Increased left ventricular mass or hypertrophy (LVH) is an independent risk factor for cardiovascular events. Genetic variation, most commonly in genes encoding the protein constituents of the sarcomere, is an important primary cause of LVH that results in hypertrophic cardiomyopathy (HCM). Genetic studies of HCM patients identify pathogenic mutations in 50-60% of adult-onset familial HCM, ~30% of adult-onset sporadic HCM and ~40% of pediatric-onset HCM. Causes of LVH that clinically presents as HCM in ~50% of adults and children, particularly in those without familial disease, remains unknown. To address this gap in knowledge, we will perform integrated analyses of genomic DNA and cardiac tissue RNA in hypertrophic subjects without a recognized genetic etiology. We will search for undetected germline and somatic variants in the nuclear and mitochondrial genomes through sequenced-based strategies and will consider pathogenic etiologies (Aim 1). To assess the pathogenicity of novel sequence variants and genes we will build upon existing RNAseq datasets to determine if candidate genes participate in hypertrophic signaling pathways and we use high-throughput strategies to modulate candidate gene expression in mice and perform detailed cardiac analyses (Aim 2). Approximately 10% of the general population carries rare non- synonymous variants in sarcomere protein genes without developing overt HCM. To understand discordance in genotype and phenotype, we will map rare non-synonymous, definitive familial HCM mutations and population-identified sarcomere variants on 3-D structures of myofilament proteins, and assess their function in myocytes derived from differentiated isogenic iPS cells (Aim 3). Collectively these studies will expand the repertoire of genetic and acquired causes of HCM and LVH and improve the accurate prediction of phenotypes that arise from rare genetic variation.
Our aims will: 1) Assess genetic variation in cardiac tissue and genomes of patients with LVH using high-throughput DNA sequencing methods. 2) Demonstrate that novel molecules cause or modify LVH in vivo. 3) Define the pathogenicity of rare human sarcomere protein gene variants found in the general population.

Public Health Relevance

Our studies will help understand the causes of inherited and non-inherited heart disease. This understanding should lead to improved diagnostic approaches to left ventricular hypertrophy and will allow patients to benefit from new therapeutic approaches to this condition. Such studies will eventually reduce the medical 'cost'of cardiomyopathy.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL084553-06A1
Application #
8759386
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Wang, Lan-Hsiang
Project Start
2006-04-01
Project End
2018-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Harvard Medical School
Department
Genetics
Type
Schools of Medicine
DUNS #
City
Boston
State
MA
Country
United States
Zip Code
02115
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