Genetics of sudden cardiac death caused by ventricular arrhythmias

Key Points

  • Sustained ventricular tachyarrhythmias are the most-common cause of sudden cardiac death (SCD), and traditional risk-stratification methods could be improved with genetic testing

  • Multiple genes affecting SCD risk in young patients have been discovered, but our understanding of the variability in disease severity is incomplete, and interpreting genetic test results is difficult

  • Next-generation sequencing in families that have inherited patterns of SCD, but are mutation-negative for the known disease genes, is expected to discover novel genes for these rare diseases

  • Genome-wide association studies (GWAS) have identified genomic loci that affect electrocardiogram indices, SCD risk in the general population, and risk of rare cardiac diseases such as Brugada syndrome

  • The unavailability of large, comprehensively phenotyped SCD cohorts has precluded the identification of genetic causes of SCD risk in patients with acquired cardiac disease

  • The mechanisms underlying loci identified through GWAS could involve functional regulatory elements in the noncoding region of the genome, and understanding them is important to understanding SCD


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.

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Figure 1: SCD in various age groups.
Figure 2: Unbiased approaches for mapping of genetic variants predisposing to SCD.
Figure 3: Family with primary electrical disease displaying reduced penetrance and variable disease expression.
Figure 4: GWAS and post-GWAS strategies.


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The authors are supported by grants from the Netherlands Organization for Scientific Research (NWO, grant ZonMW Vici 918.86.616 to H. L. Tan), the Netherlands Heart Foundation (NHS2007B202 and NHS2007B010 to C. R. Bezzina), the Center for Translational Molecular Medicine (CTMM-COHFAR project, C. R. Bezzina) and the CardioVascular Onderzoek Nederland and Netherlands Heart Foundation project PREDICT (C. R. Bezzina and H. L. Tan). We thank Yuka Mizusawa for the providing the electrocardiograms in Figure 3.

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Correspondence to Connie R. Bezzina.

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Marsman, R., Tan, H. & Bezzina, C. Genetics of sudden cardiac death caused by ventricular arrhythmias. Nat Rev Cardiol 11, 96–111 (2014) doi:10.1038/nrcardio.2013.186

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