LMNA-p.Arg78Trp and MYH6-p.Val893Met Mutations Associated with Left Ventricular Noncompaction

Left ventricular noncompaction (LVNC), an uncommon myocardial disorder, is pathologically defined by the presence of excessive trabecular meshwork and deep intertrabecular recesses within the ventricular chamber. Despite recognized genetic heterogeneity underlying LVNC pathogenesis, the molecular determinants remain incompletely elucidated.

We recruited a multigenerational Chinese LVNC pedigree and systematically collected clinical data, comprehensive family histories, and peripheral blood samples from the proband and relatives for genetic investigation.

The proband, diagnosed with LVNC by cardiac magnetic resonance, presented with classical morphological features of the disease and ultimately succumbed to sudden cardiac death. Next-generation sequencing identified compound heterozygous missense variants in the proband: LMNA(NM_001257374.1) c.232C>T (p.Arg78Trp) and MYH6(NM_002471.3) c.2677G>A (p.Val893Met). Segregation analysis of two asymptomatic younger family members - diagnosed with LVNC via cardiac magnetic resonance despite lacking obvious clinical symptoms - revealed heterozygosity for either LMNA c.232C>T (p.Arg78Trp) or the MYH6 c.2677G>A (p.Val893Met). Notably, mutation-negative relatives displayed neither clinical manifestations nor echocardiographic evidence of LVNC.

These novel pathogenic variants have established the association between genotype and phenotype in familial LVNC, providing critical biomarkers for clinical genetic screening. Our findings have expanded the range of gene mutations associated with LVNC and further enhanced the understanding of the phenotypic characteristics of these mutations.

Integrated genetic and cardiac magnetic resonance imaging analyses demonstrated that LMNA c.232C>T (p.Arg78Trp) and/or MYH6 c.2677G>A (p.Val893Met) variants were associated with LVNC.