Abstract 4364433: Systematic phenotyping, cause of death and genomics Analysis in Sudden Cardiac Arrest

Introduction: Sudden cardiac arrest (SCA) continues to have poor survival, with 90% of cases succumbing to sudden cardiac death (SCD). Despite international guidelines, high mortality rates, especially in out-of-hospital settings, and low autopsy rates, limit comprehensive evaluation to determine cause of death (COD) or perform genetic testing. Hypothesis: Pathogenic variants, in dyslipidemia, channelopathy- and cardiomyopathy-related genes, will be identified at a higher frequency than matched controls. Methods: The Gene Health Project “a community health research program” is a systematic prospective biobank of individuals aged ≥18 years who have undergone blended whole exome (WES) and genome sequencing (WGS). Cases of decedents were systematically evaluated using multi-source ascertainment, and a priori adjudication guidelines. Genetic analyses of 117 genes previously associated with SCD were categorized into ACMG pathogenicity criteria using established bioinformatic pipelines. Only ClinVar ≥** pathogenic (P) or likely pathogenic (LP) were considered significant. Results: Amongst 35,000 individuals recruited over the past 24 months, 93 (0.26%) experienced SCA/SCD (16 (17.2%) males; median age of death: 62 (20-79 years)). Genomic analysis revealed 24 cases (25.8% vs. 5% matched control; P<0.0005) to be carriers for P/LP variants in Mendelian cardiovascular genes, including LMNA, FLNC, LDLR CHD2 and MYH7, out of the 24 gene-positive cases 4 were carriers for LDLR. Conclusion: Prospective biobanking with WES and WGS has utility in evaluating the etiology of SCD cases, identifying a Mendelian cause in 25% of cases. Identifying these pathogenic variants will provide a valuable perspective on the genetic basis of SCD, highlighting the importance of familial screening, precision-based therapy and preventive care in reducing the public health burden of SCD.