Genetic & Functional Analysis of Variants Associated with Neurocognitive Disorder

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• 批准号: 8412056
• 负责人: Megan Y Dennis
• 金额: $ 3.67万
• 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 2013-08-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8412056
• 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; Societies; Technology; Testing; Validation; Variant; Zebrafish; cohort; developmental disease; exome; exome sequencing; gene discovery; gene function; genome sequencing; genome wide association study; improved; insight; novel; screening; success

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：尽管全基因组关联研究已经确定了过多的导致神经认知障碍的常见变异，但大部分遗传风险仍然无法解释。此外，特定的因果变异和基因往往没有被描述出来，导致这种疾病的潜在机制在很大程度上是未知的。最近，人们已经清楚地看到，具有大效应大小的罕见变异，如从头开始的拷贝数变异(CNV)和蛋白质编码突变，在包括非综合征性智力残疾(ID)和自闭症在内的神经认知障碍中发挥作用。在CNV的病例中，涉及的变异通常包含数十个甚至数百个基因，相同的病变与各种疾病和表型相关；因此，挑战在于识别导致致病性的缺失或重复区域中的准确基因(S)。同样，识别致病外显子突变的主要障碍是从大量无害的变异中区分出高影响的因果变异。在这里，我建议使用基因组方法来发现和表征致病CNV或导致神经认知缺陷的点突变所破坏的原因基因。我将分三步实现这一目标：(1)通过在已知的受影响个体的致病CNV内进行精细作图，确定导致ID和自闭症的候选基因的子集；(2)在部分患有严重ID和多种先天性异常的病例中，确定潜在的致病蛋白改变突变；以及(3)通过在细胞系和斑马鱼中进行实验分析，确定候选基因和变种的特征，以评估它们对发育的影响。这项研究的发现将提供对神经认知障碍的潜在病因的洞察，并为更多的基因发现和潜在的治疗方法铺平道路。随着全外显子组和基因组测序筛查成为识别高渗透性疾病相关变异的标准做法，这种方法将是最终区分因果变异和存在于每个人的大量非致病性编码变异的关键。