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Abstract：
UNASSIGNED: 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).
UNASSIGNED: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.
UNASSIGNED: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico 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.
UNASSIGNED: 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 MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 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.
UNASSIGNED: 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.
UNASSIGNED: To identify CM-associated pathogenic variants and assess their relative prevalence in participants with extensive myocardial fibrosis by CMR.
UNASSIGNED: MESA whole-genome sequencing data was evaluated to capture variants in CM-associated genes (n = 82). Coding variants with a frequency of <0.1% in gnomAD and 1,000 Genomes Project databases and damaging/deleterious effects based on in-silico 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.
UNASSIGNED: 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 MYH7, CRYAB, and SCN5A. The prevalence of P/LP rare variants in cases was higher than controls (5 in 420 [1.1%] vs. 1 in 715 [0.1%], p = 0.03). We identified two MYBPC3 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.
UNASSIGNED: 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.
摘要：
UNASSIGNED：心肌病（CM）基因中罕见的致病变异可能导致心脏重塑或纤维化。我们研究了无临床心血管疾病（CVD）的成年人中此类变体的携带者状态，在多种族动脉粥样硬化研究（MESA）中获得了心脏MRI（CMR）衍生的心肌纤维化指标。
UNASSIGNED：通过CMR确定CM相关的致病变异并评估其在广泛心肌纤维化参与者中的相对患病率。
UNASSIGNED:评估MESA全基因组测序数据以捕获CM相关基因中的变体(n=82)。通过ClinVar数据库和ACMG策展指南评估了gnomAD和1,000个基因组项目数据库中频率<0.1％的编码变体以及基于计算机评分工具的破坏性/有害影响，以获得致病性证据。病例是具有高心肌纤维化的参与者，定义为细胞外体积（ECV）的最高四分位数或T1-mappingCMR中的天然T1时间，其余参与者为对照组。
UNASSIGNED：共有1,135名MESA参与者具有可用的遗传数据和表型指标，并且在CMR时没有临床CVD。我们在整个MESA人群中确定了6,349种CM相关基因的罕见变异，其中6种致病性/可能致病性（P/LP）变异存在于表型亚群中。病例组中携带P/LP变异的基因为MYH7、CRYAB、SCN5A病例中P/LP罕见变异的患病率高于对照组(420[1.1%]中的5例与1/715[0.1%]，p=0.03)。我们在病例组中确定了两个具有临界致病性的未知意义的MYBPC3变异体（VUS）。左心室(LV)容积,质量,射血分数（EF），与整个队列相比,具有变异体的参与者的纵向和周向应变没有差异.
UNASSIGNED：我们观察到，与无明显纤维化的对照组相比，在CMR中量化有明显心肌纤维化的参与者中，罕见的潜在致病性CM相关遗传变异的患病率更高。在有或没有P/LP变体的参与者之间没有发现心脏结构或功能差异。
UNASSIGNED：通过CMR确定CM相关的致病变异并评估其在广泛心肌纤维化参与者中的相对患病率。
UNASSIGNED:评估MESA全基因组测序数据以捕获CM相关基因中的变体(n=82)。通过ClinVar数据库和ACMG策展指南评估了gnomAD和1,000个基因组项目数据库中频率<0.1％的编码变体以及基于计算机评分工具的破坏性/有害影响，以获得致病性证据。病例是具有高心肌纤维化的参与者，定义为细胞外体积（ECV）的最高四分位数或T1-mappingCMR中的天然T1时间，其余参与者为对照组。
UNASSIGNED：共有1,135名MESA参与者具有可用的遗传数据和表型指标，并且在CMR时没有临床CVD。我们在整个MESA人群中确定了6,349种CM相关基因的罕见变异，其中6种致病性/可能致病性（P/LP）变异存在于表型亚群中。病例组中携带P/LP变异的基因为MYH7、CRYAB、SCN5A病例中P/LP罕见变异的患病率高于对照组(420[1.1%]中的5例与1/715[0.1%]，p=0.03)。我们在病例组中确定了两个具有临界致病性的未知意义的MYBPC3变异体（VUS）。左心室(LV)容积,质量,射血分数（EF），与整个队列相比,具有变异体的参与者的纵向和周向应变没有差异.
UNASSIGNED：我们观察到，与无明显纤维化的对照组相比，在CMR中量化有明显心肌纤维化的参与者中，罕见的潜在致病性CM相关遗传变异的患病率更高。在有或没有P/LP变体的参与者之间没有发现心脏结构或功能差异。
