Filamin-C variant-associated cardiomyopathy: Apooled analysis of individual patient data to evaluate the clinical profile and risk of sudden cardiac death.

Rudy Celeghin,Kalliopi Pilichou,Domenico Corrado,Monica De Gaspari,Gaetano Thiene,Sabino Iliceto,Cristina Basso,Marco Cason,Alberto Cipriani,Maria Bueno Marinas,Michela Bevilacqua,Ilaria Rigato,Martina Perazzolo Marra,Stefania Rizzo,Alessandro Zorzi,Barbara Bauce,Riccardo Bariani,Stefano Da Pozzo

doi:10.1016/j.hrthm.2021.09.029

Abstract

Mutations in filamin-C (FLNC) are involved in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM), and have been associated with a left ventricular (LV) phenotype, characterized by nonischemic LV fibrosis, ventricular arrhythmias, and sudden cardiac death (SCD). The purpose of this study was to investigate the prevalence of FLNC variants in a gene-negative ACM population and to evaluate the clinical phenotype and SCD risk factors in FLNC-associated cardiomyopathies. ACM probands who tested negative for mutations in ACM-related genes underwent FLNC genetic screening. Clinical and genetic data were collected and pooled together with those of previously published FLNC-ACM and FLNC-DCM patients. In a cohort of 270 gene-elusive ACM probands, 12 (4.4%) had FLNC variants, and 13 additional family members carried the same mutation. Eighteen FLNC variant carriers (72%) had a diagnosis of ACM (72% male; mean age 45 years). On pooled analysis, 145 patients with FLNC-associated cardiomyopathies were included. Electrocardiographic (ECG) low QRS voltages were detected in 37%, and T-wave inversion (TWI) in inferolateral/lateral leads in 24%. Among 67 patients who had cardiac magnetic resonance (CMR), LV nonischemic late gadolinium enhancement (LGE) was found in 75%. SCD occurred in 28 patients (19%), 15 of whom showed LV nonischemic LGE/fibrosis. Compared with patients with no SCD, those who experienced SCD more frequently had inferolateral/lateral TWI (P = .013) and LV LGE/fibrosis (P = .033). Clinical phenotype of FLNC cardiomyopathies is characterized by late-onset presentation and typical ECG and CMR features. SCD is associated with the presence of LV LGE/fibrosis but not with severe LV systolic dysfunction.

Highlights

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited heart muscle disease characterized by myocardial scar, systolic right ventricular (RV) and/or left ventricular (LV)dysfunction, and malignant ventricular arrhythmias (VAs).[1,2,3] The hallmark of ACM is the replacement of ventricular myocardium by fibrofatty tissue, which progresses over time.[1,2,3] Approximately one-half of ACM patients harbor genetic variants in genes encoding major components of the cardiac desmosomes, mutations in nondesmosomal genes have been described in association with ACM.[3,4] Among them, mutations in gene
Two hundred seventy gene-elusive ACM index cases with genetic testing detected 12 FLNC rare variants (4.4%) (Table 1), including 7 “radical” variants (4 deletions/ insertions, 2 nonsense and 1 splice site variants) classified as pathogenic/likely pathogenic (P/LP), and 5 missense variants classified as variants of unknown significance according to American College of Medical Genetics and Genomics recommendations
(3) The clinical phenotype of patients with FLNC-associated cardiomyopathy was characterized by ECG abnormalities such as low QRS voltages and inferolateral/lateral T-wave inversion (TWI), frequent and complex VAs, and extensive nonischemic LV late gadolinium enhancement (LGE)/myocardial fibrosis on cardiac magnetic resonance (CMR) or postmortem analysis

Summary

Introduction

Arrhythmogenic cardiomyopathy (ACM) is a rare inherited heart muscle disease characterized by myocardial scar, systolic right ventricular (RV) and/or left ventricular (LV). Dysfunction, and malignant ventricular arrhythmias (VAs).[1,2,3] The hallmark of ACM is the replacement of ventricular myocardium by fibrofatty tissue, which progresses over time.[1,2,3] Approximately one-half of ACM patients harbor genetic variants in genes encoding major components of the cardiac desmosomes, mutations in nondesmosomal genes have been described in association with ACM.[3,4] Among them, mutations in gene. Mutations in filamin-C (FLNC) are involved in the pathogenesis of arrhythmogenic cardiomyopathy (ACM) and dilated cardiomyopathy (DCM), and have been associated with a left ventricular (LV) phenotype, characterized by nonischemic LV fibrosis, ventricular arrhythmias, and sudden cardiac death (SCD)

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