IN PATIENTS with LMNA cardiomyopathy, truncating variants are linked to higher risks of malignant ventricular arrhythmias regardless of their location, while missense variants located in the tail domain and exons 7 through 12 are associated with lower arrhythmic and heart failure risks.
LMNA gene variants are a recognised cause of inherited cardiomyopathy, predisposing affected individuals to arrhythmias and heart failure. Prior research has suggested that patients with truncating LMNA variants often experience worse cardiac outcomes compared to those with missense variants. However, the influence of the spatial distribution of these variants on clinical manifestations and prognosis has remained unclear.
This multicentre, retrospective cohort study analysed data from 718 patients with pathogenic or likely pathogenic LMNA variants sourced from an international registry and major tertiary cardiomyopathy centres. Patients with no prior malignant ventricular arrhythmias were followed over a median of 4.2 years. The primary endpoint was time to malignant ventricular arrhythmia (VA), comprising sudden cardiac death or appropriate implantable cardioverter-defibrillator therapy, and secondary outcomes included advanced heart failure events such as cardiac transplant or left ventricular assist device implantation. Among the cohort (mean age 41.1 years, 53.1% female, baseline left ventricular ejection fraction 55.8%), 223 experienced malignant VA and 109 developed advanced heart failure. Truncating variants were associated with a significantly increased risk of VA (hazard ratio [HR] 1.72; 95% confidence interval [CI], 1.19–2.48; P=0.004), but no difference in heart failure outcomes compared with missense variants. Location of truncating variants on the LMNA gene or transcript (head, rod, tail domains) did not significantly affect outcomes. Conversely, missense variants affecting the LMNA tail domain (HR 0.35; 95% CI, 0.16–0.78; P=0.02) and those located in exons 7 to 12 (HR 0.39; 95% CI, 0.17–0.89; P=0.035) correlated with a reduced risk of malignant VA, indicating a more favourable prognosis.
These findings suggest that while truncating LMNA variants confer a high arrhythmic risk irrespective of their gene location, missense variants in specific regions such as the tail domain can identify patients with better cardiac outcomes. Clinically, variant type and position may improve personalised risk assessment and guide monitoring or therapeutic strategies.
Reference
Bhaskaran A et al. Location of LMNA variants and clinical outcomes in cardiomyopathy. JAMA Cardiol. 2025;DOI:10.1001/jamacardio.2025.2069.
