Loss-of-Function FLNC Variants are Associated with Arrhythmogenic Cardiomyopathy Phenotypes when Identified through Exome Sequencing of a General Clinical Population

Background The FLNC gene has recently garnered attention as a likely cause of arrhythmogenic cardiomyopathy (ACM), which is considered an actionable genetic condition. However, the association with disease in an unselected clinical population is unknown. We hypothesized that individuals with loss-of-function variants in FLNC (FLNCLOF) would have increased odds for ACM-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort. Methods We identified rare, putative FLNCLOF among 171,948 individuals with exome sequencing linked to health records. Associations with ACM phenotypes from available diagnoses and cardiac evaluations were investigated. Results Sixty individuals (0.03%; median age 58 years [47 -- 70 IQR], 43% male) harbored 27 unique FLNCLOF. These individuals had significantly increased odds ratios (OR) for dilated cardiomyopathy (OR:4.9, [95% confidence interval: 2.6 -- 7.6]; p<0.001), supraventricular tachycardia (OR:3.2, [1.1 -- 5.6]; p=0.01), defibrillator implantation (OR:4.6, [1.9 -- 8.4]; p<0.001), and left-dominant ACM (OR:4.2, [1.4 -- 7.9]; p=0.003). Echocardiography revealed reduced left ventricular ejection fraction (52 {+/-} 13% vs. 57 {+/-} 9%; p=0.001) associated with FLNCLOF. Overall, at least 9% of FLNCLOF carriers demonstrated evidence of penetrant disease. Conclusions FLNCLOF variants are associated with increased odds of ventricular arrhythmia and dysfunction in an unselected clinical population. These findings support genomic screening of FLNC for actionable secondary findings.