Dilated cardiomyopathy (DCM) is a precursor of systolic heart failure (HF), the leading cause of death and indication for cardiac transplantation in the U.S. DCM has many etiologies, including genetic predisposition. Although over 300 mutations in 60 different DCM genes have been identified, these account for a small fraction of all DCM cases. Because epidemiologic studies indicate that genetics are a major contributing factor to DCM, we suggest that new strategies are needed to define the human DCM mutations. Previously defined DCM mutations alter proteins with disparate functions, implying that many different pathways can lead to HF. To uncover the relationship between DCM mutations and pathways we will define transcriptional responses in to defined gene mutations in ventricular tissues. These studies may improve gene-based diagnosis suggest interventions that ultimately limit the progression of DCM to HF. To comprehensively define the genetic architecture of DCM we will harness new technologies and methodologies. Our approach capitalizes on a low cost method to capture and analyze large numbers of known DCM genes and harnesses next generation sequencing platforms to interrogate these. We provide preliminary data of the success of this approach. These data also indicate a distinct advantage of the proposed approach over traditional strategies, in moderate sized insertions and deletions, indels, which have previously escaped detection, were found. With continued improvement of our analysis pipeline to detect indels, we expect that resequencing of known DCM genes will reveal many more "missed" mutations. After this initial screen, we will harness whole exome sequencing to discovery novel DCM genes. Together these strategies will define the spectrum of DCM genes, and will the contribution of different gene mutations to the burden of DCM, information that will inform our understanding of disease mechanisms. Next generation sequencing will also be harnessed to interrogate responses activated by gene mutations. Using this platform, we devised a strategy to interrogate RNA levels and structure. We will use this approach to characterize the left ventricular transcriptome in patients with defined mutations. By incorporating pathway analyses we expect to define the signatures associated with pathways activated by different DCM genes. We have assembled a large cohort of samples with clinical data and an investigative team with extensive experience in DCM and human molecular genetics for these studies. To define the genetic architecture and pathways of DCM we propose the following aims: 1) Subgenome-capture and sequence DCM genes in 1500 DCM cases and 3000 controls;2) Discover novel DCM genes by whole exome sequencing of mutation-negative familial DCM cases;3) Assess the role of somatic mutation in mutation-negative sporadic DCM cases;and 4) Define RNA responses to DCM mutations in experimental models and human LV tissues. 1

Public Health Relevance

Dilated cardiomyopathy is a heart disease in which the chambers of the heart are enlarged and the heart's ability to pump blood is significantly diminished. Dilated cardiomyopathy leads to heart failure, the leading cause of death in the United States. About 30% of unexplained dilated cardiomyopathy is inherited. We propose in this application to identify the contribution of gene deletion and insertion to dilated cardiomyopathy and hence more accurately identify dilated cardiomyopathy causing gene. We will use this information to define the mechanisms by which gene mutation leads to disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL080494-06
Application #
8264195
Study Section
Cardiac Contractility, Hypertrophy, and Failure Study Section (CCHF)
Program Officer
Evans, Frank
Project Start
2005-04-01
Project End
2015-04-30
Budget Start
2012-05-29
Budget End
2013-04-30
Support Year
6
Fiscal Year
2012
Total Cost
$423,750
Indirect Cost
$173,750
Name
Harvard University
Department
Genetics
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Fahed, Akl C; McDonough, Barbara; Gouvion, Cynthia M et al. (2014) UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. Ann Neurol 75:793-8
Ito, Kaoru; Bick, Alexander G; Flannick, Jason et al. (2014) Increased burden of cardiovascular disease in carriers of APOL1 genetic variants. Circ Res 114:845-50
Christodoulou, Danos C; Wakimoto, Hiroko; Onoue, Kenji et al. (2014) 5'RNA-Seq identifies Fhl1 as a genetic modifier in cardiomyopathy. J Clin Invest 124:1364-70
Naik, Rakhi P; Derebail, Vimal K; Grams, Morgan E et al. (2014) Association of sickle cell trait with chronic kidney disease and albuminuria in African Americans. JAMA 312:2115-25
van den Boogaard, Malou; Smemo, Scott; Burnicka-Turek, Ozanna et al. (2014) A common genetic variant within SCN10A modulates cardiac SCN5A expression. J Clin Invest 124:1844-52
Fatkin, Diane; Seidman, Christine E; Seidman, Jonathan G (2014) Genetics and disease of ventricular muscle. Cold Spring Harb Perspect Med 4:a021063
Dai, Jing; Matsui, Takashi; Abel, E Dale et al. (2014) Deep sequence analysis of gene expression identifies osteopontin as a downstream effector of integrin-linked kinase (ILK) in cardiac-specific ILK knockout mice. Circ Heart Fail 7:184-93
Blankenburg, Robert; Hackert, Katarzyna; Wurster, Sebastian et al. (2014) ?-Myosin heavy chain variant Val606Met causes very mild hypertrophic cardiomyopathy in mice, but exacerbates HCM phenotypes in mice carrying other HCM mutations. Circ Res 115:227-37
Palmer, Bradley M; Schmitt, Joachim P; Seidman, Christine E et al. (2013) Elevated rates of force development and MgATP binding in F764L and S532P myosin mutations causing dilated cardiomyopathy. J Mol Cell Cardiol 57:23-31
Flannick, Jason; Beer, Nicola L; Bick, Alexander G et al. (2013) Assessing the phenotypic effects in the general population of rare variants in genes for a dominant Mendelian form of diabetes. Nat Genet 45:1380-5

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