Familial laminopathy: one gene, two proteins, three distinct scenarios of atrial manifestation of a cardiomyopathy phenotype associated with a novel lamin A/C gene (LMNA) mutation. A case series

Lamin A/C gene (LMNA) variants, responsible for encoding the nuclear lamin A and C proteins, are the second most common cause (after titin gene variants) of familial dilated cardiomyopathy (FDC). Lamins A and C are structural proteins that play a critical role in maintaining nuclear integrity and stability, as well as in regulating nuclear function. The clinical manifestations of pathogenic LMNA variants range from a dila­ted cardiomyopathy phenotype to arrhythmogenic cardiomyopathy with conduction disturbances and atrial and/or ventricular arrhythmia. Laminopathy is associated with an increased risk of sudden cardiac death, even in asym­ptomatic carriers without cardiomyopathy signs. Early-stage LMNA-related cardiomyo­pathy is characterized by atrial myopathy with clinical manifestations of bradyarrhythmia and/or atrial tachyarrhythmia with impaired left atrial (LA) function without left ventricular dilation and systolic dysfunction, which develop in the late disease stages. In the present case series, relatives with a family history of sudden cardiac death were diagnosed with atrial electromechanical dysfunction with normal LA dimensions, ejection fraction, and left ventricular geometry. Three features — interat­rial block, bradyarrhythmia, and decreased LA strain — pointed to atrial myo­pathy as the first warning sign of early familial cardiomyopathy manifestation. Thus, in the case of the proband, an asymptomatic 36-year-old man, the detection of advanced interatrial block on an electrocardiogram initiated a series of investigations, including speckle-­tracking echocardiography, Holter monitoring, magnetic resonance imaging, and genetic screening. The identified specific features — familial bradyarrhythmic syndrome, decreased peak LA strain and longitudinal interventricular septum strain, linear septal fibrosis — suggested genetic cardiomyopathy. Targeted sequencing identified a new likely pathogenic variant in the LMNA gene (c.276del; p.Asp93Thrfs*3), and a diagnosis of cardiolamino­pathy associated with a deletion in exon 1, leading to a frameshift variant, was established. Cascade screening and segregation analysis confirmed the dia­gnosis of laminopathy in two additional family members (one — asymptomatic; the other — with symptoms of an unrecognized "hot phase" of cardiomyopathy for one year) with atrial myopathy features.