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, 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 ( FLNC LOF ) would have increased odds for arrhythmogenic cardiomyopathy-associated phenotypes versus variant-negative controls in the Geisinger MyCode cohort. Methods: We identified rare, putative FLNC LOF among 171 948 individuals with exome sequencing linked to health records. Associations with arrhythmogenic cardiomyopathy phenotypes from available diagnoses and cardiac evaluations were investigated. Results: Sixty individuals (0.03%; median age 58 years [47–70 interquartile range], 43% male) harbored 27 unique FLNC LOF . These individuals had significantly increased odds ratios for dilated cardiomyopathy (odds ratio, 4.9 [95% CI, 2.6–7.6]; P <0.001), supraventricular tachycardia (odds ratio, 3.2 [95% CI, 1.1–5.6]; P =0.048), and left-dominant arrhythmogenic cardiomyopathy (odds ratio, 4.2 [95% CI, 1.4–7.9]; P =0.03). Echocardiography revealed reduced left ventricular ejection fraction (52±13% versus 57±9%; P =0.001) associated with FLNC LOF . Overall, at least 9% of FLNC LOF patients demonstrated evidence of penetrant disease. Conclusions: FLNC LOF 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.