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Observational Study
. 2025 Sep 1;10(9):896-903.
doi: 10.1001/jamacardio.2025.2069.

Location of LMNA Variants and Clinical Outcomes in Cardiomyopathy

Ashwin Bhaskaran  1   2 , Rabah Ben Yaou  3   4 , Adam S Helms  5 , Abdallah Fayssoil  6 , Pascale Richard  7 , Tanya Stojkovic  3 , Frédéric Anselme  8 , Fabien Labombarda  9 , Cathy Chikhaoui  3   4 , Annachiara De Sandre-Giovannoli  10 , Isabelle Jeru  11 , France Leturcq  12 , Corinne Vigouroux  13   14 , Mohamed Dembele  15 , Perry Elliott  16 , Konstantinos Savvatis  16 , Katja Zeppenfeld  17 , Hassina Bouguerra  18 , Philippe Charron  19   20   21 , Saurabh Kumar  1   2 , Gisèle Bonne  4 , Karim Wahbi  18 , Neal K Lakdawala  22
Affiliations
Observational Study

Location of LMNA Variants and Clinical Outcomes in Cardiomyopathy

Ashwin Bhaskaran et al. JAMA Cardiol. .

Abstract

Importance: Prior studies have suggested that patients with nonmissense (ie, truncating) variants causing LMNA cardiomyopathy have worse arrhythmic outcomes compared to those with missense variants. However, the effect of the spatial distribution of missense and truncating variants on clinical outcomes remains poorly understood.

Objective: To determine the association of the spatial distribution of missense and truncating LMNA variants with cardiac outcomes.

Design, setting, and participants: This multicenter, retrospective, observational cohort study used data from an international registry (from January 2013 on) and data derived from tertiary cardiomyopathy centers (January 2000 and June 2017). Patients with likely pathogenic/pathogenic LMNA variants and no prior malignant ventricular arrhythmia (VA) were eligible for inclusion. Data analysis was completed from March 2022 to March 2025.

Main outcomes and measures: The primary outcome of time to VA was defined as sudden cardiac death, appropriate implantable cardioverter-defibrillator therapy, or other manifestations of hemodynamically unstable VA. The secondary composite outcome of advanced heart failure was defined as nonsudden cardiac death, implantation of a left ventricular assist device, or cardiac transplant. Outcomes were stratified by type of variant (missense or truncating), affected transcript position (head, rod, or tail), and location on the LMNA gene.

Results: A total of 718 patients were included, among whom mean (SD) age was 41.1 (14.3) years, 381 patients (53.1%) were female, and mean (SD) baseline left ventricular ejection fraction was 55.8% (13.3%). Over a median follow-up of 4.2 years, 223 patients experienced the primary outcome of malignant VA and 109 experienced the secondary outcome of advanced heart failure. Patients with truncating variants had a higher risk of VA (hazard ratio [HR], 1.72; 95% CI, 1.19-2.48; P = .004) but no difference in advanced heart failure (HR, 0.94; 95% CI, 0.64-1.40; P = .77) compared with patients with missense variants. There were no significant differences in the primary and secondary outcomes when stratifying truncating variants by location on the LMNA gene or transcript position. In contrast, on multivariable analysis, missense variants affecting the tail domain of LMNA (HR, 0.35; 95% CI, 0.16-0.78; P = .02) and located in exons 7 through 12 (HR, 0.39; 95% CI, 0.17-0.89; P = .035) were associated with a significantly lower risk of the primary outcome of malignant VA.

Conclusions and relevance: In this retrospective cohort study, truncating LMNA variants were associated with worse arrhythmic outcomes independent of variant position, whereas missense variants affecting the tail domain and located in exons 7 through 12 had better arrhythmic and heart failure outcomes. Understanding the mechanisms underlying these differences may have future therapeutic implications.

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Conflict of interest statement

Conflict of Interest Disclosures: Dr Bhaskaran reported grants from the Australian National Health and Medical Research Council during the conduct of the study. Dr Ben Yaou reported grants from the French National Research Agency (ANR) and from the Leducq Foundation during the conduct of the study. Dr Helms reported grants from Tenaya Therapeutics and personal fees from Bristol Myers Squibb and Lexeo Therapeutics outside the submitted work. Dr Vigouroux reported personal fees from Amryt Pharmaceuticals (now Chiesi Farmaceutici), Ipsen, Lilly, and Sanofi outside the submitted work. Dr Elliott reported consultancy or speaker fees from AstraZeneca, Bristol Myers Squibb, Cytokinetics, and Pfizer during the conduct of the study. Dr Charron reported grants from European Innovation Council Pathfinder outside the submitted work. Dr Bonne reported grants from the ANR and the Leducq Foundation during the conduct of the study. Dr Lakdawala reported personal fees from Alexion, Bayer, Bristol Myers Squibb, Cytokinetics, Lexeo Therapeutics, Nuevocor, Pfizer, and Tenaya Therapeutics and grants from Bristol Myers Squibb and Pfizer outside the submitted work. No other disclosures were reported.

Comment on

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