LMNA variants distribution and their impact on the cardiac phenotypic spectrum

Abstract Introduction A-type lamins (Lamins A and C), encoded by the lamin A/C gene (LMNA), are type V intermediate filament proteins produced through alternative RNA splicing. These proteins are essential components of the nuclear lamina. LMNA variants result in diverse clinical phenotypes, including premature aging, muscular dystrophy, lipodystrophy, and cardiomyopathies—the latter being the most prevalent. The precise correlation between specific LMNA variants and resulting phenotypes remains to be fully elucidated. Material and methods We retrospectively evaluated LMNA-carriers from inherited cardiac disease patients referred to the Cardiovascular Genetics Laboratory at our university hospital. Whole Exome Sequencing was performed, and variants were classified according to current guidelines. Only VUS >5 points (Hot VUS), likely pathogenic (LP), and pathogenic (P) variants were considered clinically significant. Results We identified 28 genetic variants in 84 subjects (mean age 46 ± 14 years, 47 males), of which 46 were index cases (34 symptomatic, 5 sudden cardiac death – SCD, 7 heart transplanted - HTx) and 38 relatives from 24 families. Twenty-seven missense and 1 nonsense LMNA variants were classified as ‘Hot VUS’ 11, LP 8, and P 9. Seven variants (25%) were recurrent in 23 index cases (52%), while the remaining 21 were private. LMNA variants spanned all protein domains, with a 2.2-fold enrichment in the Ig-Like domain (p = 0.0095). Cardiologic evaluation based on current ESC guidelines led to a wide spectrum of phenotypes including 35% dilated cardiomyopathy (DCM), 28% non-dilated left-ventricular cardiomyopathy (NDLC), 13% channelopathies, 6% arrhythmogenic and 7% hypertrophic cardiomyopathies, and in 11% of subjects, SCD was the first clinical manifestation. The distribution of genetic variants across the LMNA protein was correlated with specific cardiac phenotypes, with Coiled-Coil domain (CCD) variants predominantly associated with DCM (75%), while Ig-like domain variants were linked to NDLC (69%) (p = 0.0271). These findings were corroborated by left ventricular ejection fraction (EF) analysis, showing CCD carriers with lower EF (mean 42%) compared to Ig-like carriers (mean 57%) (p=0.0076). No significant differences were observed in late gadolinium enhancement or arrhythmic patterns. Notably, the analysis of LMNA genetic variants in HTx patients revealed that all individuals carried a variant in the CCD (p = 0.0417). LMNA-calculator score ranged between 7-43% (mean 17%± 10). Conclusion Our findings indicate that CCD-LMNA carriers are primarily DCM-affected patients, often progressing to heart transplantation, whereas those with Ig-like domain variants predominantly present with NDLC. The LMNA score calculator for missense variants appears to be inadequate. Further research is needed to clarify the underlying molecular mechanisms driving these distinct cardiac manifestations.