Abstract 4409: Phenotypic Plasticity of LMNA Mutations in Cardiovascular System Includes Isolated Cardiac Progeria, Dilated and Hypertrophic Cardiomyopathies, Atrial Fibrillation, Conduction Defects and Degenerative Valvular Diseases
Mutations in LMNA, encoding lamin A/C are notable for extensive phenotypic plasticity that comprise at least 13 distinct phenotypes including the Hutchinson-Gilford progeria. The impetus for the present study was a 27 year-old female patient who presented with premature degenerative cardiac phenotype involving coronary arteries, mitral and aortic valves, conduction system and the myocardium; a compilation, which we refer to as “isolated cardiac progeria”. Since LMNA mutations cause Hutchinson-Gilford progeria, we screened all exons and the intron-exon boundaries of LMNA and identified a novel D300N mutation in this patient. The mutation was absent in approximately 2,000 normal chromosomes, which we screened by a Taqman assay and/or direct re-sequencing. We then screened an additional 863 genetically independent individuals comprised of 133 individuals with premature coronary atherosclerosis, 271 with hypertrophic cardiomyopathy (HCM), 101 with dilated cardiomyopathy (DCM) and left bundle branch block, 56 with atrial fibrillation, 68 with degenerative valvular disease and 234 individuals without apparent cardiovascular diseases. We identified 10 different non-synonymous mutations (R50H, D300N, R331Q, R335Q, R427G, G413C, N459S, D559Y, R644C, V586M) including 9 novel mutations in 13 individuals. The R644C known mutation recurred in 2 individuals with DCM, 1 with atrial fibrillation and 1 with aortic valve insufficiency and aortic aneurysm. We also identified LMNA mutations in 4 index cases with HCM, which identified LMNA also as a causal gene for HCM. All mutations were confirmed by sequencing in sense and anti-sense directions and/or TaqMan assays, involved conserved amino acids and were absent in at least 1,000 normal chromosomes. We have and are screening 9 HCM and DCM patients with LMNA mutations for possible mutations in common genes for cardiomyopathies, namely MYH7, MYBPC3, TNNT2, TNNI and TPM1. Functional studies are ongoing to delineate the impact of the mutations on protein function and cardiac phenotype. The findings illustrate phenotypic plasticity of LMNA mutations in the cardiovascular system and establish LMNA mutations as causes of HCM, DCM, atrial fibrillation, conduction defects as well as “isolated cardiac progeria”.