Molecular Genetic Basis of Hypertrophic Cardiomyopathy.
Molecular Genetic Basis of Hypertrophic Cardiomyopathy.
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肥厚性心肌病的分子遗传基础。
DOI：
10.1161/circresaha.121.318346
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发表时间：
2021-05-14
影响因子：
20.1
通讯作者：
Marian AJ
中科院分区：
文献类型：
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作者：
Marian AJ
肥厚性心肌病（HCM）是一种心肌遗传疾病，其特征是左心室肥厚，射血分数保留或增加。心肌肥厚通常不对称，并伴有左心室流出道梗阻。心肌细胞肥大、紊乱和心肌纤维化是HCM的组织学特征。HCM是一种相对良性的疾病，但却是导致年轻人心源性猝死和老年人心力衰竭的重要原因。致病性变异（pv）基因编码的蛋白质成分的肌瘤是HCM的主要原因。pv表现出效应大小的梯度，这反映在它们的外显率和HCM的可变表型表达上。MYH7和MYBPC3分别编码β-肌球蛋白重链和肌球蛋白结合蛋白C，是两个最常见的致病基因，约占所有HCM病例的40%，但在大家庭中HCM的比例更高。编码细丝蛋白成分的基因中的pv占HCM病例的5%。虽然遗传变异在大家族中的致病性已得到牢固确立，但确定小家族和散发病例中pv的因果关系仍具有挑战性。在后一类中，pv最好被认为是HCM的概率决定因素。破译HCM的遗传基础使常规基因检测成为可能，并部分阐明了HCM的基础机制，即与肌动蛋白紧密结合的肌球蛋白分子数量增加。这些发现导致了马伐卡坦的发展，其目标是肌凝蛋白分子与肌动蛋白丝的结合，并赋予有益的临床效果。在未来的几年里，基因检测的产量有望提高，所谓的“缺失的致病基因”将被识别出来。这些进展也有望使开发更多的特异性治疗和编辑HCM中的突变成为可能。
Hypertrophic cardiomyopathy (HCM) is a genetic disease of the myocardium characterized by a hypertrophic left ventricle with a preserved or increased ejection fraction. Cardiac hypertrophy is often asymmetric, which is associated with left ventricular outflow tract obstruction. Myocyte hypertrophy, disarray and myocardial fibrosis constitute the histological features of HCM. HCM is a relatively benign disease but an important cause of sudden cardiac death in the young and heart failure in the elderly. Pathogenic variants (PVs) in genes encoding protein constituents of the sarcomeres are the main causes of HCM. PVs exhibit a gradient of effect sizes, as reflected in their penetrance and variable phenotypic expression of HCM. MYH7 and MYBPC3, encoding β-myosin heavy chain and myosin binding protein C, respectively, are the two most common causal genes and responsible for ~40% of all HCM cases but a higher percentage of HCM in large families. PVs in genes encoding protein components of the thin filaments are responsible for ~5% of the HCM cases. Whereas pathogenicity of the genetic variants in large families has been firmly established, ascertainment causality of the PVs in small families and sporadic cases is challenging. In the latter category PVs are best considered as probabilistic determinants of HCM. Deciphering the genetic basis of HCM has enabled routine genetic testing and has partially elucidated the underpinning mechanism of HCM as increased number of the myosin molecules that are strongly bound to actin. The discoveries have led to the development of mavacamten that targets binding of the myosin molecule to actin filaments and imparts beneficial clinical effects. In the coming years the yield of the genetic testing is expected to be improved and the so-called “missing causal gene” be identified. The advances are also expected to enable development of additional specific therapies and editing of the mutations in HCM.