Abstract 13122: Exome Sequencing Reveals Novel Genetic Variants Predisposing to Sudden Cardiac Death Due to Primary Myocardial Fibrosis

Introduction: Sudden cardiac death (SCD) is one of the most common modes of death in Western countries. In post-mortem investigations, myocardial fibrosis is a common finding, as more than 90% of the SCD victims have fibrotic accumulation in the myocardium. Hypothesis: Our aim was to identify novel candidate genes and variants predisposing to the development of myocardial fibrosis in SCD victims. Methods: Whole exome sequencing was performed for 127 nonischemic SCD cases with primary myocardial fibrosis as the only pathological finding. We searched for rare variants with minor allele frequency <0.005 estimated to be pathogenic and present in three or more cases. A computational approach was used to identify protein interactions for candidate genes in cardiomyocytes. Associations of the identified variants with cardiovascular disease endpoints were investigated in the Finnish national genetic study (FinnGen) dataset. Results: We identified 21 missense and one nonsense variant in SCD victims with primary myocardial fibrosis. Most variants locate in genes participating in extracellular matrix (ECM) formation, inflammation, mitochondrial function, cardiomyocyte contractility or hypertrophy. Heart enhanced protein interactions were identified for 16 candidate genes. Ten variants were significantly associated with SCD and primary myocardial fibrosis (adjusted p-value <0.05). Sixteen variants were also associated with cardiac diseases in Finnish general population. Four missense variants were highly likely to be pathogenic, significantly associated with sudden cardiac death due to primary myocardial fibrosis and were also associated with cardiac diseases in general Finnish population. These variants locate in cartilage acidic protein 1 ( CRATC1 ), the calpain 1 ( CAPN1 ), unc-45 myosin chaperone A (UNC45A) and unc-45 myosin chaperone B (UNC45B). Conclusions: We identified novel variants and candidate genes predisposing to sudden cardiac death due to primary myocardial fibrosis. Our results highlight the importance ECM pathways as well as cardiomyocyte function and survival in the pro-fibrotic process.