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Updated: May 21, 2026
07:15
Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation
Published on: January 16, 2019
Population-Based Analysis of Rare Genetic Variants in Sudden Cardiac Arrest
Evan P Kransdorf1, Marco Mathias1, Kotoka Nakamura1
1Center for Cardiac Arrest Prevention, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, California, USA.
JACC. Clinical Electrophysiology
|May 20, 2026
Summary
Rare genetic variants increase sudden cardiac arrest (SCA) risk. This population-based study found disease-causing variants in 4.0% of SCA patients, identifying 15 key genes for targeted prevention strategies.
Area of Science:
- Cardiovascular Genetics
- Population Health
- Genomic Medicine
Background:
- Over 360,000 Americans experience sudden cardiac arrest (SCA) annually.
- A subset of SCA cases is linked to rare genetic variants, but prior research was limited to non-survivors and not population-based.
Purpose of the Study:
- To determine the prevalence of disease-causing rare genetic variants in both survivors and non-survivors of SCA within the general population.
- To identify specific genes associated with increased SCA risk.
Main Methods:
- Whole genome sequencing was conducted on 3,264 SCA patients and 13,258 controls from community-based studies.
- Disease-causing variants in 63 candidate arrhythmia/cardiomyopathy genes were identified using updated ACMG criteria.
- Gene-collapsing case-control analysis and comparison with the Genome Aggregation Database were performed.
Main Results:
- Disease-causing variants were found in 4.0% of SCA patients versus 2.4% of controls (OR: 1.59, P < 0.001).
- In non-ischemic SCA cases, 6.1% harbored a disease-causing variant (OR: 2.52, P < 0.001).
- Fifteen genes, including ACTC1, KCNH2, and TTN, were associated with increased SCA risk.
Conclusions:
- Specific disease-causing variants in 15 arrhythmia and cardiomyopathy genes are linked to increased SCA risk in the community.
- These findings support the development of targeted SCA prevention strategies for families carrying these genetic variants.
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