ABSTRACT Background Although the genetic backgrounds of dilated cardiomyopathy (DCM) have been intensively investigated, the clinical impact of ultra-rare genetic variants (URVs) on DCM remains underexplored. Aims This study aimed to identify genes enriched for pathogenic coding URVs in DCM patients and elucidate their clinical and structural significance, with focus on LMNA mutations. Methods Among patients with DCM, the significance of pathogenic URVs (minor allele frequency ≤0.001%), identified based on predictions by AlphaMissense or protein truncation, was examined. Results Among 245 Japanese patients with DCM (53.1 ± 15.1 y.o., 18.0% female.), 43 patients (17.6%) had a total of 49 pathogenic URVs; 14 missense URVs in LMNA (10 patients), 3 missense URVs in SLC51A (3 patients), and 32 protein-truncating URVs in TTN (32 patients). Among the patients with URVs in SLC51A , one also carried URVs in LMNA , and another in TTN . Compared to those without any URVs, the LMNA URV carriers had increased risk of the composite of cardiovascular death, heart transplantation, and left ventricular assist device implantation (hazard ratio HR 6.44, 95% CI: 2.85-14.54; P<0.001) as well as implantable cardioverter defibrillator implantation (HR 4.49, 95%CI: 2.02-9.94; P<0.001). Among them, seven amino acid substitutions were identified, including E115M and R190W, which were found in three patients each. Six of the substitutions were localized to the 1B and 2B domains of the alpha-helical coiled-coil structure that play a role in modulating the elasticity of lamin. Histological examinations revealed abnormal nuclear morphology in cardiomyocytes of LMNA URV carriers. Conclusion Pathogenic URVs were identified in 17.6% of patients with DCM. Among them, the LMNA URV carriers were characterized by histologically abnormal nuclear structure in cardiomyocytes and increased risk of adverse cardiovascular events. CLINICAL PERSPECTIVE What’s New? This is the first comprehensive investigation to delineate both the clinical and histopathological significance of coding ultra-rare variants (URVs; allele frequency ≤0.001% in control populations) in dilated cardiomyopathy (DCM). Utilizing whole-genome sequencing in a Japanese cohort of 245 patients with DCM, this study identified pathogenic coding URVs in 17.6% of cases, with a predominance in LMNA and TTN . Carriers of LMNA URVs—including those with a potentially population-enriched variant (E115M)—demonstrated a significantly elevated risk of severe cardiovascular events and exhibited distinctive nuclear abnormalities in cardiomyocytes. What are the clinical implications? Genetic screening for LMNA URVs in patients with DCM may enable early identification of individuals at elevated risk for adverse cardiovascular outcomes. These findings support the need for genotype-guided clinical management, including early initiation of guideline-directed medical therapy and consideration of prophylactic implantable cardioverter-defibrillator (ICD) placement in LMNA URV carriers. Identification of population-specific variants, such as E115M, may enhance risk stratification and contribute to improved long-term prognosis through tailored surveillance and intervention strategies.
Kitai et al. (Sun,) studied this question.