Atrial fibrillation (AF) is the most common cardiac arrhythmia in adults requiring hospitalization and is characterized by rapid and irregular activation of the atria. Loss of effective atrial contraction leads to decreased ventricular filling and cardiac output, while stasis of blood in the atria increases the risk for thromboembolic stroke1. Although most AF develops as a consequence of other systemic processes such as hypertensive, valvular or coronary artery disease, 10–20% occurs in individuals without underlying risk factors. Genetic factors are implicated in the development of isolated AF, with nearly 40% of cases having a positive family history.2,3 Disease-causing mutations have been found in cardiac potassium channel genes, although mutations in sodium channels and connexins have also been implicated.4 An infrequent genetic etiology is mutation in the gene encoding for lamin A/C, LMNA, but the AF is typically associated with a combined cardiac and skeletal myopathy.5
The LMNA gene resides on chromosome 1q21 and it encodes for two isoforms, lamin A and C, which are generated by alternative splicing (Figure 1D). Lamins A and C are intermediate filament proteins that form the nuclear lamina, function as a nuclear scaffold to maintain the structure and size of the nucleus and are also implicated in transcriptional regulation, nuclear pore positioning and heterochromatin organization.6 Mutations in nuclear lamins and lamin-associated proteins cause more than 16 distinct human diseases, termed “laminopathies”. Lamin A/C is expressed in multiple cell types and mutations in LMNA result in a range of phenotypes including premature aging syndromes, types of muscular dystrophy, a subset of lipodystrophies, bone dysplasias and cardiovascular diseases.7 The cardiac involvement in laminopathies usually presents with progressive atrioventricular block (AVB), dilated cardiomyopathy (DCM), sudden cardiac death (SCD) and infrequently, atrial arrhythmias. It remains unknown how mutations in these ubiquitously expressed proteins cause such heterogeneous phenotypes with variable penetrance.
Here, we present a large family in which a novel mutation of LMNA segregates with affected members with cardiac disease. The phenotype consists of early-onset AF and progressive AVB that is followed by DCM and SCD. In this report, we discuss the clinical and genetic findings and emphasize that LMNA mutations are a potential cause of early-onset AF and progressive conduction system disease.