Improvement of diagnostic rate of mitochondrial cardiomyopathy by novel statistical approaches

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15863
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Juntendo University
• Principal Investigator: Okazaki Atsuko (今井敦子) 順天堂大学, 医学(系)研究科(研究院), 准教授 (70761691)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ミトコンドリア病 / 遺伝統計学 / 心筋症 / 網羅的遺伝子解析 / ミトコンドリア心筋症

Outline of Final Research Achievements

I developed novel statistical genetics methods to identify variants located in segments of identity-by-decent and chromosomal deletions by using Hamming Distance Ratio (HDR). By applying those methods, I succeeded in identifying genetic variants in 46 mitochondrial cardiomyopathy patients. Among 223 consecutive pediatric mitochondrial disease patients aged <18 years with a confirmed genetic diagnosis including 46 cardiomyopathy patients, The overall survival rate was significantly lower in patients with cardiomyopathy than in those without (p<0.001, log-rank test). By multivariable analysis, left ventricular (LV) hypertrophy (HR=4.6; 95% CI: 2.8-7.3), neonatal onset (HR=2.9; 95% CI: 1.8-4.5) and chromosomal aberrations (HR=2.9; 95% CI: 1.3-6.5) were independent predictors of all-cause mortality. Patients with LV hypertrophy with neonatal onset and/or chromosomal aberrations had higher mortality (100% in 21 patients) than those with LV hypertrophy alone (71% in 14 patients).

Free Research Field

循環器内科学

Academic Significance and Societal Importance of the Research Achievements

ミトコンドリア心筋症はミトコンドリア病の中でも特に生命予後が悪く、小児例では約80%が主に心不全で死亡する重度の高い疾患である。核遺伝子・ミトコンドリアDNAどちらの遺伝子異常でも生じ、また染色体構造異常によっても発症するため、迅速かつ網羅的な遺伝子診断法の確立が望まれていた。申請者が開発した遺伝統計を用いた新規疾患変異・染色体異常同定ツールを活用し、ミトコンドリア心筋症の診断率向上を達成した。