Investigating the Genetic Landscape of Cerebral Palsy

研究脑瘫的遗传景观

• 批准号: 10408839
• 负责人: Siddharth Srivastava
• 金额: $ 19.6万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10408839
• 关键词: Address; Affect; Ataxia; Attention; Biological; Boston; Cerebral Palsy; Characteristics; Child; Child Development; Childhood; Chorea; Classification Scheme; Clinical; Communication; Data; Development; Diagnostic; Disease; Dystonia; Enrollment; Etiology; Face; Functional disorder; Future; Genes; Genetic; Genetic Diseases; Genomics; Goals; Healthcare; Hospitals; Image; Inborn Errors of Metabolism; Individual; Institutionalized Child; Knowledge; Lead; Magnetic Resonance Imaging; Measures; Medical; Medical Care Costs; Mendelian disorder; Molecular Diagnosis; Motor; Neurodevelopmental Disability; Neurodevelopmental Disorder; Neurodevelopmental Impairment; Neurologic; Participant; Pathogenicity; Patients; Pattern; Perinatal; Persons; Phenotype; Pilot Projects; Play; Population; Precision therapeutics; Predictive Factor; Prevalence; Prospective cohort; Rare Diseases; Reproducibility; Research; Risk Factors; Role; Scientist; Severities; Statistical Models; Subgroup; Symptoms; Therapeutic; Training; United States; Variant; Work; career development; clinical practice; cohort; comorbidity; disability; economic impact; exome; exome sequencing; genetic analysis; genetic disorder diagnosis; genetic testing; health care economics; instrument; intrauterine infection; neonatal hypoxic-ischemic brain injury; neuroimaging; patient population; premature; prospective; spasticity

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is the most common childhood-onset motor disability, affecting 764,000 individuals in the United States alone. The lifetime medical costs for a single individual with CP are estimated at $1.4M, which represents a substantial healthcare and economic impact. A diverse set of risk factors contributes to CP, including prematurity, intrauterine infection, and hypoxic ischemic encephalopathy. In approximately 20% of cases, there are no clear perinatal risk factors (“cryptogenic CP”). There is accumulating evidence from rare familial cases and a growing number of isolated cases suggesting that cryptogenic CP may result in part from single gene disorders, including over 50 treatable inborn errors of metabolism. However, these studies have involved small numbers of participants, with patient populations characterized using administrative data with limited attention to precise clinical characterization. The full breadth of the genetic landscape of CP is unknown. We hypothesize that a substantial portion of individuals with cryptogenic CP will have a pathogenic or likely pathogenic variant in a single gene providing an explanation for their symptoms. We propose rigorously phenotyping a large prospective cohort of individuals with both cryptogenic and non-cryptogenic CP who have undergone exome sequencing through an institutional genomics pilot study, and then analyzing exome sequencing data to determine the presence of single gene disorders in each subgroup. To accomplish these goals, we will classify patients as cryptogenic CP or non-cryptogenic CP. We will systematically, rigorously, and longitudinally characterize neurological, motor, communication, and neuroimaging phenotypes using research measures validated for CP. Next, we will analyze exome data using an institutional pipeline for variant interpretation. Finally, we will build a statistical model that correlates the presence of a genetic disorder with phenotypic measures in order to help predict which individuals with CP are most likely to have a single gene disorder. If applied to the population at large, the proposed work could lead to identification of single gene disorders in thousands of individuals with CP, including treatable conditions where a molecular diagnosis may positively alter a child's developmental trajectory. Determining etiology represents a first step in understanding the biological substrates of CP needed for developing rational therapeutics for this highly prevalent condition.

项目摘要/摘要 脑瘫（CP）是最常见的儿童期运动障碍，影响了764,000人 仅在美国。 CP单个人的终身医疗费用估计为140万美元 这代表了实质性的医疗保健和经济影响。各种风险因素有助于CP， 包括早产，介绍性感染和缺氧缺血性脑病。大约20％ 案例，没有明显的围产期危险因素（“隐形CP”）。有罕见的证据积累 家族病例和越来越多的孤立病例表明隐源性CP可能会导致 单基因疾病，包括50多种可治疗的天生代谢错误。但是，这些研究有 涉及少数参与者，患者人数使用管理数据来表征 对精确临床表征的关注有限。 CP的遗传景观的全部广度是 未知。 我们假设有大量隐源性CP的个体将具有致病性或 单个基因中可能的致病变异为其症状提供了解释。我们严格提出建议 表现出具有隐性和非晶源CP的大量前瞻性队列 通过机构基因组试验研究进行了外显子组测序，然后分析外显子组 测序数据以确定每个亚组中单个基因疾病的存在。 为了实现这些目标，我们将将患者归类为隐性CP或非晶源CP。我们将 系统，严格和纵向表征神经，运动，通信和 使用CP验证的研究指标的神经影像型。接下来，我们将使用 用于变异解释的机构管道。最后，我们将建立一个将关联的统计模型 具有表型措施的遗传疾病的存在，以帮助预测哪些CP个体是 最有可能患有单个基因疾病。 如果应用于整个人口，则提出的工作可能导致单个基因的识别 成千上万CP患者的疾病，包括可治疗状况，分子诊断可能 确定病因是理解的第一步 为这种高度普遍的疾病开发理性治疗所需的CP的生物学底物。