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.

中文翻译：

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肌节和线粒体相关多基因变异对肥厚型心肌病内表型的不同贡献

背景肥厚型心肌病(HCM) 是一种多基因疾病，由各种遗传修饰因素引起。我们使用综合基因检测和罕见变异关联分析研究了基于表型的 HCM 患者的临床和遗传特征。方法 分析了由 82 个核 DNA（nDNA：33 个肌节相关基因、5 个表型基因和 44 个与线粒体心肌病相关的核基因）和 37 个线粒体 DNA (mtDNA) 组成的综合 HCM 特异性组合。进行稀有变异分析以确定特定基因与不同表型的关联。结果 在 212 名患者中，肌节相关基因的致病变异在非根尖型 HCM (41.4%, 46/111; P = 0.001) 中比根尖型 HCM (20.8%, 21/101) 更为普遍。顶端 HCM 比非顶端 HCM 表现出温和的表型，并且它显示的肌节突变数量少于非顶端 HCM。有趣的是，在根尖 HCM 中观察到 TNNI3 (35%) 和 MYH7 (9%) 的反向突变频率。在一项罕见的变异分析中，MT-RNR2 与心尖 HCM 呈正相关（OR：1.37，P = 0.025）。而且，MYBPC3（肌节基因）对根尖 HCM 有负面影响（OR：0.54，P = 0.027）。另一方面，肌节相关基因的致病突变（P < 0.05）和罕见变异（OR：2.78 ∼ 3.47，P < 0.05）与舒张功能障碍和左心房重构有关，这与 HCM 患者的不良预后相关. 结论 我们的结果为解释亚洲人群中根尖型 HCM 的患病率和表型之间的差异提供了线索，