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(Circulation. 2006;113:2697-2705.)
© 2006 American Heart Association, Inc.

Epidemiology

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

The Framingham Heart Study

Hiroyuki Morita, MD; Martin G. Larson, ScD; Scott C. Barr, BS; Ramachandran S. Vasan, MD; Christopher J. O’Donnell, MD, MPH; Joel N. Hirschhorn, MD, PhD; Daniel Levy, MD; Diane Corey, BS; Christine E. Seidman, MD; J.G. Seidman, PhD^*; Emelia J. Benjamin, MD, ScM^*

From The Program in Genomics Applications: CardioGenomics Group—the Department of Genetics (H.M., S.B., C.E.S., J.G.S.), Massachusetts General Hospital (C.J.O.), and Children’s Hospital (J.N.H.), Harvard Medical School; Boston University School of Medicine, Boston (M.G.L., R.S.V., D.L., E.J.B.); the National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Mass (M.G.L., R.S.V., C.J.O., D.L., D.C., E.J.B.); and Massachusetts Institute of Technology, Cambridge, Mass (J.N.H.).

Correspondence to Dr Jonathan Seidman, NRB Room 256, Department of Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115. E-mail seidman{at}genetics.med.harvard.edu

Received October 8, 2005; revision received February 7, 2006; accepted March 31, 2006.

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

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