Characterizing the spectrum of genomic and phenotypic variation in cerebral palsy

项目摘要/摘要 脑性瘫痪(CP)是一种常见的非进行性发育性脑功能障碍(DBD)，患病率为1/500 以神经运动障碍为特征的，常伴有其他神经发育和医学方面的障碍 精神错乱。出生窒息，长期以来被认为是脑瘫最常见的原因，占病例的10%和 对大多数人来说，具体原因仍不清楚。越来越多的证据表明， CP的比例是由罕见的基因组变异引起的，就像其他DBD所显示的那样。此外， 常见的基因组变异对CP的作用还没有得到充分的评价。在此，我们建议 阐明CP的完整基因组结构，包括稀有和常见基因组的贡献 变种。我们将利用来自两个互补来源的数据：1)参考的儿科CP队列 外显子组测序(ES)到临床遗传学实验室(GeneDx)和2)来自盖辛格的成人CP队列 MyCode研究，一项大规模基因组学倡议，包括配对的电子健康记录(EHR)、ES和SNP 基因分型数据。与其他DBD一样，临床变异在CP和详细的基因-表型中很常见 需要进行相关性研究，以确定表型差异的贡献者。同样，神经成像 研究显示，70%-90%的脑瘫患者存在脑部异常；然而，发现了神经成像异常 在没有进一步评估的情况下，不能确定大多数人的根本原因，而且缺乏 神经成像研究将基因组发现与CP联系起来。我们将通过以下方式解决这些重大的知识差距 以下目标：1)提取和标准化基因组学、EHR和神经成像数据，以创建一个大型、 用于分析的统一CP数据集。我们将利用来自4,000名个体的基因和表型数据 CP，并协调他们现有的基因组、EHR和神经成像数据。2)确定稀有元素的贡献 基因组变异对CP病因学的影响，发现新的基因-疾病关系和CP相关基因；3) 评估常见的基因组变异在CP中的作用以及基因组对DBD的易感性对CP的影响。我们 将全面评估CP的完整基因组图景，包括多类基因组变体。 4)开发一种基于基因组信息的脑性瘫痪神经影像解释方法，并确定基因分型。 CP相关基因的表型相关性。我们将进行基因信息神经成像解释 在一组具有致病变异的参与者中，以确定与特定基因相关的脑异常的特征 基因。我们还将探索在同一基因中存在罕见变异的个体中导致临床变异的因素 吉恩。总体而言，这个项目成功的可能性非常高，这将导致小说的识别 引起CP的基因组变异。这项研究的直接结果将是产生所需的证据 支持将临床基因组检测纳入CP患者的常规临床护理。这 该项目将促进未来对疾病分子机制的研究，这将是发展的关键 针对特定基因组变异的靶向治疗，并将为CP患者的临床基因组测试提供信息。

PROJECT SUMMARY/ABSTRACT Cerebral palsy (CP) is a common (prevalence 1 in 500), nonprogressive developmental brain disorder (DBD) characterized by neuromotor impairments often accompanied by other neurodevelopmental and medical disorders. Birth asphyxia, long considered the most frequent cause of CP, accounts for <10% of cases and a specific cause remains unknown for most individuals. A growing body of evidence suggests that a large proportion of CP is caused by rare genomic variants, as has been shown for other DBDs. Additionally, the contribution of common genomic variants to CP has not been adequately evaluated. Here, we propose to elucidate the complete genomic architecture of CP, including the contribution of rare and common genomic variants. We will capitalize on data generated from two complementary sources: 1) a pediatric CP cohort referred for exome sequencing (ES) to a clinical genetics laboratory (GeneDx) and 2) an adult CP cohort from Geisinger’s MyCode study, a large-scale genomics initiative with paired electronic health record (EHR), ES, and SNP genotype data. As with other DBDs, clinical variability is common in CP and detailed genotype-phenotype correlation studies are required to characterize the contributors to phenotypic variance. Similarly, neuroimaging studies reveal brain abnormalities in 70-90% of individuals with CP; however, finding a neuroimaging abnormality does not establish the underlying cause for most individuals without further evaluations and there is a lack of neuroimaging studies to link genomic findings with CP. We will address these significant knowledge gaps through the following aims: 1) Extract and standardize genomics, EHR, and neuroimaging data to create a large, harmonized CP dataset for analysis. We will leverage genotype and phenotype data from 4,000 individuals with CP and harmonize their available genomic, EHR, and neuroimaging data. 2) Determine the contribution of rare genomic variants to the etiology of CP and identify new gene-disease relationships and CP-related genes; 3) Evaluate the role of common genomic variants in CP and the influence of genomic liability for DBD on CP. We will comprehensively assess the full genomic landscape of CP, including multiple classes of genomic variants. 4) Develop a genomically-informed approach to neuroimaging interpretation in CP and characterize genotype- phenotype correlations for CP-related genes. We will perform genomically-informed neuroimaging interpretation in a subgroup of participants with pathogenic variants to identify profiles of brain abnormalities related to specific genes. We will also explore the contributors to clinical variability among individuals with rare variants in the same gene. Overall, there is a very high likelihood of success that this project will lead to the identification of novel genomic variants that cause CP. An immediate outcome of this study will be the generation of required evidence to support the incorporation of clinical genomic testing into routine clinical care for individuals with CP. This project will foster future research into molecular mechanisms of disease, which will be critical to developing targeted therapies for specific genomic variants, and will inform clinical genomic testing for individuals with CP.