Genomic Insights into the Neurobiology of Cerebral Palsy

脑瘫神经生物学的基因组见解

基本信息

批准号：
10078131
负责人：
Michael C Kruer
金额：
$ 73.35万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078131
关键词：
Adolescent Advocacy Affect Area Asphyxia Neonatorum Benign Biochemical Biological Assay Biological Models Brain Brain Hypoxia-Ischemia Candidate Disease Gene Cell Line Cellular biology Cerebral Palsy Child Collaborations Comb animal structure Complement Copy Number Polymorphism DNA Data Development Diagnosis Diagnostic Disease Drosophila genus Environmental Risk Factor Epilepsy Fibroblasts Gene set enrichment analysis Genes Genetic Genetic Predisposition to Disease Genome Genomics Goals Human Impairment Individual Infection Inheritance Patterns Intellectual functioning disability International Lead Life Mammalian Cell Maps Modeling Molecular Molecular Target Motor Mutation Nervous system structure Neurobiology Neurodevelopmental Disorder Neuroglia Neurons Open Reading Frames Oxygen Parents Participant Pathway Analysis Pathway interactions Patients Phenotype Polynomial Models Prevalence Process Publishing Recurrence Research Research Personnel Risk Series Single Nucleotide Polymorphism Surface System Systems Biology Validation Variant Work Yeasts autism spectrum disorder base causal variant cohort de novo mutation deprivation developmental neurobiology exome exome sequencing experimental study falls fly genome editing genome-wide hypoxic ischemic injury improved insertion/deletion mutation insight knock-down loss of function lymphoblast motor impairment mutant neurodevelopment novel overexpression premature prenatal public health relevance risk variant therapeutic development validation studies

项目摘要

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.

项目概要/摘要脑瘫 (CP) 是一种主要的神经发育障碍（患病率为 3:1000），它会改变孩子的病程尽管早产和缺氧都会影响大脑的正常发育和运动功能。发育中的大脑是脑瘫的众所周知的原因，目前的估计表明多达三分之一的脑瘫病例这可能是起源于遗传的，这代表了该领域的重大转变，该领域几乎完全专注于研究。迄今为止，只有少数 CP 的遗传原因是已知的，这表明对 CP 的研究表明。该区域可能正在“触及巨大基因组景观的表面”，与其他区域中所见的区域相比神经发育障碍，如自闭症、智力障碍和癫痫等。模式可能会导致某些患者发生 CP，该提案的中心假设是对于许多人来说对于 CP，单个基因的突变可能是其病情的原因。该项目将追随者、研究人员和倡导利益相关者联合起来，以发现和验证新颖的研究小组将利用全外显子组测序来梳理蛋白质的遗传原因。基因组的编码区域，以发现与 CP 相关的先前未被识别的基因的致病突变。重点关注患有隐源性 CP（即原因不明的 CP）的个体，因此我们的队列高度丰富强烈的遗传效应大小。我们的初步数据表明，有害突变在很大程度上导致脑瘫，并确定多个高置信度的“脑瘫基因”。这些结果表明，尽管基因与病例有关密码学的 CP 是多种多样的，许多映射到共同的途径，这个应用程序的目标是扩展我们的研究。初步调查结果涵盖了更大的群体，提供了定义基本面所需的力量建议对 500 个亲子三人组进行全外显子组测序。完成以下目标：1）发现突变发生时导致 CP 的新基因和途径；2）查明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突变通过在多个模型系统中进行一系列验证实验得出 DNA 变体。影响：成功完成拟议目标将能够立即识别新的“CP基因” 这些发现还将有助于构建共享的基因组“路线图”。连接 CP 遗传形式的途径这样，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 之间的途径。最后，这项工作将生成重要的原始数据，这些数据将在最近建立的国际脑瘫基因组学联盟，引领脑瘫基因组学领域的国际合作。