Investigating the Genetic Landscape of Cerebral Palsy

项目摘要/摘要 脑性瘫痪(CP)是最常见的儿童期起病的运动障碍，影响764,000人 仅在美国。一个CP患者一生的医疗费用估计为140万美元， 这代表着巨大的医疗保健和经济影响。一组不同的危险因素导致慢性阻塞性肺疾病， 包括早产、宫内感染和缺氧缺血性脑病。在大约20%的 病例中，没有明确的围产期危险因素(“隐源性CP”)。有越来越多的证据来自稀有的 家族性病例和越来越多的孤立病例表明隐源性CP可能部分原因是 单基因疾病，包括50多种可治疗的先天性新陈代谢疾病。然而，这些研究已经 涉及少量参与者，患者群体使用管理数据进行表征 对精确的临床特征的关注有限。CP的全部遗传图景是 未知。 我们假设相当大一部分隐源性CP患者会有致病性或 单个基因中可能的致病变异为他们的症状提供了解释。我们严谨地建议 同时患有隐匿性和非隐匿性CP的大量预期队列个体的表型分析 通过机构基因组学先导研究进行外显子组测序，然后分析外显子组 测序数据以确定每个亚组中是否存在单基因紊乱。 为了实现这些目标，我们将把患者分为隐源性CP和非隐源性CP。我们会 系统地、严格地和纵向地描述神经学、运动学、传播学和 使用研究方法对脑瘫进行验证的神经成像表型。接下来，我们将使用以下工具分析Exome数据 变式解释的制度性渠道。最后，我们将构建一个统计模型，将 存在遗传性疾病的表型测量，以帮助预测哪些人患有CP 最有可能患有单基因紊乱。 如果应用于整个种群，建议的工作可能导致单个基因的识别 数千名CP患者的疾病，包括可治疗的情况，分子诊断可能 积极地改变孩子的发展轨迹。确定病因学是理解 CP的生物底物需要为这种高度流行的疾病开发合理的治疗方法。

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.