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Hypertrophic cardiomyopathy caused by filamin-C variants has restrictive and extracardiac features and a distinctive
Carin de Villiers1, Elizabeth Ormondroyd2, Kate Thomson3
1Division of Cardiovascular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom; Department of Physiological Sciences, Faculty of Science, Stellenbosch University, Stellenbosch, South Africa.
Insights
Rare Filamin-C (FLNC) gene variants are linked to hypertrophic/restrictive cardiomyopathy (HCM/RCM), causing a distinct phenotype including ECG abnormalities and extra-cardiac issues. These non-truncating FLNC variants significantly contribute to HCM/RCM, especially in patients with a characteristic ECG.
Area of Science:
- Cardiovascular Genetics
- Molecular Cardiology
- Genetic Basis of Cardiomyopathy
Background:
- Filamin-C (FLNC) gene variants are implicated in cardiac and skeletal muscle disorders.
- Loss-of-function FLNC variants are known contributors to dilated cardiomyopathy.
Purpose of the Study:
- To investigate the role of rare FLNC variants in hypertrophic/restrictive cardiomyopathy (HCM/RCM).
- To characterize the clinical phenotype associated with FLNC variants in HCM/RCM patients.
Main Methods:
- Family-based studies and statistical modeling of rare FLNC missense variants.
- Analysis of a cohort including 3,289 sarcomere-negative HCM cases and 122,348 controls.
Main Results:
- A distinct ECG repolarization phenotype was identified in 37% of HCM/RCM patients with rare FLNC variants.
- FLNC variant carriers with the characteristic ECG showed smaller LV cavity size, reduced contractility, and more severe diastolic dysfunction.
- Higher etiological fraction for FLNC variants was observed in HCM/RCM cases with the characteristic ECG (0.98) compared to all HCM cases (0.45).
Conclusions:
- Pathogenic FLNC variants in HCM/RCM are non-truncating and present a distinct phenotype.
- This phenotype includes characteristic ECG findings, hypertrophic/restrictive features without hypercontractility, and extra-cardiac abnormalities.
- FLNC variants are a significant cause of HCM/RCM, particularly in individuals presenting with the identified ECG phenotype.
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.
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