Genetics of sudden cardiac death caused by ventricular arrhythmias

Sudden cardiac death (SCD) resulting from ventricular tachyarrhythmia is a major contributor to mortality. Clinical management of SCD, currently based on clinical markers of SCD risk, can be improved by integrating genetic information. The identification of multiple disease-causing gene variants has already improved patient management and increased our understanding of the rare Mendelian diseases associated with SCD risk in the young, but marked variability in disease severity suggests that additional genetic modifiers exist. Next-generation DNA sequencing could be crucial to the discovery of SCD-associated genes, but large data sets can be difficult to interpret. SCD usually occurs in patients with an average age of 65 years who have complex cardiac disease stemming from multiple, common, acquired disorders. Heritable factors are largely unknown, but are likely to have a role in determining the risk of SCD in these patients. Numerous genetic loci have been identified that affect electrocardiogram indices, which are regarded as intermediate phenotypes for tachyarrhythmia. These loci could help to identify new molecules and pathways affecting cardiac electrical function. These loci are often located in intergenic regions, so our evolving understanding of the noncoding regulatory regions of the genome are likely to aid in the identification of novel genes that are important for cardiac electrical function and possibly SCD.