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

项目摘要 贝勒医学院（Baylor College of Medicine）未诊断疾病网络（UDN）临床站点（CS） 成功地推进了UDN第一阶段的目标。我们建立了一个高吞吐量的综合管道 对于患有未确诊疾病（UDD）的患者， 评价我们在患者接受和亲自评估的数量方面领先于校外UDN临床研究中心， 同时是两个校外网站之一，以实现100%的这两个关键里程碑。我们开发 创新的方法，包括三重RNA测序，使我们达到了诊断率的解决， 在迄今为止完成的病例中，有45%的病例具有强候选基因。最后，我们让UDN和更广泛的 科学/非专业社区分享最佳实践、合作发现和教育。实现了这一目标 通过利用整合的遗传和基因组计划，即分子和人类科学部， 遗传学（DMHG），该部门是基础科学，临床和分子生物学的结合 病理部门。由于这些是在一个组织单位下使用的，因此我们很快就 将发现转化为实践，并作为德克萨斯州医学研究中心的研究社区的纽带。 中心，全国。DMHG在遗传和基因组医学方面的领导地位确保了 将儿科、内科和神经科的合作部门整合到第一阶段， 的CS。在第二阶段，我们建议采用这一综合办法， UDN的目标。CNOUDN CS领导层包括遗传学领域的成熟临床研究者， 儿科、内科和神经科，将领导一个主要团队，同时从合作伙伴的顾问中汲取经验 全机构各部门。临床描绘和随后的DNA分子诊断将利用这两个 建立（人类基因组测序中心，贝勒遗传学实验室，和NIH中心孟德尔 Genomics）和CNOUDN CS特定的生物信息学管道。解释和最终功能 基因组数据的研究将流向专门的器官研究中心，包括Skeleton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Jordan橙子博士领导）和NIH UDN模式微生物筛选 中心和敲除小鼠表型分析程序。为了可持续发展，联合国将1）建立和财政 支持未诊断疾病中心，2）利用新开发的DMHG虚拟平台进行医疗 遗传学护理提供平台（Consultagene.org），以提高效率，降低成本，并扩大访问 对于患者和提供者的参与，3）将研究工具转化为临床诊断竞技场，即，贝勒 遗传学实验室，4）完成正在进行的卫生经济研究，以提高这些工具的支付范围， 和5）广泛传播患者变体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.