Clinical trial NCT01873963: Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES)
Official title: Genotype-Phenotype Associations in Pediatric Cardiomyopathy
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Dilated Cardiomyopathy
Hypertrophic Cardiomyopathy
Restrictive Cardiomyopathy
Lead sponsor: Wayne State University
Sponsor class: OTHER
Collaborators: name: Carelon Research
name: Children's Hospital Medical Center, Cincinnati
name: Washington University School of Medicine
name: Children's Hospital of Philadelphia
name: Columbia University
name: Boston Children's Hospital
name: Ann & Robert H Lurie Children's Hospital of Chicago
name: Primary Children's Hospital
name: Monroe Carell Jr. Children's Hospital at Vanderbilt
name: Stollery Children's Hospital
name: National Heart, Lung, and Blood Institute (NHLBI)
name: University of Miami
name: Children's Hospital Colorado
name: Indiana University
First posted: 2013-06-10
Enrollment: 544
Sex: ALL
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
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.

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.

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

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

Primary outcomes:
measure: Time to death
timeFrame: 2 years
Secondary outcomes:
measure: Time to transplant
timeFrame: 2 years
measure: Time to normalized left ventricular size or function in dilated cardiomyopathy
timeFrame: 2 years
measure: Septal:Posterior wall thickness ratio in hypertrophic cardiomyopathy
timeFrame: 2 years
measure: Left ventricular outflow tract in hypertrophic cardiomyopathy
timeFrame: 2 years
Other outcomes:
Locations:
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: Miami
country: United States
facility: University of Miami, Jackson Memorial Hospital
state: Florida
city: Chicago
country: United States
facility: Ann and Robert H. Lurie Children's Hospital of Chicago
state: Illinois
city: Boston
country: United States
facility: Children's Hospital Boston
state: Massachusetts
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Bronx
country: United States
facility: Children's Hospital at Montefiore
state: New York
city: New York
country: United States
facility: Children's Hospital of New York, Columbia Presbyterian Medical Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Nashville
country: United States
facility: Monroe Carell Jr. Children's Hospital at Vanderbilt
state: Tennessee
city: Salt Lake City
country: United States
facility: Primary Children's Medical Center
state: Utah
city: Edmonton
country: Canada
facility: Stollery Children's Hospital
state: Alberta
Study officials:
affiliation: Wayne State University
name: Steven E Lipshultz, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.