Abstract 13583: Secondary Findings of Loss-of-function Variants in FLNC Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes in a General Clinical Population

Abstract

Introduction: The FLNC gene, encoding the Filamin C sarcomere protein, has gained recent attention as a potential cause of severe cardiomyopathy and arrhythmia phenotypes through genetic testing of individuals with known inherited heart disease. We sought to characterize the phenotypes associated with rare, putative loss-of-function variants in FLNC ascertained through secondary findings of exome sequencing in a large clinical population. Methods: We reviewed exome data from the first 135,878 sequenced participants in the Geisinger MyCode Community Health Initiative with linked electronic health records (EHR; the DiscovEHR cohort) to identify rare frameshift, stop gain, or canonical splice site variants in FLNC (FLNC LOF ). We compared data on diagnoses and cardiac diagnostic testing (i.e., ECG and echocardiography, when available) from the EHR between individuals with and without FLNC LOF using SAIGE mixed linear models adjusted for age, sex, and ancestry. Results: We observed 46 individuals (0.03%) carrying one of 24 distinct FLNC LOF variants. These individuals had significantly increased odds for diagnoses of dilated cardiomyopathy (OR: 49, 95% CI: [4-560]), ventricular tachycardia (OR: 170, [5-6317]), and supraventricular tachycardia (OR: 11, [2-77]). We also observed significantly increased left ventricular (LV) diameter (5.1 ± 0.8 cm vs. 4.6 ± 0.7 cm, p = 0.001) and decreased LV ejection fraction (Figure) by echocardiography (available in 50% of FLNC LOF individuals), and a trend toward higher prevalence of inverted T waves in any precordial lead beyond V2 (23% vs. 7%, p = 0.06). Conclusion: Loss-of-function variants in FLNC are extremely rare in a general clinical population but are associated with a clinically significant and potentially actionable, yet incompletely penetrant, cardiac phenotype marked by ventricular dysfunction and dysrhythmia. Consideration for screening and return of secondary findings may be warranted.