Genetics of Cardiomyopathy
Genetics of Cardiomyopathy
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DOI：
10.5772/intechopen.97010
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发表时间：
2021-04
期刊：
影响因子：
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通讯作者：
Evan M. Harvey;M. Almasri;Hugo R Martinez
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文献类型：
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作者：
Evan M. Harvey;M. Almasri;Hugo R Martinez
心肌病（CM）包括心肌结构和功能（收缩和舒张）异常的异质组，并且局限于心血管系统或全身性疾病的一部分。CM是发病率和死亡率的主要原因，占死亡和心脏移植的很大比例。2006年美国心脏协会（AHA）分类将CM分为原发性（遗传性、混合性或获得性）或继发性（即，浸润性或自身免疫性）。2008年，欧洲心脏病学会分类建议将CM分为家族性或遗传性和非家族性或非遗传性。2013年，世界心脏联合会推荐了MOGES疾病分类系统，该系统包括形态功能表型（M）、涉及的器官（O）、遗传遗传模式（G）、病因学注释（E）（包括遗传缺陷或潜在疾病/底物）以及基于心力衰竭症状的特定患者的功能状态（S）。心脏遗传学生物学的快速发展揭示了心肌疾病中大量的遗传和表型异质性。鉴于科学和临床领域的学科种类繁多，任何理想的分类都可能面临达成共识的挑战。尽管如此，基于遗传表型的CM分类提供了一个简单的，临床上有用的诊断方案的可能性。在本章中，我们将描述扩张型心肌病（DCM）、肥厚型心肌病（HCM）、致瘤性心肌病（ACM）、左室致密化不全型心肌病（LVNC）和限制型心肌病（RCM）的遗传基础。尽管这些类型的CM的描述性形态不同，但在临床实践中，CM类型和致瘤性病理中经常遇到重叠表型。CM似乎起源于继发于“最终共同途径”的破坏。这些破坏可能有纯粹的遗传原因。例如，单基因突变导致功能失调的蛋白质合成，从而在肌节和CM表型水平引起下游功能失调的蛋白质相互作用。肌节是一个具有多种蛋白质相互作用的复合体，包括粗肌丝蛋白、细肌丝蛋白和肌球蛋白结合蛋白。此外，其他蛋白质参与肌节的周围结构，如Z盘和肌肉LIM蛋白。一个或多个基因可以表现出组织特异性功能、发育和每种蛋白质的生理调节表达模式。或者，同一基因（复合杂合性）或不同基因（双基因杂合性）中的多个突变可能导致可能是经典的、更严重的或甚至与其他疾病形式重叠的表型。
Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional (systolic and diastolic) abnormalities of the myocardium and are either confined to the cardiovascular system or are part of a systemic disorder. CMs represent a leading cause of morbidity and mortality and account for a significant percentage of death and cardiac transplantation. The 2006 American Heart Association (AHA) classification grouped CMs into primary (genetic, mixed, or acquired) or secondary (i.e., infiltrative or autoimmune). In 2008, the European Society of Cardiology classification proposed subgrouping CM into familial or genetic and nonfamilial or nongenetic forms. In 2013, the World Heart Federation recommended the MOGES nosology system, which incorporates a morpho-functional phenotype (M), organ(s) involved (O), the genetic inheritance pattern (G), an etiological annotation (E) including genetic defects or underlying disease/substrates, and the functional status (S) of a particular patient based on heart failure symptoms. Rapid advancements in the biology of cardio-genetics have revealed substantial genetic and phenotypic heterogeneity in myocardial disease. Given the variety of disciplines in the scientific and clinical fields, any desired classification may face challenges to obtaining consensus. Nonetheless, the heritable phenotype-based CM classification offers the possibility of a simple, clinically useful diagnostic scheme. In this chapter, we will describe the genetic basis of dilated cardiomyopathy (DCM), hypertrophic cardiomyopathy (HCM), arrhythmogenic cardiomyopathy (ACM), LV noncompaction cardiomyopathy (LVNC), and restrictive cardiomyopathy (RCM). Although the descriptive morphologies of these types of CM differ, an overlapping phenotype is frequently encountered within the CM types and arrhythmogenic pathology in clinical practice. CMs appear to originate secondary to disruption of “final common pathways.” These disruptions may have purely genetic causes. For example, single gene mutations result in dysfunctional protein synthesis causing downstream dysfunctional protein interactions at the level of the sarcomere and a CM phenotype. The sarcomere is a complex with multiple protein interactions, including thick myofilament proteins, thin myofilament proteins, and myosin-binding proteins. In addition, other proteins are involved in the surrounding architecture of the sarcomere such as the Z-disk and muscle LIM proteins. One or multiple genes can exhibit tissue-specific function, development, and physiologically regulated patterns of expression for each protein. Alternatively, multiple mutations in the same gene (compound heterozygosity) or in different genes (digenic heterozygosity) may lead to a phenotype that may be classic, more severe, or even overlapping with other disease forms.