The Multifaceted Role of the FLNC Gene in Hereditary Cardiomyopathies and Prognosis.

Abstract

Variants in the filamin C (FLNC) gene are increasingly recognized as causes of cardiac and skeletal muscle disease. Cardiomyopathy-associated FLNC variants span dilated cardiomyopathy (DCM), nondilated left ventricular cardiomyopathy (NDLVC), arrhythmogenic cardiomyopathy (ACM), hypertrophic cardiomyopathy (HCM), and restrictive cardiomyopathy (RCM), but their clinical interpretation depends strongly on variant class and evidence of pathogenicity. FLNC truncating variants (FLNCtv), including nonsense, frameshift, and canonical splice-site variants, usually cause haploinsufficiency through nonsense-mediated decay and are predominantly associated with DCM/NDLVC and left-dominant ACM. These phenotypes frequently show subepicardial or circumferential ring-like fibrosis and clinically important ventricular arrhythmias that may occur despite only mild left ventricular dysfunction. On the other hand, selected pathogenic missense variants, particularly within the actin-binding domain or ROD2 immunoglobulin-like repeats 18-21, may promote protein misfolding and aggregation and have been associated with HCM or RCM, including the distinctive saw-tooth myocardial phenotype. However, most reported FLNC missense variants remain variants of uncertain significance and must not be considered disease-causing on the basis of location alone. This narrative review summarizes FLNC molecular biology, genotype-phenotype relationships, imaging features, arrhythmic risk, and implications for clinical management. It also discusses the limited evidence linking FLNCtv to arrhythmogenic mitral valve prolapse with mitral annular disjunction. Accurate variant classification and phenotype integration are essential for diagnosis and for individualized prevention of sudden cardiac death (SCD).