Center for Integrated Approached to Undiagnosed Diseases

项目总结 未确诊的疾病可能是由遗传、环境和发育因素决定的。 而一些未确诊的疾病将代表新的罕见遗传综合征，具有单基因或少基因 病因和其他疾病会反映已知疾病的罕见表现，许多很可能是由更多的 具有分析挑战性的多种遗传、环境和发育因素的组合。整体 外显子组和全基因组测序是确定遗传贡献的有力工具 然而，仅靠这些方法不太可能阐明许多(如果不是大多数)疾病的基础， 未确诊的疾病。使用集成的、基于网络的系统生物学方法 不仅包括遗传变异数据，还包括基因表达、代谢组、蛋白质组和暴露组数据，以及 仔细的深入表型，已被证明是确定途径和机制的最有效的方法 对许多未确诊的疾病负有责任。我们将继续我们的跨学科综合研究计划 哈佛大学未诊断疾病网络临床网站(哈佛大学UDN-CS)，涉及三个具体目标： 1)确诊和临床特征-我们将进行病例确诊和表型分析 成人和儿童中选定的罕见和未诊断疾病状态的特征； 2)基因组评估-我们将使用患者和家庭成员衍生的DNA序列，转录 数据和临床表型信息，以确定潜在的致病DNA序列变体、基因 表达变异，以及潜在的致病途径紊乱； 3)疾病诊断的网络方法-我们将整合其他组学数据，包括代谢组学， 蛋白质组学，以及暴露组学数据，连同候选基因变体一起进入全面 互动组，从而识别网络中靠近相关患者的疾病或疾病途径 可能有助于识别与本病病因相关的潜在病理生物学模块的基因 未确诊的疾病。 对于在2022年6月30日或之前被录取的先知，这份补充资料将允许我们继续努力 与统一数字网络密切合作，实现这些具体目标并解决总体假设问题 协调中心(UDN-CC)和其他临床站点在UDN中的开发和实施 表型、环境和基因型的评估方案，最终将定义病因和 未确诊疾病的治疗。

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. Using an integrated, network-based, systems biology approach that incorporates not only genetic variation data, but also gene expression, metabolomic, proteomic, and exposomic data, along with careful deep phenotyping, has shown to be the most effective way to identify the pathways and mechanisms responsible for many undiagnosed diseases. We will continue our integrated interdisciplinary research plan for the Harvard Undiagnosed Disease Network Clinical Site (Harvard UDN-CS) that involves three Specific Aims: 1) Ascertainment and clinical characterization - we will perform case ascertainment and phenotypic characterization for selected rare and undiagnosed disease states in adults and children; 2) Genomic assessments - we will use patient and family member-derived DNA sequence, transcriptomic data, and clinical phenotype information to identify potentially causal DNA sequence variants, gene expression variation, and potentially causative pathway derangements; and 3) Network approach to disease diagnosis - we will integrate other -omic data, including metabolomic, proteomic, and exposomic data, along with the candidate genetic variants into the comprehensive interactome, and thereby identify diseases or disease pathways in network proximity to the involved genes that may help identify potential pathobiological modules relevant to the etiology of the undiagnosed disease. For probands accepted on or before June 30, 2022, this supplement will allow us to continue our work toward meeting these specific aims and addressing the overall hypothesis in close collaboration with the UDN Coordinating Center (UDN-CC) and other clinical sites in the UDN in order to develop and implement assessment protocols of phenotype, environment, and genotype that will ultimately define the etiology and treatment of undiagnosed diseases.