Center for Integrated Approaches to Undiagnosed Diseases

项目摘要 未确诊的疾病可能是由遗传、环境和发育因素决定的。虽然一些未确诊的疾病将代表具有单基因或寡基因病因的新型罕见遗传综合征，而其他疾病将反映已知疾病的罕见表现，但许多疾病可能是由多种遗传，环境和发育因素的更具分析挑战性的组合引起的。全外显子组和全基因组测序是确定未确诊疾病的遗传贡献的有力工具;然而，仅凭这些方法不太可能阐明许多（如果不是大多数）未确诊疾病的基础。我们在此延续申请中采取的总体方法是扩展我们在UDN早期阶段建立的方法，并添加专门设计的关键组件，以继续优化病例确定和表型（目标1），完善综合多学科疾病诊断（目标2），并直接支持部署和进一步优化完全可持续的UDN模型（目标3）。这些具体要素包括：·扩大初始病例评估人群（包括健康差异人群的丰富），以便更好地定义可能受益于UDN方法的难以诊断的患者; ·为难以诊断的患者开发定量分类工具，以便继续优化病例选择和个体技术的效用;·部署创新的新序列解释管道，融合整个波士顿生态系统的最佳技术和人员（BUMC和布罗德研究所也参与其中）;·在进入UDN的病例的初步评估中更广泛地整合功能基因组学工具;·正式部署和定量评估波士顿范围内的UDN中心，该中心通过与付款人和DHHS的有效商业合同提供资金（并通过我们系统中的其他非UDN遗传学计划进行交叉补贴，例如Brigham Genomic Medicine）;以及·所有这些元素的前瞻性设计，以允许在整个UDN和其他地区传播成功的组件。这些努力将最大限度地提高UDN资源的收益，同时以完全可持续的（实际上和财政上）模式逐步扩大获取渠道。

PROJECT SUMMARY Undiagnosed diseases are likely to be determined by genetic, environmental, and developmental factors. While some undiagnosed diseases will represent novel rare genetic syndromes with monogenic or oligogenic etiologies and others will reflect rare manifestations of known diseases, many are likely to result from a more analytically challenging combination of multiple genetic, environmental, and developmental factors. Whole exome and whole genome sequencing are powerful tools with which to ascertain the genetic contributions to undiagnosed diseases; however, these methods alone are unlikely to elucidate the basis for many, if not most, undiagnosed diseases. The overarching approach we have taken in this Continuation application is to extend the methodologies that we have established in earlier phases of the UDN and to add key components specifically designed to continue to optimize case ascertainment and phenotyping (Aim 1), to refine integrated multidisciplinary disease diagnosis (Aim 2) and to directly support the deployment and further optimization of a fully sustainable UDN model (Aim 3). These specific elements include: • Broadening of the initial case assessment population (including enrichment for health disparity populations) to enable better definition of the difficult-to-diagnose patient who might benefit from UDN approaches; • Development of quantitative triage tools for difficult-to-diagnose patients enabling continued optimization of case selection and the utility of individual techniques; • Deployment of innovative new sequence interpretation pipelines merging the best techniques and personnel from across the entire Boston ecosystem (with additional engagement from BUMC and the Broad Institute); • Broader integration of functional genomics tools in the initial assessment of cases entering the UDN; • Formal deployment and quantitative evaluation of a Boston-wide UDN center funded through active commercial contracts with payers and DHHS (and cross-subsidized through other non-UDN genetics programs in our system, such as Brigham Genomic Medicine); and • Prospective design of all of these elements to allow dissemination of successful components across the entire UDN and beyond. These efforts will maximize the yield of UDN resources while progressively broadening access in a fully sustainable (both practically and financially) model.