Age-Dependent Prevalence of Pathogenic Genetic Variants in 3,000 Multi-Ethnic SCA Cases

Article Impact Level: HIGH
Data Quality: STRONG
Summary of  JACC: Clinical Electrophysiology https://doi.org/10.1016/j.jacep.2026.03.016
Dr. Evan P. Kransdorf et al.

Points

Investigators analyzed blood samples from over 3,000 multi-ethnic individuals to evaluate the prevalence of rare pathogenic genetic variants associated with sudden cardiac arrest in the general population.
Whole genome sequencing identified 15 specific genes where damaging mutations disrupt cardiac electrical functions and increase the risk of a fatal event which is currently lethal in 90 percent of cases.
The research demonstrated that genetic causes are heavily age-dependent with pathogenic variants present in 10 percent of victims under 30 compared to just three percent in those over 70.
While older populations typically experience cardiac arrest due to blocked coronary arteries younger individuals are significantly more likely to experience electrical malfunctions driven by heritable genetic defects.
The findings highlight an urgent clinical need for widespread cascade genetic testing among family members of victims to enable early medical management and preventative lifestyle interventions.

Summary

This population-based study evaluated the prevalence of rare, pathogenic genetic variants in individuals experiencing sudden cardiac arrest (SCA), an event affecting over 360,000 Americans annually with a 90% mortality rate. Utilizing whole genome sequencing, investigators from the Smidt Heart Institute at Cedars-Sinai analyzed blood samples from a representative multi-ethnic cohort of over 3,000 survivors and nonsurvivors across two distinct communities. The research mapped the patients’ entire genetic code to assess structural and functional alterations across 15 specific genes known to disrupt cardiac electrical stability and exponentially increase the risk of malignant arrhythmias.

The findings demonstrated a distinct, inverse correlation between patient age and the presence of damaging genetic mutations. Whole genome analysis revealed that 10% of individuals aged 29 and younger who experienced SCA harbored a pathogenic variant. This genetic etiology progressively declined across older cohorts, dropping to 7% in patients aged 30–49, 4% in those aged 50–69, and 3% among individuals aged 70 and older. The data suggest that while older populations are more likely to experience SCA secondary to obstructive coronary artery disease, younger cohorts are heavily predisposed by heritable channelopathies or structural variants.

These results emphasize the clinical necessity of widespread, proactive cascade genetic screening for first-degree relatives of SCA victims. Identifying asymptomatic carriers of these 15 critical genetic variants allows cardiologists to implement timely lifestyle modifications or targeted pharmacological interventions, substantially lowering the incidence of fatal electrical events. Because this study utilized geographic, multi-ethnic communities rather than single-center tertiary medical databases, the identified distribution of pathogenic variants offers a more accurate epidemiological reflection of the U.S. population, establishing a robust framework for future risk stratification guidelines.

Link to the article: https://www.jacc.org/doi/10.1016/j.jacep.2026.03.016

References

Kransdorf, E. P., Mathias, M., Nakamura, K., Chugh, H., Nguyen, D., Tyrer, J., Pharoah, P. D., Reinier, K., Akdemir, Z., Boerwinkle, E., Yu, B., & Chugh, S. S. (2026). Population-based analysis of rare genetic variants in sudden cardiac arrest. JACC: Clinical Electrophysiology, S2405500X26002598. https://doi.org/10.1016/j.jacep.2026.03.016