Dilated cardiomyopathy of unknown cause (DCM), known clinically as idiopathic dilated cardiomyopathy, is the most common cardiomyopathy and is the leading cause of heart transplantation. By our estimates DCM affects approximately one million individuals, and so has a major impact on US public health. DCM is commonly asymptomatic until very late in its course when it causes heart failure, disability, and death. Because of its clinical course, any means to identify patients at risk for DCM or to detect DCM in its asymptomatic phase could provide enormous opportunity for intervention to extend lives and prevent late-stage disease. Within this paradigm precision medicine for DCM could greatly impact health care outcomes and costs. Recent advances in DCM genetics have introduced these possibilities, but unresolved questions of familial recurrence risk, genetic etiology, racial differences, and family-based screening must be addressed to move ahead. Our central hypothesis, based on our published studies, states that DCM has substantial genetic basis. For this study we hypothesize that: (a) 35% of probands of both European and African ancestry (EA/AA) will be classified as familial in a cohort recruited in a multicenter US consortium and given explicit recommendations and assistance to achieve the clinical screening of relatives; (b) approximately 40% of DCM probands, whether categorized as familial or non-familial, or as EA or AA, will have pathogenic or likely pathogenic variants in genes previously implicated in DCM; and (c) a tailored intervention to help DCM probands communicate DCM risk to their family members will improve the uptake and impact of necessary clinical and genetic testing. To test these hypotheses, we propose to: (1) estimate and compare the frequencies of EA and AA DCM probands classified as having familial DCM; (2) estimate and compare the proportions of probands with an identifiable genetic cause of DCM in groups defined by proband classification (familial/non-familial) and ancestry (EA/AA); and (3) evaluate the impact of a randomized intervention to aid and direct family communication on participation of at-risk family members in clinical screening and appropriate follow-up surveillance for DCM.
These aims will be accomplished by recruiting a cohort of 1200 DCM probands (600 EA and 600 AA), performing cardiovascular clinical screening of 4800 family members, performing genetic testing of probands and affected family members by exome sequencing, returning genetic results, and randomizing probands to an intervention to improve family communication regarding DCM risk. Proving these hypotheses would be transformative for the field: rather than viewing DCM as only a clinical diagnosis, we would understand DCM as a genetic disease that should be managed using genetic diagnostic and family-based preventive strategies. Our study results would make precision medicine for DCM a reality.

Public Health Relevance

Dilated cardiomyopathy (DCM), after usual clinically detectable causes have been excluded, underlies much of heart failure. Determining who is at risk for DCM has been challenging, but offers enormous benefit, as detecting DCM risk or DCM early in its course may avert late-stage heart failure, which drives enormous morbidity, mortality, and cost. A genetic cause has been found in some cases of familial DCM, but most DCM presents as non-familial disease. Our data suggest that DCM, whether familial or non-familial, has substantial genetic basis. We aim to test this hypothesis in 1200 DCM patients of balanced European and African ancestry, and their 4800 family members. Proving that DCM has a genetic basis would be transformative: we would view DCM as a genetic disease and could then use family-based strategies for detection and prevention.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1)
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Desvigne-Nickens, Patrice
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Ohio State University
Internal Medicine/Medicine
Schools of Medicine
United States
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Morales, Ana; Hershberger, Ray E (2018) Variants of Uncertain Significance: Should We Revisit How They Are Evaluated and Disclosed? Circ Genom Precis Med 11:e002169
Morales, Ana; Hershberger, Ray (2017) Clinical Application of Genetic Testing in Heart Failure. Curr Heart Fail Rep 14:543-553
Kinnamon, Daniel D; Morales, Ana; Bowen, Deborah J et al. (2017) Toward Genetics-Driven Early Intervention in Dilated Cardiomyopathy: Design and Implementation of the DCM Precision Medicine Study. Circ Cardiovasc Genet 10:
Morales, Ana; Hershberger, Ray E (2015) The Rationale and Timing of Molecular Genetic Testing for Dilated Cardiomyopathy. Can J Cardiol 31:1309-12