Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Multicenter Study
. 2025 Apr 1;10(4):359-369.
doi: 10.1001/jamacardio.2024.5543.

Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants

Filamin C Registry Consortium; Marta Gigli  1   2 , Davide Stolfo  1   3 , Giulia Barbati  4 , Sharon Graw  5 , Suet Nee Chen  5 , Marco Merlo  1 , Kristen Medo  5 , Caterina Gregorio  4   6   7 , Matteo Dal Ferro  1 , Alessia Paldino  1 , Maria Perotto  1 , J Peter van Tintelen  2   8 , Anneline S J M Te Riele  2   8   9 , Annette F Baas  2   8 , Arthur M Wilde  2   10 , Ahmad S Amin  2   10 , Arjan C Houweling  2   11 , Perry Elliott  12 , Douglas Cannie  12 , Michelle Michels  2   13 , Stephan A C Schoonvelde  2   13 , Sanjay Prasad  14   15 , Paz Upasana Tayal  14   15 , Momina Yazdani  14   15 , Deborah Morris-Rosendahl  14   15 , Pablo Garcia-Pavia  2   16   17 , Eva Cabrera-Romero  2   16 , Barbara Bauce  2   18 , Kalliopi Pilichou  2   18 , Diane Fatkin  19   20   21 , Renee Johnson  19   21 , Daniel P Judge  22 , Kimberly L Foil  22 , Stephane Heymans  2   23 , Job A J Verdonschot  2   23 , Sophie L V M Stroeks  2   23 , Neal K Lakdawala  24 , Purohit Anisha  24 , Matthew O'Neill  25 , M Benjamin Shoemaker  26 , Dan M Roden  27 , Hugh Calkins  28 , Cynthia A James  28 , Brittney Murray  28 , Victoria N Parikh  29 , Euan A Ashley  29 , Chloe Reuter  29 , Massimo Imazio  30 , Marco Canepa  31   32 , Pietro Ameri  31   32 , Jiangping Song  33 , Gianfranco Sinagra  1 , Matthew R G Taylor  5 , Luisa Mestroni  5
Affiliations
Multicenter Study

Arrhythmic Risk Stratification of Carriers of Filamin C Truncating Variants

Filamin C Registry Consortium et al. JAMA Cardiol. .

Abstract

Importance: Filamin C truncating variants (FLNCtv) are a rare cause of cardiomyopathy with heterogeneous phenotypic presentations. Despite a high incidence of life-threatening ventricular arrhythmias and sudden cardiac death (SCD), reliable risk predictors to stratify carriers of FLNCtv are lacking.

Objective: To determine factors predictive of SCD/major ventricular arrhythmias (MVA) in carriers of FLNCtv.

Design, setting, and participants: This was an international, multicenter, retrospective cohort study conducted from February 2023 to June 2024. The Filamin C Registry Consortium included 19 referral centers for genetic cardiomyopathies worldwide. Participants included carriers of pathogenic or likely pathogenic FLNCtv. Phenotype negative was defined as the absence of any pathological findings detected by 12-lead electrocardiogram (ECG), Holter ECG monitoring, echocardiography, or cardiac magnetic resonance.

Exposures: Composite of SCD and MVA in carriers of FLNCtv.

Main outcomes and measures: The primary outcome was a composite of SCD and MVA, the last including aborted SCD, sustained ventricular tachycardia, and appropriate implantable cardioverter-defibrillator (ICD) interventions.

Results: Among 308 individuals (median [IQR] age, 45 [33-56] years; 160 male [52%]) with FLNCtv, 112 (36%) were probands, and 72 (23%) were phenotype negative. Median (IQR) left ventricular ejection fraction (LVEF) was 51% (38%-59%); 89 participants (34%) had LVEF less than 45%, and 50 (20%) had right ventricular dysfunction. During a median (IQR) follow-up of 34 (8-63) months, 57 individuals (19%) experienced SCD/MVA, with an annual incidence rate of 4 cases per 100 person-years (95% CI, 3-6). Incidence rates were higher in probands vs nonprobands and in phenotype-positive vs phenotype-negative individuals. A predictive model estimating SCD/MVA risk was derived from multivariable analysis, which included older age, male sex, previous syncope, nonsustained ventricular tachycardia, and LVEF with a time-dependent area under the curve (AUC) ranging between 0.76 (95% CI, 0.67-0.86) at 12 months and 0.78 (95% CI, 0.70-0.86) at 72 months. Notably, the association of LVEF with the SCD/MVA risk was not linear, showing significant lower risk for values of LVEF greater than 58%, and no increase for values less than 58%. Internal validation with bootstrapping confirmed good accuracy and calibration of the model. Results were consistent in subgroups analysis (ie, phenotype-positive carriers and phenotype-positive carriers without MVA at onset).

Conclusions and relevance: Results suggest that the risk of SCD/MVA in phenotype-positive carriers of FLNCtv was high. A 5-variable predictive model derived from this cohort allows risk estimation and could support clinicians in the shared decision for prophylactic ICD implantation. External cohort validation is warranted.

PubMed Disclaimer

Conflict of interest statement

Conflict of Interest Disclosures: Dr Gigli reported receiving a consulting speaker fee from Boot Hc. Dr Stolfo reported receiving consulting speaker and advisor fees from MSD, Janssen, AstraZeneca, Boehringer Ingelheim, Dompè, and Novartis. Dr Merlo reported receiving advisory board fees from Pfizer, Novartis, AstraZeneca, Vifor Pharma, and Novo Nordisk outside the submitted work. Dr van Tintelen reported receiving grants from ZonMW, Netherlands Heart Foundation, and Leducq Foundation during the conduct of the study. Dr Te Riele reported serving as a consultant for Tenaya Therapeutics, Rocket Pharmaceuticals, and BioMarin for unrelated work and receiving funding from the Netherlands Organization for Health Research–ZonMW (Off Road 2021). Dr Wilde reported being a member of the scientific advisory board of Thryv therapeutics, ARMGO, and Soufflé. Dr Elliott reported receiving consultant and/or speaker fees from Pfizer, Cytokinetics, AstraZeneca, BMS, Forbion, and Affinia during the conduct of the study. Dr Michels reported receiving grants from Bristol Meyers Squibb and personal fees from Bristol Meyers Squibb, Cytokinetics, Pfizer, Alnylam, and Sanofi-Genzyme outside the submitted work. Dr Tayal reported receiving grants from Medical Research Council Research funding during the conduct of the study and being a freelance research editor for the BMJ. Dr Yazdani reported receiving grants from British Heart Foundation, Myocarditis UK, Alexander Jansons Trust, and Rosetrees Trust during the conduct of the study. Dr Judge reported receiving personal fees from Alexion, Alleviant, Alnylam, Attralus, BridgeBio, Lexeo Therapeutics, Novo Nordisk, and Tenaya outside the submitted work. Dr Lakdawala reported receiving grants from BMS and Pfizer and personal fees from BMS, Cytokinetics, Pfizer, Tenaya, Alexion, Akros, and Nuevocor outside the submitted work. Dr James reported receiving grants from Leonie-Wild Foundation; The Hugh Calkins, Marvin H. Weiner, and Jacqueline J. Bernstein Cardiac Arrhythmia Center; the Leyla Erkan Family Fund for ARVD Research; the Dr Satish, Rupal, and Robin Shah ARVD Fund at Johns Hopkins; the Peter French Memorial Foundation, the Wilmerding Endowments; Lexeo Therapeutics; Arvada Therapeutics; Eicosis; and StrideBio Therapeutics; personal fees from Lexeo Therapeutics; and being a member of the NSGC Board of Directors. Dr Ashley reported being founder of Personalis, Deepcell, and Svexa; cofounder of RCD Co Founder; advisor for Sequence Bio, Foresite Labs, PacBio; receiving stock options from Oxford Nanopore, PacBio, AstraZeneca; and receiving nonfinancial support from Illumina, PacBio, and Oxford Nanopore outside the submitted work. Dr Reuter reported receiving personal fees from Rocket Pharmaceuticals outside the submitted work. Dr Ameri reported receiving personal fees from AstraZeneca, Boehringer Ingelheim, Daiichi Sankyo, MSD, Janssen, and Gossamer Bio outside the submitted work. Dr Mestroni reported receiving grants from the National Institutes of Health and Greenstone Bio; advisory board fees from Tenaya Therapeutics; and participating in a gene therapy trial for Pfizer and AstraZeneca/Axion outside the submitted work. No other disclosures were reported.

References

    1. Spezzacatene A, Sinagra G, Merlo M, et al. ; Familial Cardiomyopathy Registry . Arrhythmogenic phenotype in dilated cardiomyopathy: natural history and predictors of life-threatening arrhythmias. J Am Heart Assoc. 2015;4(10):e002149. doi:10.1161/JAHA.115.002149 - DOI - PMC - PubMed
    1. Towbin JA, McKenna WJ, Abrams DJ, et al. . 2019 HRS expert consensus statement on evaluation, risk stratification, and management of arrhythmogenic cardiomyopathy. Heart Rhythm. 2019;16(11):e301-e372. doi:10.1016/j.hrthm.2019.05.007 - DOI - PubMed
    1. Protonotarios A, Elliott PM. Arrhythmogenic cardiomyopathies (ACs): diagnosis, risk stratification and management. Heart. 2019;105(14):1117-1128. doi:10.1136/heartjnl-2017-311160 - DOI - PubMed
    1. Gigli M, Merlo M, Graw SL, et al. . Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol. 2019;74(11):1480-1490. doi:10.1016/j.jacc.2019.06.072 - DOI - PMC - PubMed
    1. Lukas Laws J, Lancaster MC, Ben Shoemaker M, et al. . Arrhythmias as presentation of genetic cardiomyopathy. Circ Res. 2022;130(11):1698-1722. doi:10.1161/CIRCRESAHA.122.319835 - DOI - PMC - PubMed

Publication types