Heart Rhythm. 2026 Feb 9:S1547-5271(26)00121-9. doi: 10.1016/j.hrthm.2026.01.054. Online ahead of print.
ABSTRACT
BACKGROUND: Filamin-C (FLNC) gene variants are associated with cardiac and skeletal muscle diseases including a clear role of loss-of-function variants in dilated cardiomyopathy.
OBJECTIVE: This study aimed to assess the contribution of rare FLNC variants to hypertrophic cardiomyopathy (HCM)/restrictive cardiomyopathy (RCM).
METHODS: Family-based studies in 2 specialist services and statistical modeling of rare FLNC missense variants were conducted, using a cohort of 3289 sarcomere-negative HCM cases and 122,348 genome aggregation database controls.
RESULTS: Clinical evaluation of patients with HCM/RCM and a rare FLNC variant identified a distinct electrocardiographic (ECG) repolarization phenotype in 37% (19 of 51 individuals, from 12 families), which was observed in only 1.0% of a control HCM cohort (2 of 197). FLNC variant carriers with the characteristic ECG had smaller left ventricular cavity size, lower contractility, and more severe diastolic dysfunction and were more likely to have a restrictive phenotype. Heart failure death, transplant, or cardiac arrest occurred in at least 1 individual in 7 of the 12 families (58%) in the "ECG-positive" group, and musculoskeletal abnormalities were present in 4 families (33%). 5 of 12 variants (41.7%) in the "ECG-positive" group cosegregated, and 2 were apparently de novo. 11 variants were missense, and 1 splice site. Rare FLNC missense variant burden indicated a low case excess among all HCM cases (etiologic fraction, 0.45; 95% confidence interval, 0.36-0.54), but in "ECG-positive" cases the etiologic fraction was substantially higher (0.98; 95% confidence interval, 0.97-0.99).
CONCLUSION: Pathogenic FLNC variants in patients with HCM/RCM are nontruncating and cause a discrete phenotype comprising a characteristic ECG, hypertrophic and restrictive features without hypercontractility, and extracardiac abnormalities.
PMID:41672210 | DOI:10.1016/j.hrthm.2026.01.054