LMNA ultra-rare variants (URVs) were found in 4% of DCM patients and associated with a 6.38-fold higher risk of LVAD, transplant, or cardiovascular death.
Does the presence of LMNA ultra-rare variants worsen clinical outcomes in patients with dilated cardiomyopathy?
Ultra-rare variants in the LMNA gene are associated with a more than 6-fold increased risk of severe heart failure outcomes in patients with dilated cardiomyopathy, likely due to structural vulnerabilities in cardiomyocyte nuclear membranes.
Abstract Background Dilated cardiomyopathy (DCM) is a heterogeneous myocardial disorder characterized by ventricular dilation and reduced contractility. While LMNA and TTN mutations are well-established genetic contributors, the role of ultra-rare variants (URVs) remains largely unexplored. Methods To identify the significance of URVs, we examined whole-genome sequencing data from 245 patients with DCM, referencing allele frequencies of 54,000 participants in the Tohoku Medical Megabank. Variants were classified as pathogenic if they had an AlphaMissense score ≥0.55 or caused protein truncation. Results Of the 245 patients (mean age 53 years, 18% female), 49 (20%) had URVs in 6 genes; 10 and 3 patients carried LMNA and SLC51A missense URVs, respectively, while 34, 1, 1, and 2 patients carried TTN, GBF1, PRORP, and RESF1 for protein-truncating URVs, respectively. Among them, those with LMNA URVs had worse clinical outcomes than those without any URVs (hazard ratio 95% confidence interval for the composite of LVAD implantation, heart transplantation, and cardiovascular death: 6.38 2.82–14.42, p 0.001) and for ICD implantation (4.49 2.02–9.95, p 0.001). Nine out of the 11 LMNA URVs identified in 10 patients were localized within the 1B and 2B domains of the alpha-helical coil structure, which are reported to modulate the elastic properties of lamin A/C (Figure 1). Histological analysis revealed significant nuclear membrane irregularities in carriers of LMNA URVs, notably those with E115M (N-3) and R190W (N-3), which were only observed in cardiomyocytes but not in other cell types (Figure 2). Conclusion URVs in LMNA are relatively common and associated with poor clinical outcomes among patients with DCM. LMNA URVs, particularly E115M and R190W, may contribute to DCM pathogenesis and prognosis via the possible formation of less elastic nuclear membrane structures susceptible to disruption by mechanical stress in cardiomyocyte contraction. Since early detection of URVs could facilitate risk stratification and personalized approaches, further validation studies are warranted in broader populations.Figure 1 Figure 2
Kitai et al. (2025) studied this question. LMNA ultra-rare variants (URVs) were found in 4% of DCM patients and associated with a 6.38-fold higher risk of LVAD, transplant, or cardiovascular death.