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Differential Contributions of Sarcomere and Mitochondria-Related Multigene Variants to the Endophenotype of Hypertrophic Cardiomyopathy

 Hyemoon Chung  ;  Yoonjung Kim  ;  Sun-Mi Cho  ;  Ho-Joon Lee  ;  Chul-Hwan Park  ;  Jong-Youn Kim  ;  Sang-Hak Lee  ;  Pil-Ki Min  ;  Young Won Yoon  ;  Byoung Kwon Lee  ;  Woo-Shik Kim  ;  Bum-Kee Hong  ;  Tae Hoon Kim  ;  Se-Joong Rim  ;  Hyuck Moon Kwon  ;  Eui-Young Choi  ;  Kyung-A Lee 
 MITOCHONDRION, Vol.53 : 48-56, 2020-07 
Journal Title
Issue Date
Hypertrophic cardiomyopathy ; Mitochondria-related genes ; Mitochondrial DNA ; Sarcomere associated genes
Background: Hypertrophic cardiomyopathy (HCM) is a multigenic disease that occurs due to various genetic modifiers. We investigated phenotype-based clinical and genetic characteristics of HCM patients using comprehensive genetic tests and rare variant association analysis.

Methods: A comprehensive HCM-specific panel, consisting of 82 nuclear DNAs (nDNAs: 33 sarcomere-associated genes, 5 phenocopy genes, and 44 nuclear genes linked to mitochondrial cardiomyopathy) and 37 mitochondrial DNAs (mtDNAs), was analyzed. Rare variant analysis was performed to determine the association of specific genes with different phenotypes.

Results: Among the 212 patients, pathogenic variants in sarcomere-associated genes were more prevalent in non-apical HCM (41.4%, 46/111; P = 0.001) than apical HCM (20.8%, 21/101). Apical HCM exhibits mild phenotypes than non-apical HCM, and it showed fewer numbers of sarcomere mutations than non-apical HCM. Interestingly, inverted mutation frequency of TNNI3 (35%) and MYH7 (9%) was observed in apical HCM. In a rare variant analysis, MT-RNR2 positively correlated with apical HCM (OR: 1.37, P = 0.025). And, MYBPC3 (sarcomere gene) negatively contributed to apical HCM (OR: 0.54, P = 0.027). On the other hand, both pathogenic mutation (P < 0.05) and rare variants in sarcomere-associated genes (OR: 2.78-3.47, P < 0.05) were related to diastolic dysfunction and left atrium remodeling, which correlated with poor prognosis in HCM patients.

Conclusions: Our results provide a clue towards explaining the difference between the prevalence and phenotype of apical HCM in Asian populations, and a foundation for genetics-based approaches that may enable individualized risk stratification for HCM patients.
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1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Laboratory Medicine (진단검사의학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Radiology (영상의학교실) > 1. Journal Papers
Yonsei Authors
Kwon, Hyuck Moon(권혁문) ORCID logo https://orcid.org/0000-0001-9901-5015
Kim, Yoon Jung(김윤정) ORCID logo https://orcid.org/0000-0002-4370-4265
Kim, Jong Youn(김종윤) ORCID logo https://orcid.org/0000-0001-7040-8771
Kim, Tae Hoon(김태훈) ORCID logo https://orcid.org/0000-0003-3598-2529
Min, Pil Ki(민필기) ORCID logo https://orcid.org/0000-0001-7033-7651
Park, Chul Hwan(박철환) ORCID logo https://orcid.org/0000-0002-0004-9475
Yoon, Young Won(윤영원) ORCID logo https://orcid.org/0000-0002-0907-0350
Lee, Kyung A(이경아) ORCID logo https://orcid.org/0000-0001-5320-6705
Lee, Byoung Kwon(이병권) ORCID logo https://orcid.org/0000-0001-9259-2776
Lee, Sang Hak(이상학) ORCID logo https://orcid.org/0000-0002-4535-3745
Rim, Se Joong(임세중) ORCID logo https://orcid.org/0000-0002-7631-5581
Choi, Eui Young(최의영) ORCID logo https://orcid.org/0000-0003-3732-0190
Hong, Bum Kee(홍범기) ORCID logo https://orcid.org/0000-0002-6456-0184
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