Loss-of-Function FLNC Variants Are Associated With Arrhythmogenic Cardiomyopathy Phenotypes When Identified Through Exome Sequencing of a General Clinical Population.

Autor: Carruth ED; Department of Translational Data Science and Informatics (E.D.C., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA., Qureshi M; The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA., Alsaid A; The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA., Kelly MA; Genomic Medicine Institute (M.A.K., A.C.S.), Geisinger, Danville, PA., Calkins H; Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)., Murray B; Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)., Tichnell C; Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)., Sturm AC; The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA.; Genomic Medicine Institute (M.A.K., A.C.S.), Geisinger, Danville, PA., Baras A; Regeneron Genetics Center, Tarrytown, NY (A.B.)., Lester Kirchner H; Department of Translational Data Science and Informatics (E.D.C., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA.; Department of Population Health Sciences (H.L.K.), Geisinger, Danville, PA., Fornwalt BK; Department of Translational Data Science and Informatics (E.D.C., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA.; The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA.; Department of Radiology (B.K.F.), Geisinger, Danville, PA., James CA; Department of Medicine, Division of Cardiology, Johns Hopkins Medical Center, Baltimore, MD (H.C., B.M., C.T., C.A.J.)., Haggerty CM; Department of Translational Data Science and Informatics (E.D.C., H.L.K., B.K.F., C.M.H.), Geisinger, Danville, PA.; The Heart Institute (M.Q., A.A., A.C.S., B.K.F., C.M.H.), Geisinger, Danville, PA.
Jazyk: angličtina
Zdroj: Circulation. Genomic and precision medicine [Circ Genom Precis Med] 2022 Aug; Vol. 15 (4), pp. e003645. Date of Electronic Publication: 2022 Jun 14.
DOI: 10.1161/CIRCGEN.121.003645
Abstrakt: 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.
Databáze: MEDLINE
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