Cardiovascular Prognostic Impact of Missense vs Non-Missense Lamin A/C Variants: A Systematic Review and Meta-Analysis

Background: Variants in LMNA gene, responsible for laminopathies, are associated with severe cardiovascular outcomes, including arrhythmias and heart failure (HF). However, the differential prognostic impact of missense versus non-missense variants remains unclear. Objective: The primary endpoint of this systematic review and meta-analysis was to compare the cardiovascular outcome defined as combined malignant ventricular arrhythmias (MVA) and HF between patients with missense versus non-missense variants in the LMNA gene. Secondary outcomes included a comparison of MVA and HF-related events analyzed separately. Methods: A systematic search of PubMed, OVID-MEDLINE, and Cochrane Library was conducted according to the PRISMA guidelines. Meta-analyses were performed using fixed or random effects models, depending on heterogeneity. PROSPERO identifier: CRD42024584721. Results: Twelve studies comprising 1818 participants were included. Of these, 969 had missense variants, and 849 had non-missense variants. The non-missense group showed a significantly higher rate of cardiovascular events (30.5% vs. 21.3-%, OR: 2.22, p < 0.001). Malignant ventricular arrhythmias were more frequent in non-missense carriers (25.5% vs. 18.9%, OR: 2.37, p < 0.001). While limited by the small number of studies (n=5) and single-study bias, the incidence of HF-related severe events appeared similar between the groups (18.2% vs. 23.9%, OR: 0.956, p = 0.801) CONCLUSION: Non-missense LMNA variants are associated with worse cardiovascular outcomes, particularly arrhythmic events, while HF-related events appear comparable between non-missense and missense variants.