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计划（UDP）创建测序核心，以及比较全基因组测序（GWS;也称为全基因组测序）与全外显子组测序（WES）用于鉴定致病变体的效用。Illumina和威斯康星州医学院（MCW）共同致力于将基因组测序推进到临床医学中;这一提议是这些实体之间的联合。UDP测序核心的所有必要组件在MCW和Illumina都能正常工作，并且满足了所需的容量和周转时间。这两个小组都支持GWS，而不是WES的遗传发现导致第二个重点;比较GWS和WES的诊断成功。MCW使用WES和GWS;沿着在检测非蛋白质编码变异方面的明显优势，我们发现GWS对可操作基因的覆盖率显著更好，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。通过一个综合团队，并使用创新的实验室和生物信息学技术，我们建议测试GWS将产生至少25%以上的诊断比WES的假设。Aim 1将为测序的所有UDP病例生成临床级GWS，并执行读段映射和变体调用。共享所产生的数据和所开发的方法将使UDP网络能够直接比较WES和GWS的诊断用途。目标2将使用我们经临床验证的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进行生产。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将使用桑格确认NextGen测序结果，并通过收集该数据，确定未来是否需要该步骤。我们设想，所有的实验室操作，方法和开发的工具将提供，并将适用于克隆在其他目前非网络医院和大型诊所。相关性：该应用程序高度 相关之处在于其寻求将MCW确立为UDP的测序核心。除了满足这一目标之外，该申请还试图通过确定与WES相比，GWS的应用是否提供诊断优势来扩展UDN的益处。

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.