Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES)

NCT ID: NCT01873963

Last Updated: 2018-05-01

Basic Information

• Recruitment Status: COMPLETED
• Total Enrollment: 544 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2013-04-30
• Study Completion Date: 2018-03-31

Brief Summary

Cardiomyopathy in children is a serious disease which can result in death, disability, heart transplantation or serious heart rhythm disorders. Doctors know little about the causes of cardiomyopathy but would like to learn more. In fact, up to 50-75% of cases in children have no known cause. For this reason, the purpose of this study is to identify genes that cause cardiomyopathy or that influence how people with cardiomyopathy do over time. These findings could improve disease prevention, surveillance, early management, and prognosis.

Detailed Description

Pediatric cardiomyopathy is a heterogeneous genetic disease with high morbidity and mortality in which children often present with fulminant disease leading to death or transplant. The long-term goal of this project is to identify the genetic basis of cardiomyopathy and to correlate these findings with clinical phenotypes for risk stratification. These findings could improve disease prevention, surveillance, early management, and prognosis.

The specific aims of this study are:

1. To identify the disease-causing and disease-associated genetic variants underlying pediatric cardiomyopathy in a carefully phenotyped cohort.

2. To identify genotype-phenotype correlations that allow for risk stratification and improve management and therapy.

Exome sequencing will be used as part of a tiered genetic analysis in a large cohort of up to 700 pediatric cardiomyopathy subjects with systolic (dilated cardiomyopathy) or diastolic (hypertrophic or restrictive cardiomyopathy) dysfunction. The biological parent(s) of enrolled participants will also be approached about participating and providing a blood sample for genetic testing. In addition to the parent(s), the participants siblings and other relatives may also be approached regarding enrollment, based on the pedigree and family history.

This study will significantly increase our understanding of pediatric cardiomyopathy by defining the prevalence of mutations in genes known to cause cardiomyopathy as well as identifying novel disease-causing genes in the pediatric population. Genetic association tests will identify variants that modify disease. Novel bioinformatics and systems biology applications for interpretation of exome level genetic information will contribute fundamental knowledge and technical innovation to the translation of genomic data to clinical utility. These aims will provide critical genetic architecture data, identify variants with large effects, and enable genotype-phenotype correlations necessary for advancing management and therapy.

The Study will have two components: 1) clinical data collection by chart review and family interview, and 2) biospecimen collection and genetic testing.

Conditions

Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Restrictive Cardiomyopathy

Study Design

• Observational Model Type: COHORT
• Study Time Perspective: PROSPECTIVE

Study Groups

Pediatric cardiomyopathy

Diagnosis of primary or idiopathic dilated, hypertrophic or restrictive cardiomyopathy. Diagnosis must have been made before the age of 18 and must be confirmed by established echocardiographic criteria or cardiac MRI (cMRI) at the time of diagnosis.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Patient is alive. (except samples from deceased relatives who have consented for testing).Patients who are status-post heart transplant are eligible if pre-transplant longitudinal data are available.
• Under age 18 years at the time of diagnosis of either primary or idiopathic dilated, hypertropic, or restrictive cardiomyopathy.
• A diagnosis of cardiomyopathy which, at the time of diagnosis, was confirmed by echocardiographic criteria or cardiac MRI

• Malignancy
• Systemic Hypertension
• Pulmonary parenchymal or vascular disease (e.g., cystic fibrosis, cor pulmonale, or pulmonary hypertension)
• Ischemic coronary vascular disease
• Association with drugs known to cause hypertrophy (e.g., growth hormone, corticosteroids, cocaine)
• Genetic syndrome or chromosomal abnormality known to be associated with cardiomyopathy

Exclusion Criteria

A patient is not eligible for enrollment if one or more of the following conditions are met at the time of presentation with cardiomyopathy:

• Arrhythmogenic right ventricular dysplasia
• Neuromuscular disease (defined by specific conditions)
• Endocrine disease known to cause heart muscle disease (including infants of diabetic mothers)
• History of rheumatic fever
• Toxic exposures known to cause heart muscle disease (anthracyclines, mediastinal radiation, iron overload or heavy metal exposure)
• HIV infection or born to an HIV positive mother
• Kawasaki disease
• Immunologic disease
• Invasive cardiothoracic procedures or major surgery during the preceding month, except those specifically related to cardiomyopathy including left ventricular assist device (LVAD), extracorporeal membrane oxygenator (ECMO), and automatic implantable cardioverter/defibrillator (AICD) placement.
• Uremia, active or chronic
• Abnormal ventricular size or function that can be attributed to intense physical training or chronic anemia

• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Carelon Research

OTHER

Sponsor Role: collaborator

Children's Hospital Medical Center, Cincinnati

OTHER

Sponsor Role: collaborator

Washington University School of Medicine

OTHER

Sponsor Role: collaborator

Children's Hospital of Philadelphia

OTHER

Sponsor Role: collaborator

Columbia University

OTHER

Sponsor Role: collaborator

Boston Children's Hospital

OTHER

Sponsor Role: collaborator

Ann & Robert H Lurie Children's Hospital of Chicago

OTHER

Sponsor Role: collaborator

Primary Children's Hospital

OTHER

Sponsor Role: collaborator

Monroe Carell Jr. Children's Hospital at Vanderbilt

OTHER

Sponsor Role: collaborator

Stollery Children's Hospital

OTHER

Sponsor Role: collaborator

National Heart, Lung, and Blood Institute (NHLBI)

NIH

Sponsor Role: collaborator

University of Miami

OTHER

Sponsor Role: collaborator

Children's Hospital Colorado

OTHER

Sponsor Role: collaborator

Indiana University

OTHER

Sponsor Role: collaborator

Wayne State University

OTHER

Sponsor Role: lead

Responsible Party

Steve Lipshultz

Schotanus Family Endowed Chair of Pediatrics, Professor and Chair, Carman and Ann Adams Department of Pediatrics, Wayne State University School of Medicine; President, University Pediatricians and Pediatrician-in-Chief, Children's Hospital of Michigan

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Steven E Lipshultz, MD

Role: PRINCIPAL_INVESTIGATOR

Wayne State University

Locations

Children's Hospital Colorado

Aurora, Colorado, United States

University of Miami, Jackson Memorial Hospital

Miami, Florida, United States

Ann and Robert H. Lurie Children's Hospital of Chicago

Chicago, Illinois, United States

Children's Hospital Boston

Boston, Massachusetts, United States

Washington University School of Medicine

St Louis, Missouri, United States

Children's Hospital of New York, Columbia Presbyterian Medical Center

New York, New York, United States

Children's Hospital at Montefiore

The Bronx, New York, United States

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States

Monroe Carell Jr. Children's Hospital at Vanderbilt

Nashville, Tennessee, United States

Primary Children's Medical Center

Salt Lake City, Utah, United States

Stollery Children's Hospital

Edmonton, Alberta, Canada

Countries

United States; Canada

References

Ware SM, Wilkinson JD, Tariq M, Schubert JA, Sridhar A, Colan SD, Shi L, Canter CE, Hsu DT, Webber SA, Dodd DA, Everitt MD, Kantor PF, Addonizio LJ, Jefferies JL, Rossano JW, Pahl E, Rusconi P, Chung WK, Lee T, Towbin JA, Lal AK, Bhatnagar S, Aronow B, Dexheimer PJ, Martin LJ, Miller EM, Sleeper LA, Razoky H, Czachor J, Lipshultz SE; Pediatric Cardiomyopathy Registry Study Group. Genetic Causes of Cardiomyopathy in Children: First Results From the Pediatric Cardiomyopathy Genes Study. J Am Heart Assoc. 2021 May 4;10(9):e017731. doi: 10.1161/JAHA.120.017731. Epub 2021 Apr 28.

Reference Type: DERIVED

PMID: 33906374 (View on PubMed)

Other Identifiers

1R01HL111459-01

Identifier Type: NIH

Identifier Source: secondary_id

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1R01HL111459-01

Identifier Type: NIH

Identifier Source: org_study_id

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