UCLA clinical site for the investigation of undiagnosed disorders

描述(由申请人提供)：未诊断的疾病对卫生保健系统以及受影响的患者和家庭造成不成比例的损失。我们的提案建立了一个由研究人员和医疗保健提供者组成的合作网络，所有这些都与改善医疗保健和各种罕见遗传疾病患者的结局息息相关。我们的方法将通过使用尖端的表型技术、一系列世界级的专家以及将整个外显子组测序翻译到床边来协同基础和临床研究。这将导致诊断过程的发展，迅速将临床证据转化为更好的医疗保健服务。未诊断疾病网络(UDN)将为促进额外的多学科和跨学科的基础、翻译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，这带来了相当大的挑战，从对大量基因变异的解释到它们与症状的相关性，到与披露这些变异相关的沟通问题，以及它们对临床管理的影响。我们的建议为UDN临床网站提供了一个平台，该网站在本地发挥作用，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首要目标：目标1：创建一个在当地和整个网络范围内发挥作用的UDN临床模式目标2：调查新的和罕见疾病的临床表型目标3：调查新的和罕见疾病的潜在机制目标4：为新的和罕见的疾病的翻译研究建立一个网络范围的可持续基础设施我们的项目整合了(1)临床和翻译科学研究所的基础设施，允许对复杂的最先进的临床调查， (2)来自所有专业领域的经验丰富的临床医生团队，提供整个外显子组测序的临床应用，并将其整合到罕见的、未诊断的疾病的诊断过程中；(3)加州大学洛杉矶分校临床基因组中心，提供生物信息学数据处理，以及临床实验室外显子组测序，将解释和报告临床相关的DNA变异；(4)在环境对临床症状的影响调查方面的专业知识；(5)在表型和基因型信息标准化方面具有长期经验的注册基础设施；(6)获得大量不同种族人口的机会；(7)采取可持续的办法，提供对未参保/保险不足患者的护理。总体而言，我们的方法旨在通过利用我们在医学遗传学、遗传咨询、临床外显子组测序和统计基因组学方面的经验，与其他临床站点、协调中心和IRP-UDP合作。

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.