Clinical Genome Wide Sequencing Core for the Undiagnosed Disease Network

描述(由申请人提供)：本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)和全外显子组测序(WES)在鉴定因果变异方面的效用。Illumina和威斯康星医学院(MCW)已经合作将基因组测序推进到临床医学中；这项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都正常运行，并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来发现导致第二个焦点的基因；比较GWS和WES在诊断成功方面的作用。MCW同时使用WES和GWS；除了在检测非蛋白质编码变异方面的明显优势外，我们发现GWS对可操作基因的覆盖率显著更高，诊断成功率更高。因此，我们建议对UDP中登记的所有参与者进行GWS，从而创造机会比较WES和GWS的效用。通过一个集成的团队，并使用创新的实验室和生物信息学技术，我们建议测试GWS将产生的诊断至少比WES多25%的假设。AIM 1将为所有已测序的UDP病例生成临床分级GW，并执行读取映射和变体调用。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的诊断使用情况。AIM 2将使用我们的临床验证分析平台对数据进行临床级别的第三级分析；我们还将为所有请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来制作。AIM 2还将支持该方法的传播，并向所有UDN站点提供第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来确定未来是否有必要执行这一步骤。我们设想，开发的所有实验室操作、方法和工具都将可用，并将适用于其他目前非网络医院和大型诊所的克隆。相关性：此应用程序高度 相关之处在于，它寻求将MCW确立为UDP的排序核心。除了实现这一目标外，应用程序还寻求通过确定与WES相比应用GWS是否提供诊断优势来扩展UDN优势。

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.