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Deep mutational scanning of CHD2 for variant interpretation in neurodevelopmental disorders

CHD2 的深度突变扫描以解释神经发育障碍的变异

基本信息

批准号：
10811491
负责人：
Gemma Louise Carvill
金额：
$ 42.08万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-09-15 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10811491
关键词：
Address Affect Award Benign Biological Assay Brain Cell Line Cells Chromatin Classification Clinical Trials DNA Methylation Detection Discrimination Disease Eligibility Determination Family Foundations Future Gene Expression Genes Genotype Goals Haploid Cells Haploidy Human Individual Intellectual functioning disability Intractable Epilepsy Knock-out Label Life Maintenance Malignant Neoplasms Measures Medical Genetics Methods Methylation Modality Mus Myoblasts Nature Neurodevelopmental Disorder Neurons Pathogenicity Patients Precision therapeutics Proteins Proteomics Recurrence Reporting Research Research Proposals Resolution Science Site Testing Validation Variant Western Blotting Work autism spectrum disorder design genetic testing genome editing high risk high throughput screening innovation leukemia loss of function methylation pattern multimodality multiplex assay mutation screening nervous system disorder novel prime editing protein expression protein function stem cells transcriptome sequencing variant of unknown significance

项目摘要

Project summary De novo pathogenic variants in CHD2 are one of the most common causes of the neurodevelopmental disorders (NDDs) that include refractory epilepsy, intellectual disability and autism spectrum disorders. In addition, somatic CHD2 variants, acquired later in life, are highly recurrent in certain types of leukemias. For both types of conditions, loss-of-CHD2 function is the likely pathogenic mechanism, and most variants are truncations. However, there is also evidence that missense variants can disrupt or abrogate CHD2 function, leading to loss-of-function, though they are harder to interpret, and many are classified as variants of uncertain significance (VUS). VUS are one of the biggest challenges for human geneticists, and represent the biggest class of variants returned on clinical genetic test reports, in part because we have a poor understanding of how missense variants impact protein function. Our research addresses these challenges by designing a bimodal high-throughput assay to determine the impact of VUS on CHD2 function using downstream protein abundance (Aim 1) and the CHD2 episignature (Aim 2). We will leverage the fact that CHD2 is a chromatin remodeler and thus affects both downstream protein expression and the DNA methylation landscape to develop a high-throughput, multimodal approach to identify variants that alter CHD2 function. We will also implement prime-editing using pools of pegRNAs to create 30 CHD2 variants and multiplex this assays, with a view to scale to hundreds of CHD2 variants in future work. Our work and approach has broad appeal as it can be scaled to include other NDDs and cancers in the future. Finally, the goal of this research is to develop an experimental paradigm that can be scaled to resolve all CHD2 VUS, providing answers for patients and families, and identifying those individuals that will be eligible for precision therapies in the future.

项目总结