Domain-specific association of single-nucleotide variants in the LMNA gene with the phenotypic expression of dilated cardiomyopathy.

Background: LMNA gene variants cause a spectrum of phenotypes referred to as laminopathies. However, the topological distribution of the LMNA variants and their phenotypic effects have not been delineated. We investigated the associations of variants located at different LMNA domains with clinical phenotypes in dilated cardiomyopathy (DCM) patients.

Methods: All reported single-nucleotide variants (SNVs) in LMNA were obtained from the ClinVar, HGMD and PubMed databases. The associated phenotypes were collected from PubMed. The pathogenicity of the variants was determined according to the 2015 ACMG/AMP criteria.

Results: 236 DCM-related pathogenic/likely pathogenic (P/LP) nonsynonymous SNVs (nsSNVs) were enriched at the intermediate filament (IF) Rod region. Left ventricular ejection fraction was lower in DCM patients carrying P/LP nsSNVs at the Coil 1B and Tail regions than at those with P/LP variants at the Coil 2 region. Similarly, atrioventricular block and pacemaker implantation-related P/LP nsSNVs were enriched at the IF rod region; ventricular tachycardia/fibrillation and implantable cardiac defibrillator implantation-related P/LP nsSNVs were enriched at the Tail domain. Representative mutations in IF Rod and Tail region were selected for mechanism investigation. The ryanodine receptor (RYR2) and membrane Cav1.2 protein expression was significantly increased with variants in Tail region (C1621T and C1718T) compared with variants in IF Rod region (G497C and A575G) and WT group.

Conclusion: LMNA P/LP nsSNVs were found to be enriched in the IF rod domain, and a domain-dependent association of the variants with the phenotypic features of DCM was identified. These findings are provisional and, upon replication in independent studies, might be useful in genotype-phenotype correlation studies in DCM caused by LMNA mutations.