UCLA clinical site for the investigation of undiagnosed disorders

描述（由申请人提供）：未确诊的疾病对卫生保健系统和受影响的患者和家庭造成了不成比例的损失。我们的建议建立了一个研究人员和医疗保健提供者的合作网络，所有这些都与改善各种罕见遗传疾病患者的医疗保健和结果有关。我们的方法将协同基础和临床研究，使用尖端的表型技术，一批世界级的专家，并将全外显子组测序翻译到床边。这将导致诊断过程的发展，迅速将临床证据转化为改善的医疗保健服务。未确诊疾病网络（UDN）将为刺激更多多学科和跨学科的基础、转化和临床研究提供基础。调查涉及多个系统的罕见疾病并将全面的基因组数据纳入临床护理带来了相当大的挑战，从对大量遗传变异的解释到它们与症状的相关性，到与其披露相关的沟通问题，以及它们对临床管理的影响。我们的建议为UDN临床站点提供了一个平台，该平台在当地发挥作用，并作为网络的一部分，以解决将基因组信息纳入临床工作流程的问题，以标准化和可重复的方式分析患者的症状，并进行研究调查，以进一步阐明未诊断疾病的机制。我们将通过实施以下具体目标来实现这些总体目标：目标1：创建一个在本地和网络范围内起作用的UDN临床模型；目标2：研究新型和罕见疾病的临床表型；目标3：研究新型和罕见疾病的潜在机制；目标4：我们的项目整合了以下资源：(1)临床和转化科学研究所的基础设施，允许对复杂的、

DESCRIPTION (provided by applicant): Undiagnosed diseases take a disproportionate toll on the health care system and on affected patients and families. Our proposal builds a collaborative network of researchers and healthcare providers, all with a stake in improving healthcare and outcomes for persons affected by various rare genetic disorders. Our approach will synergize basic and clinical research with the use of cutting-edge phenotyping technologies, an array of world class experts, and the translation of whole exome sequencing to the bedside. This will result in the development of a diagnostic process, rapidly translating clinical evidence into improved healthcare delivery. The Undiagnosed Disease Network (UDN) will provide the foundation to stimulate additional multi-and interdisciplinary basic, translational, and clinical research. Investigating rare diseases involving multiple systems and incorporating comprehensive genomic data into clinical care creates considerable challenges, from the interpretation of vast amounts of genetic variants to their relevance to the symptoms, to the communication issues linked to their disclosure, and to their impact on clinical management. Our proposal delivers a platform for a UDN Clinical Site that functions locally and as part of a network to tackle the incorporation of genomic information into the clinical workflow, analyze patients' symptoms in a standardized and reproducible fashion, and perform research investigations to elucidate further the mechanisms of undiagnosed diseases. We will reach these overarching goals by implementing the following specific aims: Aim 1: Create a UDN clinic model that functions locally and network-wide Aim 2: Investigate the clinical phenotypes of new and rare disorders Aim 3: Investigate the underlying mechanisms of new and rare disorders Aim 4: Build a network-wide sustainable infrastructure for translational research on new and rare disorders Our project integrates the resources of (1) the infrastructure of a Clinical and Translational Science Institute, allowing for a state-of-the-art clinical investigation of complex, multisystemic disorders, within a maximum of a week stay; (2) an experienced, team of clinicians from all specialty fields, that delivers clinical use of whole- exome sequencing, and it integration in the diagnostic process of rare, undiagnosed disorders; (3) the UCLA Clinical Genomic Center that offers bioinformatics data handling, and clinical laboratory exome sequencing, that will interpret and report clinically relevant DNA variants; (4) expertise in the investigation of environmental effects on clinical symptoms; (5) a registry infrastructure with longstanding experience in standardization of phenotypic and genotypic information; (6) access to a large, ethnically varied population and (7) a sustainable approach, with provisions to care for un/underinsured patients. Overall, our approach is designed to work cooperatively with the other Clinical Sites, the Coordinating Center, and the IRP-UDP, by capitalizing on our experiences in medical genetics, genetic counseling, clinical exome sequencing, and statistical genomics.