Abstract
Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Mutations in LMNA gene, encoding for lamin A/C, account for 10% of familial DCM. LMNA-related cardiomyopathies are characterized by heterogeneous clinical manifestations that vary from a predominantly structural heart disease, mainly mild-to-moderate left ventricular (LV) dilatation associated or not with conduction system abnormalities, to highly pro-arrhythmic profiles where sudden cardiac death (SCD) occurs as the first manifestation of disease in an apparently normal heart. In the present study, we select, among 77 DCM families referred to our center for genetic counselling and molecular screening, 15 patient heterozygotes for LMNA variants. Segregation analysis in the relatives evidences other eight heterozygous patients. A genotype–phenotype correlation has been performed for symptomatic subjects. Lastly, we perform in vitro functional characterization of two novel LMNA variants using dermal fibroblasts obtained from three heterozygous patients, evidencing significant differences in terms of lamin expression and nuclear morphology. Due to the high risk of SCD that characterizes patients with lamin A/C cardiomyopathy, genetic testing for LMNA gene variants is highly recommended when there is suspicion of laminopathy.
Highlights
We report the genotype–phenotype correlation of 18 Dilated cardiomyopathy (DCM) patients evidenced heterozygotes for Lamin A/C gene (LMNA) variants out of 77 referred to our Medical
LMNA-related DCMs have a more aggressive clinical course compared to other forms of dilated cardiomyopathies with higher rates of potentially fatal arrhythmias and end-stage heart failure [25]
Both the genetic and phenotypic heterogeneities together with variable penetrance of LMNA variants make the pathogenic classification of the variants difficult
Summary
Dilated cardiomyopathy (DCM) refers to a spectrum of heterogeneous myocardial disorders characterized by ventricular dilation and depressed myocardial performance in the absence of hypertension, valvular, congenital, or ischemic heart disease. Diverse aetiologies for DCM have been revealed, including genetic mutations, infections, inflammation, autoimmune diseases, exposure to toxins, and endocrine or neuromuscular causes [1]. As regards to genetic forms of DCM, more than 40 genes have been identified, causing defects in various cellular compartments and pathways such as the nuclear envelope, the contractile apparatus, the Z-disk, and calcium handling [2]. Mutations in LMNA (MIM 150330) gene, encoding for lamin A/C, account for 0.5–5%
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