Genetics of Sudden Cardiac Death

Abstract

Sudden cardiac death (SCD) is defined by the World Health Organization (WHO) as death within 1 h of symptom onset (witnessed) or within 24 h of being observed alive and symptom free (unwitnessed). It affects more than 3 million people annually worldwide and affects approximately 1/1000 people each year in the USA. Familial studies of syndromes with Mendelian inheritance, candidate genes analyses, and genome-wide association studies (GWAS) have helped our understanding of the genetics of SCD. We will review the genetics of arrhythmogenic hereditary syndromes with Mendelian inheritance from familial studies with structural heart disease (hypertrophic cardiomyopathy, dilated cardiomyopathy, and arrhythmogenic cardiomyopathy) as well as primary electrical causes (long QT syndrome, Brugada syndrome, catecholaminergic polymorphic ventricular tachycardia, and short QT syndrome). In addition, we will review the genetics of intermediate phenotypes for SCD such as coronary artery disease and electrocardiographic variables (QT interval, QRS duration, and RR interval). Finally, we will review rare and common variants that are associated with SCD in the general population and were identified from candidate gene analyses and GWAS. Our understanding of the genetics of SCD will improve by the use of next-generation sequencing/whole-exome sequencing as well as whole-genome sequencing which have the potential to discover unsuspected common and rare genetic variants that might be associated with SCD.

Exome Sequencing Identifies a Novel <b><i>DES</i></b> Mutation (R227C) in a Chinese Dilated Cardiomyopathy Family

“…It is characterized by cardiac dilation and systolic dysfunction, and, in most patients, left ventricular enlargement or dilatation [3]. In the clinic, the symptoms of DCM include heart failure and are often related to sudden cardiac death [4]. According to Olmstead County study data, the prevalence of DCM is greater than 1 in 2,500 individuals [5].…”

Molecular mechanisms in the pathogenesis of arrhythmogenic cardiomyopathy

“…ACM is caused, in most cases, by mutations in genes that encode desmosomal proteins [3–5]. Mutations in all known desmosomal genes (encoding the desmosomal cadherins desmocollin-2 and desmoglein-2, and intracellular linker proteins plakophilin-2, plakoglobin and desmoplakin) have been implicated in ACM [3–5].…”

“…Mutations in all known desmosomal genes (encoding the desmosomal cadherins desmocollin-2 and desmoglein-2, and intracellular linker proteins plakophilin-2, plakoglobin and desmoplakin) have been implicated in ACM [3–5]. Mutations in other genes including some previously linked to dilated cardiomyopathy, such as phospholamban [8], or hypertrophic cardiomyopathy, such as titin [9], have also been reported in subjects who fulfill diagnostic criteria for ACM.…”

“…In most cases, ACM is inherited as an autosomal dominant trait with variable penetrance [3–5]. Digenic, compound heterozygous and recessive forms have been reported and are typically associated with more severe clinical phenotypes [10–12].…”

Polymorphisms in the GNAS Gene as Predictors of Ventricular Tachyarrhythmias and Sudden Cardiac Death: Results From the DISCOVERY Trial and Oregon Sudden Unexpected Death Study

“…On the other hand, observational studies suggest a distinct contribution of inherited factors to the risk of SCD . This has stimulated the search for genetic variants that may increase susceptibility to SCD . Only recently has the focus been expanded from classical ion channelopathies to other potential mechanisms contributing to arrhythmogenesis.…”