Characterizing the spectrum of genomic and phenotypic variation in cerebral palsy

项目总结/摘要 脑性瘫痪（CP）是一种常见的（患病率1/500），非进行性脑发育障碍（DBD） 以神经运动障碍为特征，通常伴有其他神经发育和医学障碍。 紊乱长期以来，出生窒息被认为是CP最常见的原因，占病例的<10%， 对于大多数人来说，具体的原因仍然未知。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，如其他DBD所示。另夕h 尚未充分评估常见基因组变异对CP的贡献。在此，我们建议 阐明CP的完整基因组结构，包括罕见和常见基因组结构的贡献。 变体。我们将利用来自两个互补来源的数据：1）儿科CP队列， 用于外显子组测序（ES）的成年CP队列，2）来自Geisinger's的临床遗传学实验室（GeneDx）， MyCode研究，一项大规模基因组学计划，包括配对电子健康记录（EHR）、ES和SNP 基因型数据。与其他DBD一样，临床变异性在CP和详细的基因型-表型中很常见 需要相关性研究来表征表型方差的贡献者。同样，神经成像 研究显示，70-90%的CP患者大脑异常;然而，发现神经影像学异常 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， 神经影像学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大的， 用于分析的统一CP数据集。我们将利用来自4,000名个体的基因型和表型数据， CP和协调其可用的基因组，EHR和神经影像数据。2)确定罕见的贡献 基因组变异对CP病因学的影响，并确定新的基因-疾病关系和CP相关基因; 3） 评估常见基因组变异在CP中的作用以及DBD基因组易感性对CP的影响。我们 将全面评估CP的完整基因组景观，包括多个类别的基因组变异。 4)开发一种基因组学方法来解释CP的神经影像学，并描述基因型- CP相关基因的表型相关性。我们将进行基因组信息的神经成像解释 在一个有致病性变异的参与者亚组中， 基因.我们还将探讨具有相同基因罕见变异的个体之间临床变异的贡献者。 基因总的来说，这个项目成功的可能性很大，它将导致新的识别。 导致CP的基因变异这项研究的一个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，这对发展 该研究将为特定基因组变异的靶向治疗提供指导，并将为CP患者的临床基因组检测提供信息。

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.