Modifiers of FMR1-associated Disorders: Application of High Throughput Technologi

描述（由申请人提供）：本中心的目标是“FMR1相关疾病的修饰剂：高通量技术的应用”，针对RFA研究领域，以推进对FMR1相关疾病病理生理的理解。完成这三个研究项目的目标将导致确定FMR1相关疾病的可变表达性或不完全外显性的遗传基础。A项目将重点关注患有脆性X染色体综合征（FXS）的男孩癫痫的可变表达，这是一种共病，发生在15%的受影响男孩中，我们推测基因组其他地方的变异是负责的。同样，B项目将关注男性脆性X震颤/共济失调综合征（FXTAS）的不完全外显率，这是一种排列（PM）患者的神经退行性疾病，男性终生患病率为30%。项目C关注脆性X相关性原发性卵巢功能不全（FXPOI），在20%的PM携带者中表现为卵巢早衰（POF），或在40岁之前停止月经。POF导致不孕症和雌激素缺乏相关疾病，通常留给老年人。我们的目标是确定和理解修改基因对这三种孟德尔疾病的认知影响的程度。该中心将包括三个项目和两个共享核心，全部由行政核心管理。每个拟议的研究项目都将采用相同的新方法来定义一组候选基因，以便在哺乳动物系统中进一步研究。他们将：1)使用招募核心B确定从每种疾病的极端表型尾部提取的100例病例和100例对照，2)使用基因组学和分析核心C的专业知识和经验对100/100例/对照系列中的每个进行全基因组测序，3)验证变异后，使用建立的表型分析评估优先基因的功能在相应的果蝇模型中。我们在我们中心提出的研究是高度创新的，使用尖端技术，回答与脆性x相关疾病相关的基本问题。所有研究中心的研究人员都是埃默里大学的一部分，埃默里大学可能是研究脆性x相关疾病的最大的独立教师团体，在该领域有近30年的贡献历史。此外，所有项目的共同主题推动了中心内的协同作用和兴奋，确保了一个高度互动和富有成效的研究环境。

DESCRIPTION (provided by applicant): The goals of our Center, "Modifiers of FMR1-associated disorders: application of high throughput technologies", are targeted to the RFA research area to Advance the understanding of the pathophysiology of FMR1 Related Conditions. The completion of the proposed aims from the three research projects will lead to the identification of the genetic basis of variable expressivity or incomplete penetrance of FMR1- associated conditions. Project A will focus on the variable expression of epilepsy among boys with Fragile X syndrome (FXS), a co-morbid condition that occurs among 15% of affected boys and we speculate that variation elsewhere in the genome is responsible. Likewise, Project B will focus on the incomplete penetrance of Fragile X tremor/ataxia syndrome (FXTAS) in men, a neurodegenerative disorder among those with the permutation (PM), with a lifetime prevalence of 30% among males. Project C focuses Fragile X association primary ovarian insufficiency (FXPOI), which manifests in 20% of PM carriers as premature ovarian failure (POF), or cessation of menses prior to age 40. POF leads to infertility and estrogen-deficiency related disorders usually reserved for the aged. Our goal is to identify and understand the extent of the epistemic effects of modifying genes on these three Mendelian disorders. The Center will include three projects and two shared cores, all administered by an Administrative Core. Each proposed research project will take the same novel approach to define a set of candidate genes for further study in mammalian systems. They will: 1) use the Recruitment Core B to ascertain the 100 cases and 100 controls drawn from extreme phenotypic tails of each disorder, 2) conduct whole genome sequencing on each of the 100/100 cases/controls series using the expertise and experience of the Genomics and Analytical Core C, and 3) after validating variants, assess the function of prioritized genes using the established phenotypic assays in the corresponding Drosophila models. The research we propose in our Center is highly innovative, using cutting-edge technologies, to answer fundamental questions related to Fragile X-related disorders. All Center investigators are part of Emory University, an institution with possibly the largest group of independent faculty working on Fragile X-related disorders and with nearly a 30-year history of contributions to the field. Moreover, an added synergy and excitement within this Center is driven by the common theme among all the projects, ensuring a highly interactive and productive research environment.