Genotype-Phenotype Associations in Pediatric Cardiomyopathy
试验速览
- 阶段
- 不适用
- 状态
- 已完成
- 入组人数
- 544
- 试验地点
- 12
- 主要终点
- Time to death
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
结局指标
主要结局
Time to death
时间窗: 2 years
次要结局
- 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)
研究者
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
Wayne State University