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，但大部分遗传风险仍然无法解释。此外，特定的致病变异和基因往往没有特征，留下的潜在机制，有助于这些疾病在很大程度上是未知的。最近，已经清楚的是，具有大效应量的罕见变体，例如从头拷贝数变体（CNV）和蛋白质编码突变，在包括非综合征性智力残疾（ID）和自闭症的神经认知障碍中起作用。在CNV的情况下，涉及的变体通常包括数十个基因，如果不是数百个基因，具有与各种病症和表型相关的相同病变;因此，挑战在于辨别导致致病性的缺失或重复区域内的精确基因。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出高影响的致病变异。在这里，我建议使用基因组方法来发现和表征致病性CNVs或点突变，导致神经认知缺陷的破坏的因果基因。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CNV内的精细定位来鉴定导致ID和自闭症的候选基因子集;（2）在患有严重ID和多种先天性异常的病例子集中鉴定潜在致病性蛋白质改变突变;以及（3）使用细胞系和斑马鱼中的实验测定来表征候选基因和变体，以评估它们对发育的影响。这项研究的结果将提供深入了解神经认知障碍的潜在病因，并为更多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选成为鉴定高度渗透性疾病相关变体的标准实践，这种方法对于最终区分致病性变体与存在于每个个体中的大量非致病性编码变体至关重要。

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.