The Multiple Faces of Cardiomyopathy Due to Filamin C Gene Variants (FLNC)

Abstract

Filamin C is an essential protein for the integrity of the sarcomere and cytoskeleton of cardiomyocytes. Pathogenic variants in the FLNC gene are associated with a wide range of cardiomyopathies and may present distinct phenotypes depending on the type of genetic alteration. Truncated variants are frequently associated with dilated and arrhythmogenic cardiomyopathy, while missense variants are more related to hypertrophic and restrictive forms. These phenotypic differences reflect the molecular and structural impact of the FLNC variant on filamin C protein, with direct implications for clinical management. Diagnosis and risk stratification are challenging, requiring a multimodal approach that integrates clinical, genetic, and imaging data, especially cardiac magnetic resonance imaging, which is essential for the detection of myocardial fibrosis and for prognostic assessment. Recent evidence indicates that pathogenic FLNC variants have also been rarely associated with severe acute myocarditis, often presenting with malignant ventricular arrhythmias and systolic dysfunction. Accurate diagnosis, continuous monitoring, and family counseling are essential to define the best therapeutic and prognostic approach for patients, especially those at high risk of sudden cardiac death (SCD), thus allowing personalized and preventive interventions.