Phenotypic Variability of Filamin C-related Cardiomyopathy: Insights from a Novel Dutch Founder Variant

BACKGROUND: Dilated cardiomyopathy (DCM) can be caused by truncating variants in the filamin C gene (FLNC). A new pathogenic FLNC variant, c.6864_6867dup, p.(Val2290Argfs*23), was recently identified in Dutch DCM patients. OBJECTIVE: The report aimed to evaluate the phenotype of FLNC variant carriers and to determine whether this variant is a founder variant. METHODS: Clinical and genetic data were retrospectively collected from variant carriers. Cardiovascular magnetic resonance (CMR) studies were reassessed. Haplotypes were reconstructed to determine a founder effect. The geographical distribution and age of the variant were determined. RESULTS: Thirty-three individuals (70% female) from nine families were identified. Sudden cardiac death was the first presentation in a carrier at 28 years of age. Median age at diagnosis was 41 years (range 19-67). The phenotype was heterogeneous. DCM with left ventricular (LV) dilation and reduced ejection fraction (<45%) was present in eleven individuals (33%), three (9%) of whom underwent heart transplantation. CMR showed late gadolinium enhancement (LGE) in 65% of the assessed individuals, primarily in a ring-like distribution. Non-sustained ventricular arrhythmias were detected in six (18%), and five (15%) individuals received an implantable cardioverter defibrillator. A shared haplotype spanning 2.1 Mb was found in all haplotyped individuals. The variant originated between 275-650 years ago. CONCLUSION: The pathogenic FLNC variant c.6864_6867dup, p.(Val2290Argfs*23) is a founder variant originating from the south of the Netherlands. Carriers are susceptible to developing heart failure and ventricular arrhythmias. The cardiac phenotype is characterized by ring-like LGE, even in individuals without significantly reduced LV function.