Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES)

Hypertrophic Cardiomyopathy Clinical Trial

Official title:

Genotype-Phenotype Associations in Pediatric Cardiomyopathy

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01873963
• Other study ID #: 1R01HL111459-01
• Secondary ID: 1R01HL111459-01
• Status: Completed
• Start date: April 2013
• Est. completion date: March 31, 2018

Study information

• Verified date: April 2018
• Source: Wayne State University
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 544
• Est. completion date: March 31, 2018
• Est. primary completion date: February 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: N/A and older

Eligibility

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

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

• Chronic arrhythmia, unless there are studies documenting inclusion criteria prior to the onset of arrhythmia (except a patient with chronic arrhythmia, subsequently ablated, whose cardiomyopathy persists after two months is not to be excluded).

• 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

Related Conditions & MeSH terms

• Cardiomyopathies
• Cardiomyopathy, Dilated
• Cardiomyopathy, Hypertrophic
• Dilated Cardiomyopathy
• Hypertrophic Cardiomyopathy
• Hypertrophy
• Restrictive Cardiomyopathy

Locations

Country	Name	City	State
Canada	Stollery Children's Hospital	Edmonton	Alberta
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Children's Hospital Boston	Boston	Massachusetts
United States	Children's Hospital at Montefiore	Bronx	New York
United States	Ann and Robert H. Lurie Children's Hospital of Chicago	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	University of Miami, Jackson Memorial Hospital	Miami	Florida
United States	Monroe Carell Jr. Children's Hospital at Vanderbilt	Nashville	Tennessee
United States	Children's Hospital of New York, Columbia Presbyterian Medical Center	New York	New York
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	Primary Children's Medical Center	Salt Lake City	Utah

Sponsors (15)

Lead Sponsor

Collaborator

Wayne State University

Ann & Robert H Lurie Children's Hospital of Chicago, Boston Children’s Hospital, Children's Hospital Colorado, Children's Hospital Medical Center, Cincinnati, Children's Hospital of Philadelphia, Columbia University, Indiana University, Monroe Carell Jr. Children's Hospital at Vanderbilt, National Heart, Lung, and Blood Institute (NHLBI), New England Research Institutes, Primary Children's Hospital, Stollery Children's Hospital, University of Miami, Washington University School of Medicine

Countries where clinical trial is conducted

United States,  Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to death		2 years
Secondary	Time to transplant		2 years
Secondary	Time to normalized left ventricular size or function in dilated cardiomyopathy		2 years
Secondary	Septal:Posterior wall thickness ratio in hypertrophic cardiomyopathy		2 years
Secondary	Left ventricular outflow tract in hypertrophic cardiomyopathy		2 years