Genetic & Functional Analysis of Variants Associated with Neurocognitive Disorder

遗传

• 批准号: 8254117
• 负责人: Megan Y Dennis
• 金额: $ 5.22万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8254117
• 关键词: Address; Affect; Autistic Disorder; Biological; Biological Assay; Candidate Disease Gene; Cell Line; Code; Complex; Congenital Abnormality; Defect; Development; Developmental Process; Diagnostic Procedure; Disease; Etiology; Genes; Genetic; Genetic Risk; Genetic Variation; Genomics; Goals; Hereditary Disease; Heterogeneity; Human Cell Line; Impairment; Individual; Intellectual functioning disability; Lead; Left; Lesion; Life; Maps; Methods; Modeling; Mutation; Neurocognitive; Neurologic; Organism; Pathogenicity; Pathway interactions; Patients; Phenotype; Play; Point Mutation; Population; Processed Genes; Proteins; Recurrence; Research; Role; Screening procedure; Societies; Technology; Testing; Validation; Variant; Zebrafish; cohort; developmental disease; exome; gene discovery; gene function; genome sequencing; genome wide association study; improved; insight; novel; success

Though genome-wide association studies have identified a plethora of common variants contributing to neurocognitive disorders, much of the genetic risk remains unexplained. Additionally, specific causal variants and genes are often not characterized, leaving the underlying mechanisms contributing to such disorders largely unknown. Recently, it has become clear that rare variants with large effect sizes, such as de novo copy- number variants (CNVs) and protein-coding mutations, play a role in neurocognitive disorders including nonsyndromic intellectual disability (ID) and autism. In the case of CNVs, implicated variants often encompass tens if not hundreds of genes, with the same lesion associated with a variety of disorders and phenotypes; therefore, the challenge lies in discerning the precise gene(s) within the deleted or duplicated regions that contribute to pathogenicity. Likewise, the major obstacle in identifying disease-causing exonic mutations is discerning high-impact causal variants from a surplus of innocuous variants. Here, I propose the use of genomic approaches to discover and characterize causal genes disrupted by pathogenic CNVs or point mutations that contribute to neurocognitive defects. I will address this goal in three steps: (1) identify a subset of candidate genes contributing to ID and autism using fine-scale mapping within known pathogenic CNVs in affected individuals; (2) identify potentially pathogenic protein-altering mutations in a subset of cases with severe ID and multiple congenital abnormalities; and (3) characterize candidate genes and variants using experimental assays in cell lines and zebrafish to assess their impact on development. The findings of this research will offer insight into the underlying etiology of neurocognitive disorders and pave the way for additional gene discovery and potential treatments. As whole-exome and -genome sequencing screens become standard practice in identifying highly penetrant disease-associated variants, such methods will be vital to ultimately distinguish causal variants from a large list of non-pathogenic coding variants residing in every individual.

尽管全基因组关联研究已经确定了有助于神经认知疾病的大量常见变异，但许多遗传风险仍然无法解释。此外，通常没有表征特定的因果变异和基因，从而导致这种疾病的基本机制在很大程度上未知。最近，很明显，具有较大效应大小的稀有变体，例如从头拷贝数变体（CNV）和蛋白质编码突变，在神经认知疾病中起作用，包括非同伴智力障碍（ID）和自闭症。在CNV的情况下，涉及的变体通常包含数十个基因的基因，而与多种疾病和表型相同的病变相同。因此，挑战在于辨别导致致病性的已删除或重复区域内的精确基因。同样，识别引起疾病的外显子突变的主要障碍是从无害变体的盈余中辨别出高影响的因果变异。在这里，我提出了使用基因组方法来发现和表征因致病性CNV或点突变而破坏的因果基因，从而导致神经认知缺陷。我将通过三个步骤解决这个目标：（1）在受影响的个体中使用已知病原CNV中的精细尺度映射确定候选基因的子集； （2）在严重ID和多个先天性异常的一部分中确定潜在的致病蛋白质改变突变； （3）使用细胞系和斑马鱼中的实验测定法对候选基因和变体进行表征，以评估其对发育的影响。这项研究的发现将洞悉神经认知障碍的潜在病因，并为其他基因发现和潜在治疗铺平道路。随着全外观和 - 基因组测序筛选成为识别高度渗透性疾病相关变体的标准实践，因此，这种方法对于最终将因果变体与每个个体中居住的非致病编码变体列表区分开至关重要。