Clinical Genome Wide Sequencing Core for the Undiagnosed Disease Network

描述（由申请人提供）：该提案侧重于为未诊断疾病项目（UDP）创建测序核心，以及全基因组测序（GWS；也称为全基因组测序）与全外显子组测序（WES）在鉴定因果变异方面的效用的比较。Illumina和威斯康星医学院（Medical College of Wisconsin， MCW）合作，推动基因组测序进入临床医学；这个提议是这些实体联合提出的。UDP测序核心的所有必要组件都可以在MCW和Illumina上运行，并且满足所需的容量和周转时间。这两个团体都支持GWS，而不是WES，因为基因发现导致了第二个焦点；GWS与WES诊断成功率的比较。MCW同时使用WES和GWS；GWS在检测非蛋白质编码变异方面具有明显优势，我们发现GWS对可操作基因的覆盖范围明显更好，诊断成功率更高。因此，我们建议对所有参加UDP的参与者进行GWS，从而有机会比较WES与GWS的效用。通过一个整合的团队，并使用创新的实验室和生物信息学技术，我们建议测试GWS将比WES产生至少25%的诊断的假设。Aim 1将为所有UDP病例测序并执行读取映射和变体调用生成临床级GWS。共享生成的数据和开发的方法将使UDP网络能够直接比较WES和GWS的诊断使用。Aim 2将使用我们的临床验证分析平台对数据进行临床级三级分析；我们还将为所有要求的病例提供临床解释和报告生成。这些将使用我们现有的临床方法和工具。目标2还将支持方法的传播，并向所有UDN站点提供三级分析和临床解释。Aim 3将使用Sanger确认NextGen测序结果，并通过收集这些数据，确定将来是否需要这一步。我们设想开发的所有实验室操作、方法和工具都将可供使用，并将适用于目前其他非网络医院和大型诊所的克隆。相关性：此应用程序是高度

DESCRIPTION (provided by applicant): This proposal focuses on creation of a sequencing core for the Undiagnosed Disease Program (UDP) as well as comparison of the utility of genome-wide sequencing (GWS; also known as whole genome sequencing) versus Whole Exome Sequencing (WES) for the identification of causal variants. Illumina and the Medical College of Wisconsin (MCW) have worked together to advance genomic sequencing into clinical medicine; this proposal is joint between these entities. All of the necessary components for the UDP sequencing core are functional at MCW and Illumina and required capacity and turnaround are met. Both groups have championed GWS as opposed to WES for genetic discovery leading to the second focus; comparison of GWS and WES for diagnostic success. MCW uses both WES and GWS; along with obvious advantages in detecting non protein coding variants, we find significantly better coverage of actionable genes with GWS, and a higher diagnostic success rate. We thus propose to conduct GWS for all participants enrolled in the UDP creating the opportunity to compare utility of WES versus GWS. With an integrated team and using innovative lab and bioinformatics techniques we propose to test the hypothesis that GWS will produce at least 25% more diagnoses than WES. Aim 1 will generate clinical grade GWS for all UDP cases sequenced and perform read mapping and variant calling. Sharing of the data generated and the methods developed will enable the UDP network to directly compare diagnostic use of WES and GWS. Aim 2 will undertake clinical grade tertiary analysis of the data using our clinically validated analysis platform; we will also provide clinical interpretation and report generation for all cases requested. These will be produced using our existing clinical methodology and tools. Aim 2 will also support dissemination of the methodology and offer tertiary analysis and clinical interpretation to all UDN sites. Aim 3 will confirm the NextGen sequencing results using Sanger and, through gathering of this data, determine whether this step will be necessary in the future. We envision that all of the laboratory operations, methodologies, and tools developed will be made available and will be suited for cloning in additional currently non network hospitals and large clinics. Relevance: This application is highly relevant in that it seeks to establish MCW as the sequencing core for the UDP. In addition to meeting this goal, the application seeks to extend the UDN benefit by determining whether application of GWS as compared to WES provides a diagnostic advantage.