Characterizing the spectrum of genomic and phenotypic variation in cerebral palsy

描述脑瘫的基因组和表型变异谱

• 批准号: 10454011
• 负责人: Andres Moreno De Luca
• 金额: $ 66.66万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10454011
• 关键词: Address; Adult; Affect; Architecture; Asphyxia Neonatorum; Biological; Brain Diseases; Candidate Disease Gene; Cerebral Palsy; Childhood; Clinical; Clinical Data; Cohort Analysis; Collaborations; Common Data Element; Copy Number Polymorphism; Correlation Studies; Data; Data Set; Databases; Development; Disease; Electronic Health Record; Enrollment; Etiology; Evaluation; Fostering; Frequencies; Gene Family; Generations; Genes; Genome; Genomics; Genotype; Guidelines; Healthcare; Heritability; Human; Impairment; Individual; Intellectual functioning disability; Investigation; Knowledge; Laboratories; Link; Medical; Medical Genetics; Molecular; Motor; National Institute of Neurological Disorders and Stroke; Ontology; Outcome Study; Participant; Pathogenicity; Pathway interactions; Patients; Pediatric cohort; Phenotype; Prevalence; Publishing; Research; Risk Factors; Role; SNP genotyping; Site; Source; Standardization; Subgroup; Testing; Variant; autism spectrum disorder; base; bioinformatics tool; brain abnormalities; clinical care; cohort; comorbidity; cost effective; exome sequencing; genetic variant; genome wide association study; genomic data; neuroimaging; novel; novel strategies; phenotypic data; population based; rare variant; recruit; success; targeted treatment; transmission process

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.

项目概要/摘要 脑瘫 (CP) 是一种常见（患病率为五百分之一）的非进行性发育性脑部疾病 (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 失调。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% 以下，并且 对于大多数人来说，具体原因仍然未知。越来越多的证据表明，大量 正如其他 DBD 所示，部分 CP 是由罕见的基因组变异引起的。此外， 常见基因组变异对 CP 的贡献尚未得到充分评估。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的贡献 变种。我们将利用两个互补来源生成的数据：1) 转介的儿科 CP 队列 用于临床遗传学实验室 (GeneDx) 的外显子组测序 (ES) 和 2) 来自 Geisinger’s 的成人 CP 队列 MyCode 研究，一项包含配对电子健康记录 (EHR)、ES 和 SNP 的大规模基因组学计划 基因型数据。与其他 DBD 一样，CP 和详细的基因型-表型的临床变异很常见 需要进行相关性研究来描述表型变异的影响因素。同样，神经影像学 研究表明 70-90% 的脑瘫患者大脑存在异常；然而，发现神经影像学异常 在没有进一步评估的情况下，无法确定大多数人的根本原​​因，并且缺乏 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： 目标如下： 1) 提取并标准化基因组学、EHR 和神经影像数据，以创建大型、 用于分析的统一 CP 数据集。我们将利用 4,000 名个体的基因型和表型数据 CP 并协调其可用的基因组、EHR 和神经影像数据。 2）确定稀有贡献 CP 病因的基因组变异并鉴定新的基因-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 的基因组责任对 CP 的影响。我们 将全面评估 CP 的完整基因组景观，包括多类基因组变异。 4) 开发一种基因组学方法来解释 CP 的神经影像并表征基因型 CP相关基因的表型相关性。我们将进行基因组学神经影像解读 在具有致病性变异的参与者亚组中，识别与特定相关的大脑异常概况 基因。我们还将探讨同一疾病中具有罕见变异的个体之间临床变异的影响因素。 基因。总体而言，该项目很有可能成功识别新的 导致 CP 的基因组变异。这项研究的直接结果将是生成所需的证据 支持将临床基因组检测纳入脑瘫患者的常规临床护理中。这 该项目将促进未来对疾病分子机制的研究，这对于发展疾病至关重要 针对特定基因组变异的靶向治疗，并将为脑瘫患者的临床基因组测试提供信息。