Single-Gene Mutations and Increased Left Ventricular Wall Thickness in the Community

Abstract

Background— Mutations in sarcomere protein, PRKAG2 , LAMP2 , α-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.