Phenotypic variability of FLNC-related cardiomyopathy: insights from a novel Dutch founder variant

Abstract Background Truncating variants in filamin C (encoded by the FLNC gene) are an important cause of dilated cardiomyopathy (DCM). Recently, a new pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs*23) was identified in a number of families with DCM in the south of the Netherlands. Objectives The aim of this study was to: (i) investigate whether this FLNC variant is a founder variant; and (ii) to evaluate the clinical phenotype of the affected individuals. Material and methods Genetic and clinical data from these FLNC carriers were retrospectively collected. To determine a possible founder effect, haplotypes were reconstructed. The geographical distribution and age of the variant were determined. Clinical characteristics and outcomes were retrieved from electronic medical records. Cardiac magnetic resonance imaging (CMR) studies were reviewed. Results In total 33 individuals from 9 families carrying this FLNC variant were identified. A shared haplotype spanning 2.1 Mb was present in all subjects that were haplotyped. The variant appears to have originated in the south of the Netherlands between 275 and 650 years ago. Median age was 53 years (range 20–79). Nine (27%) individuals were male. The clinical presentation is heterogeneous, ranging from the presence of DCM with heart failure with reduced ejection fraction in 11 (33%) subjects (median age 57, range 36–79 years), to presentation with sudden cardiac death (SCD) in 1 subject at 28 years of age with LV dilation and fibrosis on pathology, without prior symptoms. Seven subjects (21%) had left ventricular (LV) dilation with normal LV function, and one had midrange LV function without dilation. Nine (27%) subjects had no cardiac abnormalities, with a median age of 56 (range 26–70). CMR was available in 18 subjects and showed late gadolinium enhancement (LGE), indicating fibrosis, in 11 subjects (61%), including 2 with preserved LV function. The LGE was extensively present in epicardial and infrequently in the subepicardial LV segments, with ring-like distributions being observed in 4 (22%) of the assessed patients. During follow-up 1 subject experienced SCD and 3 developed end-stage heart failure and underwent heart transplantation. Six (18%) subjects had asymptomatic non-sustained ventricular arrhythmias detected by Holter monitoring, and 4 (12%) subjects received an implantable cardioverter defibrillator for primary prevention and 1 for secondary prevention. Conclusion The c.6864_6867dup, p.(Val2290Argfs*23) pathogenic FLNC variant is a founder variant originating from the south of the Netherlands. The phenotype is characterized by extensive myocardial fibrosis, even in subjects with preserved LV function, making subjects prone to both arrhythmias and heart failure. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Dutch Heart Foundation