Single-gene mutations and increased left ventricular wall thickness in the community - The Framingham Heart Study

Background - Mutations in sarcomere protein, PRKAG2, LAMP2, alpha-galactosidase A ( GLA), and several mitochondrial genes can cause rare familial cardiomyopathies, but their contribution to increased left ventricular wall thickness ( LVWT) in the community is unknown. Methods and Results - We studied 1862 unrelated participants ( 52% women; age, 59 +/- 9 years) from the community-based Framingham Heart Study who had echocardiograms and provided DNA samples but did not have severe hypertension, aortic prosthesis, or significant aortic stenosis. Eight sarcomere protein genes, 3 storage cardiomyopathy - causing genes, and 27 mitochondrial genes were sequenced in unrelated individuals with increased LVWT ( maximum LVWT > 13 mm). Fifty eligible participants ( 9 women) had unexplained increased LVWT. We detected 8 mutations in 9 individuals ( 2 women); 7 mutations in 5 sarcomere protein genes ( MYH7, MYBPC3, TNNT2, TNNI3, MYL3), and 1 GLA mutation. In individuals with increased LVWT, participants with sarcomere protein and storage mutations were clinically indistinguishable from those without mutations. Conclusions - In a community-based cohort, about 3% of eligible participants had increased LVWT, of whom 18% had sarcomere protein or lipid storage gene mutations. Increased LVWT in the community is a very heterogeneous condition, which sometimes may arise from single-gene variants in one of a number of genes.