TY - JOUR
T1 - Cardiovascular prognostic impact of missense vs nonmissense lamin A/C variants
T2 - A systematic review and meta-analysis
AU - Guaricci, Andrea Igoren
AU - Faggiano, Andrea
AU - Wahbi, Karim
AU - Barriales-Villa, Roberto
AU - Carella, Maria Cristina
AU - Carugo, Stefano
AU - Christensen, Alex Hørby
AU - Forleo, Cinzia
AU - Gherbesi, Elisa
AU - Haugaa, Kristina H
AU - Merlo, Marco
AU - Larrañaga-Moreira, José M
AU - Mushtaq, Saima
AU - Novelli, Valeria
AU - Peretto, Giovanni
AU - Resta, Nicoletta
AU - Rootwelt-Norberg, Christine
AU - Ben Yaou, Rabah
AU - Ciccone, Marco Matteo
AU - Sinagra, Gianfranco
AU - Pontone, Gianluca
N1 - Copyright © 2026 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.
PY - 2026/1/5
Y1 - 2026/1/5
N2 - BACKGROUND: Variants in the LMNA gene, responsible for laminopathies, are associated with severe cardiovascular outcomes, including arrhythmias and heart failure (HF). However, the differential prognostic impact of missense vs nonmissense variants remains unclear.OBJECTIVE: The primary end point of this systematic review and meta-analysis was to compare the cardiovascular outcome defined as combined malignant ventricular arrhythmias (MVAs) and HF among patients with missense vs nonmissense variants in the LMNA gene. Secondary outcomes included a comparison of MVAs and HF-related events analyzed separately.METHODS: A systematic search of PubMed, Ovid MEDLINE, and Cochrane Library was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses were performed using fixed or random effects models, depending on heterogeneity. PROSPERO identifier: CRD42024584721.RESULTS: 12 studies comprising 1818 participants were included. Of these, 969 had missense variants, and 849 had nonmissense variants. The nonmissense group showed a significantly higher rate of cardiovascular events (30.5% vs 21.3%; odds ratio [OR] 2.22; P < .001). MVAs were more frequent in nonmissense carriers (25.5% vs 18.9%; OR 2.37; P < .001). Although limited by the small number of studies (n = 5) and single-study bias, the incidence of HF-related severe events seemed similar between the groups (18.2% vs 23.9%; OR 0.956; P = .801).CONCLUSION: Nonmissense LMNA variants are associated with worse cardiovascular outcomes, particularly arrhythmic events, whereas HF-related events seem comparable between nonmissense and missense variants.
AB - BACKGROUND: Variants in the LMNA gene, responsible for laminopathies, are associated with severe cardiovascular outcomes, including arrhythmias and heart failure (HF). However, the differential prognostic impact of missense vs nonmissense variants remains unclear.OBJECTIVE: The primary end point of this systematic review and meta-analysis was to compare the cardiovascular outcome defined as combined malignant ventricular arrhythmias (MVAs) and HF among patients with missense vs nonmissense variants in the LMNA gene. Secondary outcomes included a comparison of MVAs and HF-related events analyzed separately.METHODS: A systematic search of PubMed, Ovid MEDLINE, and Cochrane Library was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses were performed using fixed or random effects models, depending on heterogeneity. PROSPERO identifier: CRD42024584721.RESULTS: 12 studies comprising 1818 participants were included. Of these, 969 had missense variants, and 849 had nonmissense variants. The nonmissense group showed a significantly higher rate of cardiovascular events (30.5% vs 21.3%; odds ratio [OR] 2.22; P < .001). MVAs were more frequent in nonmissense carriers (25.5% vs 18.9%; OR 2.37; P < .001). Although limited by the small number of studies (n = 5) and single-study bias, the incidence of HF-related severe events seemed similar between the groups (18.2% vs 23.9%; OR 0.956; P = .801).CONCLUSION: Nonmissense LMNA variants are associated with worse cardiovascular outcomes, particularly arrhythmic events, whereas HF-related events seem comparable between nonmissense and missense variants.
U2 - 10.1016/j.hrthm.2025.12.038
DO - 10.1016/j.hrthm.2025.12.038
M3 - Review
C2 - 41500486
SN - 1547-5271
JO - Heart Rhythm
JF - Heart Rhythm
ER -