Genetic & Functional Analysis of Variants Associated with Neurocognitive Disorder

描述（由申请人提供）：尽管全基因组关联研究已经确定了大量导致神经认知障碍的常见变异，但许多遗传风险仍未得到解释。此外，特定的因果变异和基因往往没有特征，导致这些疾病的潜在机制在很大程度上是未知的。近年来，人们已经清楚地认识到，具有大效应量的罕见变异，如新生拷贝数变异（CNVs）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起着重要作用。在CNVs的情况下，涉及的变异通常包括数十甚至数百个基因，相同的病变与各种疾病和表型相关；因此，挑战在于在导致致病性的缺失或重复区域中识别精确的基因。同样，识别致病外显子突变的主要障碍是从多余的无害变异中识别高影响的因果变异。在这里，我建议使用基因组方法来发现和表征被致病性CNVs或导致神经认知缺陷的点突变破坏的因果基因。我将分三步实现这一目标：(1)在受影响个体中使用已知致病性CNVs的精细图谱确定导致ID和自闭症的候选基因子集；(2)在一些严重ID和多种先天性异常的病例中发现潜在的致病性蛋白改变突变；(3)利用细胞系和斑马鱼的实验分析来表征候选基因和变异，以评估它们对发育的影响。这项研究的发现将有助于深入了解神经认知障碍的潜在病因，并为进一步的基因发现和潜在的治疗铺平道路。随着全外显子组和全基因组测序筛查成为鉴定高渗透性疾病相关变异的标准做法，这些方法对于最终区分每个个体中的因果变异和大量非致病性编码变异至关重要。

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.