Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive ECG
Year: 2026
Type: article
Study design: Observational Study
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.
Source: Heart Rhythm
Authors: Carin de Villiers, Elizabeth Ormondroyd, Kate Thomson, Julian O.M. Ormerod, Rizwan Sarwar, Adam Waring, Richard D. Bagnall, Alexander Sparrow, Violetta Steeples, Edward Blair, Rachel J. Buchan, Alfonso Bueno-Orovio, Timothy Dent, Martin Farrall, Andrew R. Harper, Robert Hastings, Samuel Jones, Neesha Krishnan, Stefano Lise, Alistair T. Pagnamenta, Silvia Salatino, Lydia Seed, Jenny C. Taylor, Robert G. Weintraub, Dominique West, James S. Ware, Jodie Ingles, Christopher Semsarian, Hugh Watkins
Institutions: Stellenbosch University, University of Oxford, National Institute for Health and Care Research, NIHR Oxford Biomedical Research Centre, Oxford University Hospitals NHS Trust, The University of Sydney, Centenary Institute, Guy's and St Thomas' NHS Foundation Trust, Harefield Hospital, MRC London Institute of Medical Sciences, Imperial College London, Cambridge University Hospitals NHS Foundation Trust, Garvan Institute of Medical Research, UNSW Sydney, University College London, Royal Children's Hospital, The University of Melbourne, Royal Prince Alfred Hospital
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $4,790
Funders: National Institute on Handicapped Research, Wellcome Trust, National Institute for Health and Care Research, British Heart Foundation, Department of Health and Social Care, Imperial College London, NSW Ministry of Health, NIHR BioResource, Medical Research Council, National Health and Medical Research Council, NIHR Oxford Biomedical Research Centre
Awards: G1080657738, Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, G1216262684, Research Excellence (round 3), G1905341482, An integrated approach to the muscle Z-disk: from atomic structure to human disease, Curing genetic heart muscle disease (CureHeart), G3873106536, Research Excellence (renewal), Clinical, genetic and psychosocial care of families with inherited heart diseases, G7227888905, Human Genetics and Disease Biology: Core Renewal for the Wellcome Trust Centre for Human Genetics, G7511858294, G780909024, Translating Genomics into Improved Care of Inherited Heart Disease and Sudden Death Families, G8387252776
OpenAlex ID: W7128433976