, Satoh M, KC A, Burch M, Zhu W , Dai W, Liu J, Mahadevan A, Buys E, and MacRae C
  • Organizer: AHA2020
  • Int'l Joint Research
• [Presentation] Impact of B-type Natriuretic Peptide Level on Risk Stratification of Thromboembolism and Death in Patients with Nonvalvular Atrial Fibrillation (2019)
  • Author(s): Kenshi Hayashi
  • Organizer: The 12th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases. (2019)
  • Author(s): Kenshi Hayashi,et al.
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Predictors for Exacerbating Kidney Function in Patients with Nonvalvular Atrial Fibrillation: The Hokuriku-plus AF Registry. (2019)
  • Author(s): Kenshi Hayashi, Toyonobu Tsuda, Akihiro Nomura, Noboru Fujino, Atsushi Nohara, Hiroshi Furusho, Kenji Sakata, Takeshi Kato, Chiaki Nakanishi, Hayato Tada, Yoshihiro Tanaka, Masa-aki Kawashiri, Masakazu Yamagishi, Masayuki Takamura.
  • Organizer: Annual Meeting of the Japanese Heart Rhythm Society 2019
• [Presentation] 非弁膜症性心房細動を合併した肥大型心筋症の血栓塞栓症発症リスク (2019)
  • Author(s): 林 研至
  • Organizer: 第５回日本心筋症研究会
  • Invited
• [Presentation] Impact of functional studies on exome sequence variant interpretation in early-onset cardiac conduction system diseases (2019)
  • Author(s): Kenshi Hayashi, Akihiro Nomura, Ryota Teramoto, Yoshihiro Asano, Noboru Fujino1, Hiroshi Furusho, Kenji Sakata, Takeshi Kato, Hayato Tada, Chiaki Nakanishi1, Toyonobu Tsuda1, Seiji Takashima, Masakazu Yamagishi, Masa-aki Kawashiri, and Masayuki Takamura
  • Organizer: The 64th Annual Meeting of the Japan Society of Human Genetics
• [Presentation] Cardiac Events during Competitive Sports and Daily Activities in Children and Adolescents with Long QT Syndrome (2019)
  • Author(s): Kenshi Hayashi, Kunio Ohta, Takekatsu Saito, Noboru Fujino, Yasuhiro Todo, Kenji Sakata, Hayato Tada, Akihiro Nomura, Toyonobu Tsuda, Yoshihiro Tanaka, Masakazu Yamagishi, Masa-aki Kawashiri
  • Organizer: JCS2019
• [Presentation] EXOME SEQUENCING AND FUNCTIONAL ANALYSIS FOR PATIENTS WITH EARLY ONSET CARDIAC CONDUCTION-SYSTEM DISEASES (2018)
  • Author(s): Kenshi Hayashi, Akihiro Nomura, Yoshihiro Asano, Manu Beerens, Yasutaka Kurata, Noboru Fujino, Hayato Tada, Calum A MacRae, Seiji Takashima, Masakazu Yamagishi
  • Organizer: INTERNATIONAL ACADEMY OF CARDIOLOGY ANNUAL SCIENTIFIC SESSIONS 2018 23rd WORLD CONGRESS ON HEART DISEASE
  • Int'l Joint Research
• [Presentation] J Wave for Predicting Cardiac Events in Hypertrophic Cardiomyopathy (2018)
  • Author(s): Kenshi Hayashi, Toyonobu Tsuda, Akihiro Nomura, Noboru Fujino, Masakazu Yamagishi
  • Organizer: 11th Asia Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research
• [Presentation] Predictors for Exacerbating Kidney Function in Patients with Nonvalvular Atrial Fibrillation: The Hokuriku-plus AF Registry (2018)
  • Author(s): Kenshi Hayashi, Toyonobu Tsuda, Akihiro Nomura, Noboru Fujino, Atsushi Nohara, Kenji Sakata, Chiaki Nakanishi, Hayato Tada, Yoshihiro Tanaka, Masa-aki Kawashiri, and Masakazu Yamagishi
  • Organizer: AHA Scientific sessions 2018
  • Int'l Joint Research
• [Book] 不整脈診療ロジック×プラクティス (2020)
  • Author(s): 加藤 武史、松尾 征一郎
  • Total Pages: 392
  • Publisher: 南江堂
  • ISBN: 9784524248940