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: 10651821
• 负责人: Andres Moreno De Luca
• 金额: $ 68.02万
• 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/10651821
• 关键词: 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; bioinformatics tool; brain abnormalities; candidate identification; 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.

项目摘要/摘要 脑瘫（CP）是一种常见（500中的患病率1），非进化发育脑部疾病（DBD） 以神经运动障碍为特征，通常伴有其他神经发育和医学 疾病。长期认为最常见的CP原因的出生窒息，占病例的<10％，A 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一个很大的证据 CP的比例是由罕见的基因组变异引起的，如其他DBD所示。另外， 共同基因组变异对CP的贡献尚未得到充分评估。在这里，我们建议 阐明CP的完整基因组结构，包括稀有基因组和常见基因组的贡献 变体。我们将利用从两个完成来源生成的数据：1）儿科CP队列推荐 用于临床遗传学实验室（GenEDX）和2）Geisinger's的成人CP队列的外显子组测序（ES） MyCode研究，一项具有配对电子健康记录（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，临床变异性在CP和详细的基因型 - 表型中也很常见 需要相关研究以表征表型差异的贡献者。同样，神经影像学 研究揭示了70-90％的CP患者的脑异常。但是，发现神经影像异常 没有在没有进一步评估的情况下为大多数人建立根本原因，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 以下目的：1）提取和标准化基因组学，EHR和神经影像学数据，以创建一个大型， 协调的CP数据集用于分析。我们将利用4,000名患者的基因型和表型数据 CP并协调其可用的基因组，EHR和神经影像学数据。 2）确定稀有的贡献 基因组变体对CP的病因，并鉴定新的基因酶关系和与CP相关的基因； 3） 评估常见基因组变异在CP中的作用以及基因组责任对DBD对CP的影响。我们 将全面评估CP的完整基因组景观，包括多种基因组变体。 4）开发一种基因形式的方法，用于CP中的神经影像学解释并表征基因型 - CP相关基因的表型相关性。我们将执行基因形式的神经影像学解释 在具有致病变异的参与者的亚组中，以鉴定与特定的脑异常的特征 基因。我们还将探索稀有变体的个体中临床变异性的贡献者 基因。总体而言，成功的可能性很高，该项目将导致新颖的识别 引起CP的基因组变体。这项研究的直接结果将是生成所需的证据 支持将临床基因组测试纳入CP患者的常规临床护理中。这 项目将促进对疾病分子机制的未来研究，这对于发展至关重要 针对特定基因组变异的靶向疗法，并将为CP患者提供临床基因组测试。

项目成果

Implications of Genetic Variants in Cerebral Palsy-Reply.

遗传变异对脑瘫应答的影响。

• DOI: 10.1001/jamapediatrics.2023.1858
• 发表时间: 2023
• 期刊: JAMA pediatrics
• 影响因子: 26.1
• 作者: Myers,ScottM;Martin,ChristaL;Moreno-De-Luca,Andres
• 通讯作者: Moreno-De-Luca,Andres

It's time to offer genetic testing to all individuals diagnosed with cerebral palsy.

是时候为所有被诊断患有脑瘫的人提供基因检测了。

• DOI: 10.1016/j.parkreldis.2023.105449
• 发表时间: 2023
• 期刊: Parkinsonism & related disorders
• 影响因子: 4.1
• 作者: Moreno-De-Luca,Andrés

PI4K2A deficiency causes innate error in intracellular trafficking with developmental and epileptic-dyskinetic encephalopathy.

• DOI: 10.1002/acn3.51634
• 发表时间: 2022-09
• 期刊: ANNALS OF CLINICAL AND TRANSLATIONAL NEUROLOGY
• 影响因子: 5.3
• 作者: Dafsari, Hormos Salimi;Pemberton, Joshua G.;Ferrer, Elizabeth A.;Yammine, Tony;Farra, Chantal;Mohammadi, Mohammad Hasan;Karimiani, Ehsan Ghayoor;Hashemi, Narges;Souaid, Mirna;Sabbagh, Sandra;Torbati, Paria Najarzadeh;Khan, Suliman;Roze, Emmanuel;Moreno-De-Luca, Andres;Bertoli-Avella, Aida M.;Houlden, Henry;Balla, Tamas;Maroofian, Reza
• 通讯作者: Maroofian, Reza

A novel SMARCC1 -mutant BAFopathy implicates epigenetic dysregulation of neural progenitors in hydrocephalus.

一种新的 SMARCC1 突变 BAF 病涉及脑积水神经祖细胞的表观遗传失调。

• DOI: 10.1101/2023.03.19.23287455
• 发表时间: 2023
• 期刊: medRxiv : the preprint server for health sciences
• 作者: Singh,AmritaK;Viviano,Stephen;Allington,Garrett;McGee,Stephen;Kiziltug,Emre;Mekbib,KedousY;Shohfi,JohnP;Duy,PhanQ;DeSpenza,Tyrone;Furey,CharutaG;Reeves,BenjaminC;Smith,Hannah;Ma,Shaojie;Sousa,AndréMM;Cherskov,Adriana