Loss-of-Function <i>FLNC</i> Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population
Eric Carruth, Maria Qureshi, Amro Alsaid, Melissa Kelly, Hugh Calkins, Brittney Murray, Crystal Tichnell, Amy C. Sturm, Aris Baras, H. Lester Kirchner, Brandon K. Fornwalt, Cynthia A. James, Christopher M. Haggerty
Abstract
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.