Severe Myocardial Fibrosis Caused by a Deletion of the 5’ End of the Lamin A/C Gene Original Research Article

Objectives The goal of this study was to identify the underlying gene defect in a family with inherited myocardial fibrosis. Background A large family with an autosomal dominantly inherited form of myocardial fibrosis with a highly malignant clinical outcome has been investigated. Because myocardial fibrosis preceded the clinical and echocardiographic signs, we consider the disease to be a hereditary form of cardiac fibrosis. Methods Twenty-five family members were clinically evaluated, and 5 unaffected and 8 affected family members were included in a genome-wide linkage study. Results The highest logarithm of the odds (LOD) score (LOD = 2.6) was found in the region of the lamin AC (LMNA) gene. The LMNA mutation analysis, both by denaturing gradient gel electrophoresis and sequencing, failed to show a mutation. Subsequent Southern blotting, complementary deoxyribonucleic acid sequencing, and multiplex ligation-dependent probe amplification analysis, however, revealed a deletion of the start codon-containing exon and an adjacent noncoding exon. In vitro studies demonstrated that the deletion results in the formation of nuclear aggregates of lamin, suggesting that the mutant allele is being transcribed. Conclusions This novel LMNA deletion causes a distinct, highly malignant cardiomyopathy with early-onset primary cardiac fibrosis likely due to an effect of the shortened mutant protein, which secondarily leads to arrhythmias and end-stage cardiac failure.