Pourebrahim Kimia, Marian John Garrity, Tan Yanli, Chang Jeffrey T, Marian Ali J
Center for Cardiovascular Genetics, Institute of Molecular Medicine and Department of Medicine, University of Texas Health Sciences Center at Houston, Houston, TX 77030, USA.
Upper school, St John's school, Houston, TX 77030, USA.
J Cardiovasc Aging. 2021;1. doi: 10.20517/jca.2021.15. Epub 2021 Sep 3.
Primary dilated cardiomyopathy (DCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC) are the two common and distinct forms of hereditary cardiomyopathies caused by defined pathogenic variants (PVs) typically in different sets of genes. DCM is characterized by left ventricular dilatation, dysfunction, and failure, whereas ARVC classically involves the right ventricle and is characterized by fibrofatty infiltration of the myocardium. DCM is caused primarily by the PVs in genes encoding sarcomere and cytoskeletal protein, while ARVC is mainly a disease of the desmosome proteins. DCM and ARVC exhibit partial phenotypic and genetic overlaps.
To analyze the genetic basis of the phenotypic heterogeneity of cardiomyopathy in members of a single family.
We recruited, clinically characterized, and performed whole-exome sequencing in five affected, three probably affected, and two clinically unaffected members of a single family. The family members mainly exhibited late-onset DCM associated with conduction defects and arrhythmias. One family member who died suddenly was diagnosed with the classic ARVC at autopsy and another presented with isolated ventricular tachycardia. A novel splicing (truncating) and a rare missense variant in the gene, likely in cis, co-segregated with the phenotype in all affected and probably affected family members and were likely the causal variants. Several PVs and LPVs in other genes involved in cardiomyopathies and arrhythmias were also identified that seem to modify the expression of the phenotype. Notably, LPVs in the and genes, which are known genes for ARVC, were identified in the family member who also carried the variants but developed the classic ARVC.
The findings indicate the causal role of the variants, exhibiting an age-dependent penetrance in late-onset DCM, and highlight the potential modifying role of the concomitant LPVs in additional genes on the expression of the phenotype, including a phenotypic switch from the anticipated DCM to ARVC. The findings support an oligogenic basis of the cardiac phenotype in hereditary cardiomyopathies. A comprehensive genetic analysis involving all PVs and LPVs along with detailed phenotypic characterization is necessary to gain insights into the molecular pathogenesis of hereditary cardiomyopathies.
原发性扩张型心肌病（DCM）和致心律失常性右室心肌病（ARVC）是两种常见且不同的遗传性心肌病形式，通常由不同基因中的特定致病变异（PVs）引起。DCM的特征是左心室扩张、功能障碍和衰竭，而ARVC典型地累及右心室，其特征是心肌的纤维脂肪浸润。DCM主要由编码肌节和细胞骨架蛋白的基因中的PVs引起，而ARVC主要是桥粒蛋白疾病。DCM和ARVC表现出部分表型和遗传重叠。
分析一个家族成员中心肌病表型异质性的遗传基础。
我们招募了一个家族的五名患病成员、三名可能患病成员和两名临床未患病成员，对他们进行了临床特征分析并进行了全外显子组测序。家族成员主要表现为与传导缺陷和心律失常相关的迟发性DCM。一名突然死亡的家族成员尸检时被诊断为典型的ARVC，另一名表现为孤立性室性心动过速。一个新的剪接（截断）变异和一个罕见的错义变异，可能处于顺式构型，在所有患病和可能患病的家族成员中与表型共分离，可能是致病变异。还鉴定出了其他参与心肌病和心律失常的基因中的几个PVs和低致病性变异（LPVs），它们似乎改变了表型的表达。值得注意的是，在也携带该变异但发展为典型ARVC的家族成员中，鉴定出了已知的ARVC相关基因中的LPVs。
这些发现表明该变异的致病作用，在迟发性DCM中表现出年龄依赖性外显率，并突出了其他基因中伴随的LPVs对表型表达的潜在修饰作用，包括从预期的DCM到ARVC的表型转换。这些发现支持遗传性心肌病中心脏表型的寡基因基础。涉及所有PVs和LPVs以及详细表型特征的综合遗传分析对于深入了解遗传性心肌病的分子发病机制是必要的。
