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

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)48-56
Number of pages9
Publication statusPublished - 2020 Jul

Bibliographical note

Funding Information:
This work was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education. ( 2014R1A1A2055872 ).

Publisher Copyright:
© 2020 Elsevier B.V. and Mitochondria Research Society

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Molecular Biology
  • Cell Biology


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