An integrated and diverse genomic medicine program for undiagnosed diseases

描述（由申请人提供）：该RFA旨在建立临床研究中心，作为未诊断疾病网络（UDN）的一部分，为经过诊断冒险而未发现诊断的患者提供进一步评估。杜克的研究团队有能力建立这样的临床研究中心。建立在以下方面的强有力合作基础之上： 在两位主要研究人员的共同努力下，为患有不明遗传疾病的患者建立了一个成功的基因组测序诊所。利用仔细的临床筛选、详细的表型分析、排除环境因素和拷贝数变异;已进行全外显子组测序，并在约50%的患者中鉴定出致病变异。已通过遗传咨询向患者/家属传达了致病变异，并为患者安排了进一步的医疗护理。除了在基因组测序方面的经验外，我们还拥有罕见疾病方面的专家，作为调查团队的一部分，以及对通过UDN转诊的患者进行评估所必需的基础设施。这包括一个由世界级临床医生组成的多学科团队，由儿科和成人专家组成，他们将对患者进行深入的临床评估，并将参加有关基因序列数据临床相关性的研究相关讨论，数据分析和最终结论以及杜克临床研究单位（DCRU），该单位有能力在医学上-危重患者，并为所有必要的专家评估提供临床氛围。我们的目标是：具体目标1：利用我们中心的一系列诊断专业，全面评估患有未确诊疾病的患者，并选择符合基因组测序条件的患者。具体目标二：分析基因组序列数据，以确定因果变异和其他感兴趣的表型变异，利用我们在罕见的突变鉴定的经验，孤立的遗传性疾病。具体目标3：有效地传达结果，并为患者及其家属提供遗传咨询，借鉴我们迄今为止获得的经验。具体目标4：评估患者对诊断基因组测序结果的期望和理解，并协助制定通用方案，以在整个UDN中评估这一点。我们建议的一个创新方面是评估病人和家属对过程和结果的看法。这种做法将特别有助于在UDN内制定共同做法的协议。凭借研究和临床团队积累的经验以及提出的框架，我们有能力成为罕见和未诊断疾病的临床研究中心，并有能力在整个生命周期内评估患者。

DESCRIPTION (provided by applicant): This RFA intends to establish clinical sites, as part of an undiagnosed diseases network (UDN), to provide further evaluation for patients that have been through the diagnostic odyssey with no diagnosis found. The research team at Duke is robustly positioned to establish such a clinical site. Building on the strong collaboration between the two principal investigators, a successful genome sequencing clinic has been established for patients with unidentified genetic disorders. Utilizing careful clinical screening, detailed phenotyping, exclusion of contributing environmental factors and copy number variants; whole exome sequencing has been performed and causal variants have been identified in approximately 50% of patients. The causal variants have been communicated to the patients/families with genetic counseling and further medical care for the patients has been arranged. In addition to experience with genome sequencing, we also have experts in rare disorders as part of the investigative team and the infrastructure essential to evaluate patients referred through the UDN. This includes a multidisciplinary team of world-class clinicians consisting of both pediatric and adult specialists who will be performing in-depth clinical evaluations of the patients and will take part in research- related discussions regarding clinical correlation of genetic sequence data, data analysis and final conclusions and the Duke Clinical Research Unit (DCRU) that has the capability to house medically-critical patients and provides a clinical atmosphere for all necessary specialist evaluations. Our aims are: Specific Aim 1: Comprehensively evaluate patients with undiagnosed diseases, capitalizing on our center's range of diagnostic specialties and select patients eligible for genome sequencing. Specific Aim 2: Analyze genome sequence data to identify causal variants and other variants of interest to the phenotypes, utilizing our experience in mutation identification in rare, isolated genetic disorders. Specific Aim 3: Effectively communicate results and provide genetic counseling to the patients and their families, drawing upon the experience we have gained thus far. Specific Aim 4: Assess the patients' expectations and understanding of the results of the diagnostic genome sequencing and assist in the development of common protocols to assess this across the UDN. An innovative aspect of our proposal is the assessments of patients and families' perceptions about the process and outcomes. This practice would be particularly useful to help develop protocols for common practices within the UDN. With the experience the research and clinical team has accrued and the framework proposed, we are strongly positioned to be a clinical site for rare and undiagnosed diseases, with the ability to evaluate patients across the life-span.