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  • Review Article
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Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death

Nature Reviews Cardiology volume 18, pages 774–784 (2021)Cite this article

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Abstract

A genetic risk of sudden cardiac arrest and sudden death due to an arrhythmic cause, known as sudden cardiac death (SCD), has become apparent from epidemiological studies in the general population and in patients with ischaemic heart disease. However, genetic susceptibility to sudden death is greatest in young people and is associated with uncommon, monogenic forms of heart disease. Despite comprehensive pathology and genetic evaluations, SCD remains unexplained in a proportion of young people and is termed sudden arrhythmic death syndrome, which poses challenges to the identification of relatives from affected families who might be at risk of SCD. In this Review, we assess the current understanding of the epidemiology and causes of SCD and evaluate both the monogenic and the polygenic contributions to the risk of SCD in the young and SCD associated with drug therapy. Finally, we analyse the potential clinical role of genomic testing in the prevention of SCD in the general population.

Key points

  • Sudden cardiac death (SCD) is a leading cause of death in Western countries, and a genetic risk of SCD is well established.

  • Rare variants in genes encoding proteins linked with cardiac structure or electrical activity have been associated with the risk of SCD in the young (aged <35 years).

  • Common genetic variants in the general population are increasingly recognized to contribute to the phenotypic expression of cardiac diseases and the risk of SCD.

  • A better understanding of the influence of genomic variation on the individual risk of SCD is needed to implement clinical strategies, such as polygenic risk scores, to predict and prevent SCD.

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Fig. 1: Aetiology of unexpected SCD.
Fig. 2: Aetiology of unexpected SCA.
Fig. 3: Genetic variant frequency, effect size and classification.
Fig. 4: Genetic analysis approach to rare and common diseases.

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Acknowledgements

C.S. and E.R.B. are supported by the Robert Lancaster Memorial Fund sponsored by McColl’s Retail Group Ltd. C.R.B. is supported by the Dutch Heart Foundation (CVON Predict2 project), the Netherlands Organization for Scientific Research (VICI fellowship, 016.150.610) and Fondation Leducq (17CVD02). M.J.A. is supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program.

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Authors and Affiliations

  1. Cardiovascular Clinical Academic Group, Molecular and Clinical Sciences Institute, St George’s University of London and St George’s University Hospitals NHS Foundation Trust, London, UK

    Chiara Scrocco & Elijah R. Behr

  2. Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands

    Connie R. Bezzina

  3. Departments of Cardiovascular Medicine, Pediatric and Adolescent Medicine, and Molecular Pharmacology & Experimental Therapeutics; Divisions of Heart Rhythm Services and Pediatric Cardiology, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

  4. Windland Smith Rice Genetic Heart Rhythm Clinic and the Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN, USA

    Michael J. Ackerman

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  4. Elijah R. Behr
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Contributions

C.S. researched data for and wrote the article. All the authors contributed substantially to discussion of the content and reviewed and/or edited the manuscript before submission.

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Correspondence to Elijah R. Behr.

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Nature Reviews Cardiology thanks C. Napolitano, C. Semsarian and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

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Related links

gnomAD: https://gnomad.broadinstitute.org/

HapMap: https://www.genome.gov/10001688/international-hapmap-project

Human Genome Project: https://www.genome.gov/human-genome-project

Glossary

Alleles

An allele is one of several alternative forms of a gene occupying a specific locus on a chromosome.

Minor allele frequency

The frequency at which the second most common allele occurs in a given population.

Founder variants

Disease-causing genetic variants that are found repeatedly in a given population and that are derived from a shared ancestor who harboured that variant.

Primary arrhythmia syndromes

Inheritable cardiac conditions predisposing individuals to arrhythmias in the absence of structural heart disease.

Exonic

Relating to a coding segment of DNA.

Single-nucleotide polymorphisms

Substitutions of individual nucleotides that occur with a measurable frequency.

Risk alleles

Alleles that confer a risk of developing a disease.

Linkage disequilibrium

Non-random association between particular DNA variants at two sites that are physically close to one another on the chromosome (that is, the frequency is significantly greater than that expected from the product of the observed allelic frequencies at each site independently).

Intronic

Relating to a non-coding segment of DNA.

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Scrocco, C., Bezzina, C.R., Ackerman, M.J. et al. Genetics and genomics of arrhythmic risk: current and future strategies to prevent sudden cardiac death. Nat Rev Cardiol 18, 774–784 (2021). https://doi.org/10.1038/s41569-021-00555-y

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