Genotype-Phenotype Associations in Pediatric Cardiomyopathy (PCM GENES)

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:

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

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