Idiopathic dilated cardiomyopathy (DCM) is a heritable, genetically heterogeneous disorder that causes progressive human heart failure and death. Candidate gene and family-based mapping studies have uncovered defects in diverse molecular pathways, yet DCM remains an idiopathic condition in the vast majority of patients. This proposal is based on recruitment and phenotypic characterization of a large cohort of unrelated subjects with DCM, including multigenerational families and multiple children with early-onset heart failure.
The first aim i s to identify novel genes for autosomal dominant DCM by combined genetic linkage and exome sequencing strategies.
The second aim i s to identify inherited and de novo mutations that underlie pediatric DCM.
The third aim i s to determine the frequency and spectrum of mutations in novel DCM genes in a well-characterized cohort.
These aims are designed to overcome existing technological barriers to DCM gene discovery by capitalizing on the emerging technology of whole-exome sequencing. The overall objectives of this work are to provide new insight into the molecular basis of myopathic heart failure, advance knowledge of the genetic basis of pediatric-onset DCM, and improve prediction, prevention, and treatment of DCM.

Public Health Relevance

Dilated cardiomyopathy (DCM) is a major public health problem, resulting in heart failure, arrhythmia, and death. DCM is the most common reason for cardiac transplantation, due to lack of diagnostic tests for early detection and ineffective treatments for advanced disease. Discovering the genetic basis of DCM will lead to better ways to diagnose and prevent the progressive weakening of heart muscle that afflicts patients with this disorder.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Genetics of Health and Disease Study Section (GHD)
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Fabsitz, Richard
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Mayo Clinic, Rochester
United States
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Long, Pamela A; Theis, Jeanne L; Shih, Yu-Huan et al. (2017) Recessive TAF1A mutations reveal ribosomopathy in siblings with end-stage pediatric dilated cardiomyopathy. Hum Mol Genet 26:2874-2881
Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2017) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 2:
Long, Pamela A; Zimmermann, Michael T; Kim, Maengjo et al. (2016) De novo RRAGC mutation activates mTORC1 signaling in syndromic fetal dilated cardiomyopathy. Hum Genet 135:909-917
Ding, Yonghe; Long, Pamela A; Bos, J Martijn et al. (2016) A modifier screen identifies DNAJB6 as a cardiomyopathy susceptibility gene. JCI Insight 1:
Long, Pamela A; Evans, Jared M; Olson, Timothy M (2015) Exome sequencing establishes diagnosis of Alström syndrome in an infant presenting with non-syndromic dilated cardiomyopathy. Am J Med Genet A 167A:886-90
Long, Pamela A; Larsen, Brandon T; Evans, Jared M et al. (2015) Exome Sequencing Identifies Pathogenic and Modifier Mutations in a Child With Sporadic Dilated Cardiomyopathy. J Am Heart Assoc 4:
Theis, Jeanne L; Zimmermann, Michael T; Larsen, Brandon T et al. (2014) TNNI3K mutation in familial syndrome of conduction system disease, atrial tachyarrhythmia and dilated cardiomyopathy. Hum Mol Genet 23:5793-804
Terzic, Andre; Alekseev, Alexey E; Yamada, Satsuki et al. (2011) Advances in cardiac ATP-sensitive K+ channelopathies from molecules to populations. Circ Arrhythm Electrophysiol 4:577-85
Theis, Jeanne L; Sharpe, Katharine M; Matsumoto, Martha E et al. (2011) Homozygosity mapping and exome sequencing reveal GATAD1 mutation in autosomal recessive dilated cardiomyopathy. Circ Cardiovasc Genet 4:585-94
Olson, Timothy M; Terzic, Andre (2010) Human K(ATP) channelopathies: diseases of metabolic homeostasis. Pflugers Arch 460:295-306

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