An integrated and diverse genomic medicine program for undiagnosed diseases

项目摘要 目前迫切需要为大约3000万未确诊的美国人提供诊断。 疾病绝大多数（85%）未确诊的疾病被认为有潜在的遗传原因， 全外显子组测序（WES）的利用，以及较小程度的全基因组测序（WGS）， 如先前文献中所报道的，导致诊断率为25- 40%。在未确诊的第一阶段， 疾病网络（UDN），杜克/哥伦比亚临床站点已经利用了这两种技术， 以及深入的表型分析和创新的生物信息学，以实现约50%的总体诊断率， 最具挑战性病例的诊断率约为40%：既往WES结果阴性的患者。该网站的 UDN第一阶段的研究结果也表明，未确诊的患者/未确诊的父母 孩子们经历混乱，患有未确诊疾病的孩子的父母有很高的焦虑率， 萧条这导致了一项调查的发展，以衡量病人和父母的期望， 利用基因组测序结果。除此之外，该团队还为UDN政策做出了贡献， 成功的合作，并一直活跃在关键的网络领导职位。与已经建立的 基础设施和成功的结果，杜克/哥伦比亚网站是很好的定位，继续这项工作的 未来四年，并继续保持下去。本提案的具体目标如下：具体目标1： 每年对30例未确诊疾病患者进行综合评估。我们将利用我们网站的 诊断专业优势，在一周内评估任何专业（成人和儿科）的患者 时间框架，使用表型数据来帮助基因组解释，并有效地将结果传达给患者 和他们的家人进行遗传咨询。具体目标2：分析患者的WES和WGS， 当WES/WGS不能提供诊断时，使用RNA测序作为辅助。具体目标 3：Profectin检查与未确诊相关的心理社会特征（目标3A）， 基因组测序结果的预期和利用（目标3B）。具体目标4：促进 UDN致力于建立一个合作和可持续的网络。杜克/哥伦比亚临床研究中心拥有所有 在UDN的第二阶段成为一个成功的临床研究中心所需的能力，有助于实现 网络的目标是评估患有未诊断疾病的患者，并最终改善健康状况， 这些人和他们的家庭。

PROJECT SUMMARY There is an urgent need to provide diagnoses for the approximately ~30 million Americans with undiagnosed disease. With the vast majority (85%) of undiagnosed diseases believed to have underlying genetic causes, the utilization of whole exome sequencing (WES), and to a lesser extent whole genome sequencing (WGS), has resulted in diagnosis rates of 25-40%, as reported in the prior literature. In Phase I of the Undiagnosed Diseases Network (UDN), the Duke/Columbia clinical site has capitalized upon both of these technologies, as well as deep phenotyping and innovative bioinformatics, to achieve an overall diagnosis rate of ~50%, and a diagnostic rate of ~40% for the most challenging cases: patients with prior negative WES results. The site's findings from Phase I of the UDN also demonstrated that undiagnosed patients/parents of undiagnosed children experience chaos and parents of children with undiagnosed diseases have high rates of anxiety and depression. This led to the development of a survey to measure patients' and parents' expectations and utilization of genome sequencing results. Beyond this, the team has contributed to UDN policies, established successful collaborations, and been active in key network leadership positions. With an already established infrastructure and successful outcomes, the Duke/Columbia site is well positioned to continue this work for the next four years and to sustain it beyond. The Specific Aims of this proposal are as follows: Specific Aim 1: Comprehensively evaluate 30 patients annually with undiagnosed diseases. We will capitalize on our site's diagnostic specialty strengths, to evaluate patients in any specialty, adult and pediatric, within the one-week timeframe, use phenotypic data to aid genome interpretations, and effectively communicate results to patients and their families with genetic counseling. Specific Aim 2: Analyze the WES and WGS of patients to provide diagnoses and use RNA-sequencing as an adjunct when WES/WGS do not provide a diagnosis. Specific Aim 3: Prospectively examine psychosocial characteristics associated with being undiagnosed (Aim 3A) and expectations and utilization of genomic sequencing results (Aim 3B). Specific Aim 4: Contribute to activities of the UDN to foster a collaborative and sustainable network. The Duke/Columbia clinical site has all the capabilities required to be a successful clinical site in Phase II of the UDN, contributing to achieve the network's goal of evaluating patients with undiagnosed diseases and ultimately improve the health and well- being of these individuals and their families.