Loss-of-Function FLNC Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population. (14th June 2022)

• Record Type: Journal Article
• Authors: Carruth, Eric D.; Qureshi, Maria; Alsaid, Amro; Kelly, Melissa A.; Calkins, Hugh; Murray, Brittney; Tichnell, Crystal; Sturm, Amy C.; Baras, Aris; Lester Kirchner, H.; Fornwalt, Brandon K.; James, Cynthia A.; Haggerty, Christopher M.
• Is Part Of: Circulation. Volume 15:Number 4(2022)
• Page Start: e003645
• Publication Date: 2022-06-14
• Subjects: cardiomyopathy -- electronic health records -- genotype -- magnetic resonance imaging -- phenotype; Cardiovascular system -- Diseases -- Periodicals; Cardiovascular system -- Genetics -- Periodicals; Cardiovascular Diseases -- genetics; Precision Medicine; Periodical; Fulltext; Internet Resources; Periodicals; Electronic journals; Periodicals; 616.1042
• DOI: 10.1161/CIRCGEN.121.003645
• Languages: English
• ISSNs: 2574-8300

Abstract

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.