Hyemoon Chung1, Yoonjung Kim2, Sun-Mi Cho3, Ho-Joon Lee4, Chul-Hwan Park5, Jong-Youn Kim6, Sang-Hak Lee7, Pil-Ki Min6, Young Won Yoon6, Byoung Kwon Lee6, Woo-Shik Kim8, Bum-Kee Hong6, Tae Hoon Kim5, Se-Joong Rim6, Hyuck Moon Kwon6, Eui-Young Choi9, Kyung-A Lee10. 1. Division of Cardiology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul 02447, South Korea; Department of Internal Medicine, the Graduate School of Yonsei University, Seoul 03722, Korea. 2. Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea. 3. Department of Laboratory Medicine, CHA Bundang Medical Center, CHA University, Sungnam 13496, South Korea. 4. Department of Genetics, Yale University School of Medicine, New Haven, CT 06510, USA. 5. Department of Radiology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea. 6. Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea. 7. Division of Cardiology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, Seoul 03722, South Korea. 8. Division of Cardiology, Department of Internal Medicine, Kyung Hee University School of Medicine, Seoul 02447, South Korea. 9. Division of Cardiology, Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea. Electronic address: choi0928@yuhs.ac. 10. Department of Laboratory Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06273, South Korea. Electronic address: KAL1119@yuhs.ac.
Abstract
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.
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.
Authors: Cristina Mazzaccara; Bruno Mirra; Ferdinando Barretta; Martina Caiazza; Barbara Lombardo; Olga Scudiero; Nadia Tinto; Giuseppe Limongelli; Giulia Frisso Journal: Int J Mol Sci Date: 2021-05-27 Impact factor: 6.208