Rare Genetic Variants Associated with Sudden Cardiac Arrest in the Young: A Prospective, Population-Based Study

Abstract

Background: Sudden cardiac arrest (SCA) is a rare and tragic event among the young and often caused by inherited cardiac disease. Previous studies have investigated referral cohorts, but the prevalence of disease-associated variants is unclear at the community level. We investigated the prevalence of genetic variants among community-based cases of SCA aged <21 years. Methods: The study sample is obtained from two prospective, community-based studies of out-of-hospital SCA ongoing in the Portland, OR metro area (population ~1 million) and Ventura County CA (population ~850,000). We performed next-generation whole genome sequencing and then rare variant analysis of candidate genes associated with arrhythmic syndromes and cardiomyopathy in ClinGen. Results: The mean age of the study subjects was 11.3 years (SD 8.0 years, 30% non-white, 45% female). We found that 36 of 52 young SCA victims (69%) harbored uncertain, likely pathogenic (LP), or pathogenic (P) variants. Eight subjects (15%) carried 9 LP/P variants. Patients with clinical histories suggesting primary arrhythmic syndromes or hypertrophic cardiomyopathy were more likely to harbor clinically actionable variants or variants of unknown significance (VUS), than subjects with myocarditis, sudden infant death syndrome, or sudden arrhythmic death. Variants were more likely to be classified as LP/P among Whites (8/9, 88.9%) as compared to non-Whites (1/9, 11.1%, p = 0.036). Conclusions: A notable proportion of young SCA victims in the community harbor rare, potentially disease-associated gene variants, and further studies are needed to understand variants of unknown significance. We identified differences by phenotype groups and race that have potential implications for genetic testing.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

This work is funded, in part, by National Institutes of Health, National Heart Lung and Blood Institute Grants R01HL145675 and R01HL147358 to SSC. SSC holds the Pauline and Harold Price Chair in Cardiac Electrophysiology at Cedars-Sinai. LH is a postdoctoral fellow visiting from the Research Unit of Internal Medicine, Medical Research Center Oulu, University of Oulu and Oulu University Hospital, Oulu, Finland, and is funded by Sigrid Juselius Foundation, The Finnish Cultural Foundation, Instrumentarium Science Foundation, Orion Research Foundation, and Paavo Nurmi Foundation. The funding sources had no involvement in the preparation of this work or the decision to submit it for publication.

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

The study protocol was approved by the institutional review boards of Ventura County Medical Center, Oregon Health and Science University, and the Cedars-Sinai Health System. This study includes both deceased and alive subjects. All analysis of deceased subjects is conducted in a de-identified manner. All subjects who are alive were approached and provided their consent to participate. There are no specific patient IDs in this study. Samples are numbered 1 through 52 and the IDs are not known to anyone outside the research group.

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Data Availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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