A Knowledge Base for Clinically Relevant Genes and Variants

描述（由申请人提供）：人类基因组计划刺激了基因测序技术的基本进展，现在反过来又改变了基因组科学和医学。然而，由于缺乏关于基因对疾病的作用的确切信息来源，基因组医学的前景仍然有限。虽然许多团体正在试图单独解决这一差距，但如果它们仍然脱节，这种努力最终将功亏一篑。临床相关变异资源代表了遗传学界的合作努力，以建立一个基于证据的资源，用于评估基因和变异的临床相关性。该知识库对于自信、高效地分析和解释基因组规模的序列数据至关重要。其目的是提供一个公开的共识总结的证据，从医学文献，基础科学研究人员和临床实验室有关的基因和变异，涉及人类健康和疾病。将为研究人员、临床实验室、医生、患者和电子健康记录提供专门的门户网站，以确保资源的广泛访问。研究人员联盟将通过追求五个具体目标来实现这一目标：1）开发一种用于评估基因-表型对的“临床可操作性”的半定量方法，这将使利益相关者群体能够为报告和使用此类遗传结果提供指导; 2）建立一种标准化程序，用于评估变异是否是良性的、与疾病相关的或具有不确定的意义; 3）部署信息学基础设施以通过聚集来自不同来源的信息并将其呈现用于人类评估来支持联合体的活动; 4）组装临床领域特异性工作组以系统地评估临床相关的基因（和那些基因中的变体）;以及5）确保资源与电子医疗记录系统的互操作性。该方法通过开发用于评估基因和变异的新方法进行创新，这些方法具有鲁棒性和可重复性，并通过建立用于聚合和显示信息的分布式信息学系统，以及更新和重新分析的机制。该提案具有前瞻性，因为将注意确保该资源与包括电子健康记录在内的各种最终用户的互操作性。拟议的资源项目意义重大，因为它将以透明和循证的方法，在大量临床领域提供免费的人类基因组专家策展。

DESCRIPTION (provided by applicant): Fundamental advances in genetic sequencing technologies were stimulated by the human genome project and are now in turn transforming genome science and medicine. Yet the promise of genomic medicine remains limited by the lack of definitive sources of information about the genetic contributions to disease. Although many groups are attempting to address this gap individually, such efforts will ultimately fall shor if they remain disconnected. The Clinically Relevant Variants Resource represents a collaborative effort of the genetics community to establish an evidence-based resource for the assessment of the clinical relevance of genes and variants. This knowledge base is critical for confident, efficient analysis and interpretation of genome-scale sequence data. The objective is to provide a publicly available consensus summary of the evidence from the medical literature, basic science researchers, and clinical laboratories regarding the genes and variants that are implicated in human health and disease. Dedicated portals will be provided for researchers, clinical laboratories, physicians, patients, and electronic health records to ensure that the resource is widely accessible. The consortium of investigators will accomplish this objective by pursuing five specific aims: 1) developing a semi-quantitative methodology for assessing the "clinical actionability" of gene- phenotype pairs, which will allow stakeholder groups to provide guidance on the reporting and use of such genetic results; 2) establishing a standardized process for evaluating whether variants are benign, related to disease, or of uncertain significance; 3) deploying an informatics infrastructure to support the activities of the consortiu by aggregating information from disparate sources and presenting it for human evaluation; 4) assembling clinical domain-specific working groups to systematically evaluate the genes (and the variants in those genes) that are clinically relevant; and 5) ensuring the interoperability of he resource with electronic medical record systems. The approach innovates by developing novel approaches for the assessment of genes and variants that are robust and reproducible, and by establishing a distributed informatics system for aggregating and displaying information, with mechanisms for updating and reanalysis. The proposal is forward-thinking in that attention will be paid to ensuring the interoperability of the resource with diverse end-users, including electronic health records. The proposed resource project is significant because it will provide freely available expert curation of the human genome across a substantial number of clinical domains, with a transparent and evidence-based approach.