Genomic Insights into the Neurobiology of Cerebral Palsy

脑瘫神经生物学的基因组见解

• 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
• 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

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.

项目摘要/摘要 脑瘫（CP）是一种主要的神经发育障碍（患病率3：1000），它改变了过程 正常的大脑发育并损害运动功能。尽管早产和缺氧 开发大脑是CP的众所周知的原因，目前的估计表明，多达三分之一的CP病例 可能是遗传的起源。这代表了该领域的一个重大转变，该领域几乎只关注 迄今为止的环境贡献。仅知道少数CP的遗传原因，这表明研究 该区域可能正在“刮擦庞大的基因组景观表面”，可与其他地方相媲美 自闭症，智力残疾和癫痫等神经发育障碍。虽然其他继承 模式可能导致某些患者的CP，该提议的中心假设是，对于许多人来说 使用CP，单个基因中的突变可能解释其状况。 该项目将临床医生，研究人员和倡导利益相关者团结起来，以发现和验证新颖 CP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 - 基因组的编码区域以在与CP相关的先前未识别基因中找到属突变。我们 关注具有隐性CP的个体（即未知原因的CP），因此我们的队列非常丰富 强遗传效应大小。 我们的初步数据表明，有害突变大大促成脑瘫，并确定 多种高信心“脑瘫基因”。这些结果表明，尽管在情况下实施了基因 隐藏性CP是潜水员，许多映射到常见途径。该应用的目的是扩展我们 初步发现，以涵盖更大的队列，提供定义基本所需的权力 CP遗传基础的各个方面。提出了500个亲子三重奏的整个外显子组测序 完成以下目的：1）发现发生突变时导致CP的新基因和途径； 2） 确定基因对于正常运动神经发育至关重要； 3）区分善良的突变与良性 通过多个模型系统中的一系列验证实验进行DNA变体。 影响：成功完成拟议的目标将允许立即识别新的“ CP基因” 诊断含义。这些发现还将允许建造共享的基因组“路线图” 连接CP的遗传形式的途径。这样，这些研究将为CP提供一个窗口 CP的遗传和环境形式之间的神经生物学将比较和对比途径。 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，率先在CP基因组学领域进行国际合作。