BCM Clinical Site for an Undiagnosed Disease Network (UDN) Phase II (U01)

项目摘要 贝勒医学院(BCM)未诊断疾病网络(UDN)临床站点(CS) 成功地推进了第一阶段统一数字网络的目标。我们建立了一条高通量的综合管道 为患有未诊断疾病(UDD)的患者提供最先进的诊断、临床和分子信息 评估。我们在患者接受度和面对面评估方面领先于UDN临床站点， 同时成为这两个关键里程碑100%实现的两个校外网站之一。我们开发了 创新的方法，包括三重RNA测序，使我们实现了已解决和 到目前为止，45%的病例已经完成了强候选基因的检测。最后，我们与UDN和更广泛的 在分享最佳实践、协作发现和教育方面的科学/非专业社区。这是实现的 通过利用分子和人类系的综合遗传和基因组计划 遗传学(DMHG)。该部门是基础科学、临床和分子科学的结合体 病理科。因为这些是在一个组织单位下消费的，所以我们迅速地 将发现转化为实践，并成为BCM研究社区的纽带，德克萨斯医学 中心，以及全国。DMHG在BCM遗传和基因组医学方面的领导确保了 将儿科、内科和神经科的伙伴关系整合到第一阶段 BCM UDNCS。在第二阶段，我们建议应用这一综合方法来实现新的和正在进行的 UDN的目标。BCM UDN CS的领导层包括在遗传学方面的成熟临床研究人员， 儿科、医学和神经科将领导一个主要团队，同时从合作伙伴的顾问中抽调人员 机构范围内的各部门。临床描述和随后的DNA分子诊断将利用这两个 已建立(人类基因组测序中心、贝勒遗传学实验室和美国国立卫生研究院孟德尔中心 基因组学)和BCM UDNCS特定生物信息学管道。解读与终极功能 基因组数据的研究将流向专门的器官研究中心，包括骨骼中心 医学和生物学(由Brendan Lee博士领导)、神经学研究所(由Huda Zoghbi博士领导)、 人类免疫学中心(由乔丹·奥兰治博士领导)和NIH UDN模式生物筛选 中心和击倒鼠标表型程序。为了可持续发展，BCM将1)建立和财务 支持未诊断疾病中心，2)利用新开发的DMHG医疗虚拟平台 提高效率、降低成本和扩大获取途径的遗传学关怀提供平台(Consultagene.org) 对于患者和提供者的参与，3)将研究工具转换到临床诊断领域，即贝勒 遗传学实验室，4)完成正在进行的健康经济研究，以提高这些工具的付款人覆盖率， 以及5)广泛传播患者变种，以刺激与基础科学家合作进行功能研究。

Project Summary The Baylor College of Medicine (BCM) Undiagnosed Diseases Network (UDN) Clinical Site (CS) has successfully advanced the objectives of phase I UDN. We established a high throughput integrated pipeline for patients with undiagnosed diseases (UDD) to access a state of the art diagnostic, clinical, and molecular evaluation. We led extramural UDN clinical sites in number of patient acceptances and in person evaluations, while being one of two extramural sites to achieve 100% for these two key milestones. We developed innovative approaches including trio RNA sequencing that led us to achieve a diagnostic rate for solved and strong candidate genes in 45% of cases completed to date. Finally, we engaged the UDN and the broader scientific/lay community in sharing best practices, collaborative discovery, and education. This was achieved by leveraging the integrated genetic and genomic program that is the Department of Molecular and Human Genetics (DMHG) at BCM. The Department is a combination of basic science, clinical, and molecular pathology departments. Because these are consumed under one organizational unit, we have rapidly translated discovery to practice, and served as a nexus for the research community at BCM, the Texas Medical Center, and nationally. The leadership of the DMHG in genetic and genomic medicine at BCM has ensured the integration of the partnering Departments of Pediatrics, Internal Medicine, and Neurology into phase I of the BCM UDN CS. In phase II we propose to apply this integrated approach to achieve the new and ongoing objectives of the UDN. The BCM UDN CS leadership includes established clinical investigators in Genetics, Pediatrics, Medicine, and Neurology who will lead a primary team while drawing from consultants in partner Departments institution-wide. Clinical delineation and subsequent DNA molecular diagnosis will leverage both established (Human Genome Sequencing Center, Baylor Genetics laboratory, and NIH Center for Mendelian Genomics) and BCM UDN CS-specific bioinformatics pipelines. The interpretation and ultimate functional study of genomic data will flow to specialized organ-based research centers including the Center for Skeletal Medicine and Biology (led by Dr. Brendan Lee), the Neurological Research Institute (led by Dr. Huda Zoghbi), the Center for Human Immunology (led by Dr. Jordan Orange), and the NIH UDN Model Organism Screening Center and Knockout Mouse Phenotyping programs. For sustainability, BCM will 1) establish and financially support a Center for Undiagnosed Diseases, 2) leverage a newly developed DMHG virtual platform for medical genetics care delivery platform (Consultagene.org) to increase efficiency, decrease cost, and expand access for patient and provider engagement, 3) translate research tools to the clinical diagnostic arena, i.e., Baylor Genetics laboratory, 4) complete ongoing health economic studies to improve payor coverage for these tools, and 5) widely disseminate patient variants to stimulate collaboration with basic scientists for functional studies.