Elucidating the genetics of idiopathic ventricular fibrillation through whole exome sequencing analysis

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K17543
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: National Cardiovascular Center Research Institute
• Principal Investigator: CHA PEI CHIENG 国立研究開発法人国立循環器病研究センター, 研究所, 上級研究員 (20623896)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 特発性心室細動 / 心臓突然死 / 全エクソンシーケンス解析 / 全ゲノムシーケンス解析 / 遺伝子変異

Outline of Final Research Achievements

Through whole exome sequencing analysis of 204 idiopathic ventricular fibrillation (IVF) patients, we found that 18% of the patients carry rare pathogenic/likely pathogenic mutations in genes previously reported to be associated with cardiovascular diseases including ventricular arrhythmias, cardiomyopathies, and muscular dystrophies. The finding that 91.4% among these IVF-associated rare pathogenic variants were detected in only single IVF subject suggests that IVF is genetically heterogeneous and complex. To further elucidate the genetic background of IVF, whole exome or whole genome sequencing analysis were conducted for members from 26 IVF families. Pedigree analysis successfully identified the causal mutation for two IVF families. For the remaining families with causal mutation inconclusive, several rare non-synonymous variants residing in genes with potential cardiovascular-related functions that were commonly detected in the probands of multiple IVF families were identified.

Free Research Field

ゲノム医学

Academic Significance and Societal Importance of the Research Achievements

心疾患または心臓構造の異常を認めない突発する致死的不整脈IVFは、心臓突然死の原因の一つである。IVF蘇生後の患者は、診断がつかないため、発症原因の解明、予後と突然死の予防、そしてより効果的な治療法の開発が大きな課題となっている。また、家族歴は重要な危険因子であるため、確実な診断につかない発症者のみならず、その家族の不安を増長し心理負担も計り知れないものである。IVF原因遺伝子変異の同定ができれば、IVFの遺伝背景と発症機序の解明のみならず、今後の臨床現場において、同定されたIVF原因遺伝子変異を持つ者に対し、将来的に発症するリスクに関する遺伝カウンセリングにもつながる。