Shabani Mahsima, Dutta Diptavo, Ambale-Venkatesh Bharath, Post Wendy S, Taylor Kent D, Rich Stephen S, Wu Colin O, Pereira Naveen L, Shah Sanjiv J, Chatterjee Nilanjan, Rotter Jerome I, Arking Dan E, Lima Joao A C
Division of Cardiology, Department of Medicine, School of Medicine, Johns Hopkins University, Baltimore, MD, United States.
Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, United States.
Front Cardiovasc Med. 2022 Feb 21;9:804788. doi: 10.3389/fcvm.2022.804788. eCollection 2022.
Rare pathogenic variants in cardiomyopathy (CM) genes can predispose to cardiac remodeling or fibrosis. We studied the carrier status for such variants in adults without clinical cardiovascular disease (CVD) in whom cardiac MRI (CMR)-derived measures of myocardial fibrosis were obtained in the Multi-Ethnic Study of Atherosclerosis (MESA).
To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.
MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes ( = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on scoring tools were assessed by ClinVar database and ACMG curation guidelines for evidence of pathogenicity. Cases were participants with high myocardial fibrosis defined as highest quartile of extracellular volume (ECV) or native T1 time in T1-mapping CMR and controls were the remainder of participants.
A total of 1,135 MESA participants had available genetic data and phenotypic measures and were free of clinical CVD at the time of CMR. We identified 6,349 rare variants in CM-associated genes in the overall MESA population, of which six pathogenic/likely pathogenic (P/LP) variants were present in the phenotyped subpopulation. The genes harboring P/LP variants in the case group were , and . The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], = 0.03). We identified two Variants of Unknown Significance (VUS)s with borderline pathogenicity in the case group. The left ventricle (LV) volume, mass, ejection fraction (EF), and longitudinal and circumferential strain in participants with the variants were not different compared to the overall cohort.
We observed a higher prevalence of rare potentially pathogenic CM associated genetic variants in participants with significant myocardial fibrosis quantified in CMR as compared to controls without significant fibrosis. No cardiac structural or functional differences were found between participants with or without P/LP variants.
心肌病（CM）基因中的罕见致病变异可导致心脏重塑或纤维化。我们在多民族动脉粥样硬化研究（MESA）中，研究了无临床心血管疾病（CVD）的成年人中此类变异的携带情况，并通过心脏磁共振成像（CMR）获得了心肌纤维化的测量值。
识别与CM相关的致病变异，并评估其在CMR显示有广泛心肌纤维化的参与者中的相对患病率。
评估MESA全基因组测序数据，以捕获CM相关基因（n = 82）中的变异。根据gnomAD和千人基因组计划数据库中频率<0.1%的编码变异，以及基于评分工具的有害/致病变异，通过ClinVar数据库和美国医学遗传学与基因组学学会（ACMG）的评估指南评估其致病性证据。病例为心肌纤维化程度高的参与者，定义为T1映射CMR中细胞外容积（ECV）或固有T1时间处于最高四分位数，对照组为其余参与者。
共有1135名MESA参与者有可用的遗传数据和表型测量值，且在CMR检查时无临床CVD。我们在整个MESA人群中识别出6349个CM相关基因的罕见变异，其中在有表型的亚组中有6个致病性/可能致病性（P/LP）变异。病例组中携带P/LP变异的基因有、和。病例组中P/LP罕见变异的患病率高于对照组（420例中有5例[1.1%] vs. 715例中有1例[0.1%]，P = 0.03）。我们在病例组中识别出两个意义未明的变异（VUS），其致病性处于临界状态。有这些变异的参与者的左心室（LV）容积、质量、射血分数（EF）以及纵向和圆周应变与整个队列相比无差异。
我们观察到，与无明显纤维化的对照组相比，CMR定量显示有明显心肌纤维化的参与者中，罕见的潜在致病性CM相关基因变异的患病率更高。有或无P/LP变异的参与者之间未发现心脏结构或功能差异。
