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

A significant portion (~12-30%) of children/young adults with sudden cardiac arrest (SCA) have identifiable pathogenic gene variants 1 .Prior studies have largely been performed in referral cohorts with mostly European ancestry, and the prevalence of rare variants among unselected young SCA victims in a diverse community is not fully known.In this study, we used data from two community-based SCA cohorts to analyze rare gene variants in young SCA victims.Our study subjects are drawn from 2 prospective, community-based studies of SCA in the United States: the Oregon SUDS (Portland Oregon metro area, population ~1 million, since 2002) and Ventura PRESTO studies (Ventura County, CA, population ~850,000, since 2015).The study protocols have been described earlier in more detail 2, 3 .Between March 2002 and January 2021, 8,210 SCA cases were ascertained in the two communities.Of these 209 were <21 years of which 52 underwent next-generation whole genome sequencing and were included in the present study.DNA was sequenced at Baylor Human Genomic Science Center and processed using the validated Mercury pipeline 4 .We included genes with "definitive", "strong", and "moderate" associations with inherited arrhythmia syndromes and cardiomyopathies in the ClinGen Gene-Disease Validity expert panels.We excluded variants with minor allele frequency (MAF) > 0.5%.Variant classification was performed with Sherloc.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.The data that support the findings are available from the corresponding author upon reasonable request.