Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES)

Genotype-Phenotype Associations in Pediatric Cardiomyopathy

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.

Study Overview

• Status: Completed
• Conditions: Dilated Cardiomyopathy; Hypertrophic Cardiomyopathy; Restrictive Cardiomyopathy

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.

• Study Type: Observational
• Enrollment (Actual): 544

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Edmonton, Alberta, Canada, T6G 2B7
      • Stollery Children's Hospital
• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital Colorado
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami, Jackson Memorial Hospital
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Ann and Robert H. Lurie Children's Hospital of Chicago
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Children's Hospital Boston
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Washington University School of Medicine
  • New York
    • Bronx, New York, United States, 10467
      • Children's Hospital at Montefiore
    • New York, New York, United States, 10032
      • Children's Hospital of New York, Columbia Presbyterian Medical Center
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Cincinnati Children's Hospital Medical Center
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104
      • Children's Hospital of Philadelphia
  • Tennessee
    • Nashville, Tennessee, United States, 37232
      • Monroe Carell Jr. Children's Hospital at Vanderbilt
  • Utah
    • Salt Lake City, Utah, United States, 84113
      • Primary Children's Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Pediatric cases of dilated, hypertrophic or restrictive cardiomyopathy and select relatives will be enrolled at 11 pediatric cardiology centers in the US and Canada.

Description

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

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Time to death	2 years

Secondary Outcome Measures

Outcome Measure	Time Frame
Time to transplant	2 years
Time to normalized left ventricular size or function in dilated cardiomyopathy	2 years
Septal:Posterior wall thickness ratio in hypertrophic cardiomyopathy	2 years
Left ventricular outflow tract in hypertrophic cardiomyopathy	2 years

Collaborators and Investigators

• Sponsor: Wayne State University
• Collaborators: Children's Hospital of Philadelphia; Washington University School of Medicine; National Heart, Lung, and Blood Institute (NHLBI); University of Miami; Columbia University; Children's Hospital Colorado; Boston Children's Hospital; Ann & Robert H Lurie Children's Hospital of Chicago; HealthCore-NERI; Children's Hospital Medical Center, Cincinnati; Indiana University; Primary Children's Hospital; Stollery Children's Hospital; Monroe Carell Jr. Children's Hospital at Vanderbilt

Publications and helpful links

General Publications

• 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. Erratum In: J Am Heart Assoc. 2021 Jun;10(11):e020840.

Study record dates

Study Major Dates

• Study Start: April 1, 2013
• Primary Completion (Actual): February 1, 2017
• Study Completion (Actual): March 31, 2018

Study Registration Dates

• First Submitted: June 6, 2013
• First Submitted That Met QC Criteria: June 6, 2013
• First Posted (Estimate): June 10, 2013

Study Record Updates

• Last Update Posted (Actual): May 1, 2018
• Last Update Submitted That Met QC Criteria: April 30, 2018
• Last Verified: April 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Genetic Diseases, Inborn; Aortic Valve Disease; Heart Valve Diseases; Cardiomegaly; Laminopathies; Aortic Stenosis, Subvalvular; Aortic Valve Stenosis; Cardiomyopathies; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Cardiomyopathy, Restrictive
• Other Study ID Numbers: 1R01HL111459-01 (U.S. NIH Grant/Contract)