Single-Gene Mutations and Increased Left Ventricular Wall Thickness in the Community The Framingham Heart Study

Boston University, Boston, Massachusetts, United States
Circulation (Impact Factor: 14.43). 06/2006; 113(23):2697-705. DOI: 10.1161/CIRCULATIONAHA.105.593558
Source: PubMed


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.
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.
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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    • "Yasuda et al. found the D313Y alteration in 0.45% of subjects in a normal Caucasian population.43 However, D313Y has been found as the single genetic alteration in Fabry disease patients with highly reduced enzymatic activity and end-stage renal disease,42 in those with stroke,58 and in Fabry disease presenting with cardiovascular symptoms.59 We do not have information about any possible associated diseases in our healthy controls. "
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    • "Hypertrophic cardiomyopathy (HCM) is a common autosomal dominant cardiac disease affecting at least 1 in 500 persons worldwide [Maron et al., 1995; Zou et al., 2004; Morita et al., 2006], characterized by hypertrophy of the ventricular myocardial wall with variable age at onset. Symptomatic patients may show dyspnea, exertional angina, palpitations and (pre)syncope and sudden cardiac death (SCD) at a young age [Maron, 2002]. "
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