Genomic Insights into the Neurobiology of Cerebral Palsy

项目摘要/摘要 脑性瘫痪(CP)是一种主要的神经发育障碍(患病率为3：1000)，它改变了 大脑发育正常，运动功能受损。虽然早产儿和缺氧都会导致 大脑发育是CP的众所周知的原因，目前的估计表明高达三分之一的CP病例 可能是遗传的。这代表着该领域的一个重大转变，该领域几乎完全专注于 到目前为止对环境的贡献。只有少数几个CP的遗传原因是已知的，这表明 这一区域可能是一个巨大的基因组图景的“皮毛”，可以与其他 神经发育障碍，如自闭症、智力残疾和癫痫。虽然其他遗产 在一些患者中，模式可能导致CP，该提议的中心假设是对许多个体 对于CP来说，单个基因的突变可能是他们病情的原因。 该项目将临床医生、研究人员和倡导利益相关者团结在一起，以发现和验证新的 慢性阻塞性肺病的遗传原因。研究小组将使用整个外显子组测序来梳理蛋白质- 在基因组的编码区寻找以前未被识别的与CP相关的基因的致病突变。我们 关注患有隐源性CP(即原因不明的CP)的个人，因此我们的队列高度丰富 强大的遗传效应大小。 我们的初步数据表明，有害的突变在很大程度上导致脑性瘫痪，并确定 多个高自信的“脑瘫基因”。这些结果表明，尽管与病例有关的基因 隐蔽基因CP的基因是多样的，许多映射到共同的途径。此应用程序的目标是扩展我们的 初步发现涵盖了一个更大的队列，提供了定义基本概念所需的力量 CP的遗传基础的几个方面。500个亲子三元组的外显子全基因组测序 实现以下目标：1)当突变发生时，发现导致CP的新基因和新途径；2) 精确定位对正常运动神经发育至关重要的基因；3)区分真正的突变和良性的突变 通过在多个模型系统中的一系列验证实验来确定DNA变异体。 影响：成功完成拟议的目标将使我们能够立即识别新的‘CP基因’ 诊断性暗示。这些发现还将有助于构建共享的基因组“路线图”。 连接CP遗传形式的途径。通过这样做，这些研究将为了解CP提供一个窗口 神经生物学将比较和对比遗传形式和环境形式的CP的途径。 最后，这项工作将生成重要的主要数据，这些数据将在最近建立的 国际脑瘫基因组学联盟，引领CP基因组学的国际合作。

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a major neurodevelopmental disorder (prevalence 3:1000) that alters the course of normal brain development and impairs motor function. Although both prematurity and lack of oxygen to the developing brain are well-known causes of CP, current estimates suggest that up to one third of cases of CP may be genetic in origin. This represents a major shift for the field, which has almost exclusively focused on environmental contributions to date. Only a handful of genetic causes of CP are known, suggesting research in this area may be ‘scratching the surface’ of a vast genomic landscape, comparable to that seen in other neurodevelopmental disorders such as autism, intellectual disability and epilepsy. Although other inheritance patterns likely lead to CP in some patients, the central hypothesis of this proposal is that for many individuals with CP, mutations in a single gene may account for their condition. This project unites clinicians, researchers and advocacy stakeholders in order to discover and validate novel genetic causes of CP. The research team will employ whole exome sequencing to comb through the protein- coding regions of the genome to find causative mutations in previously unrecognized genes relevant to CP. We focus on individuals with cryptogenic CP (i.e. CP of unknown cause) and thus our cohort is highly enriched for strong genetic effect sizes. Our preliminary data indicate that deleterious mutations substantially contribute to cerebral palsy, and identify multiple high-confidence “cerebral palsy genes.” These results suggest that although genes implicated in cases of cryptogenic CP are diverse, many map to common pathways. The goal of this application is to extend our preliminary findings to encompass a much larger cohort, providing the power required to define fundamental aspects of the genetic basis of CP. Whole exome sequencing of 500 parent-child trios is proposed to accomplish the following aims: 1) discover new genes and pathways that lead to CP when mutations occur; 2) pinpoint genes crucial for normal motor neurodevelopment; 3) distinguish bona fide mutations from benign DNA variants through a series of validation experiments in multiple model systems. Impact: Successful completion of the proposed aims will allow identification of new ‘CP genes’ with immediate diagnostic implications. These findings will also allow the construction of a genomic “roadmap” of shared pathways connecting genetic forms of CP. In so doing, these studies will provide a window into CP neurobiology that will compare and contrast pathways between genetic and environmental forms of CP. Finally, this work will generate important primary data that will be shared within the recently established International Cerebral Palsy Genomics Consortium, spearheading international collaboration in CP genomics.