Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource
Evaluating the Clinical Validity of Gene-Disease Associations: An Evidence-Based Framework Developed by the Clinical Genome Resource
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DOI：
10.1016/j.ajhg.2017.04.015
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发表时间：
2017-06-01
影响因子：
9.8
通讯作者：
Berg, Jonathan S.
中科院分区：
文献类型：
--
作者：
Strande, Natasha T.;Riggs, Erin Rooney;Berg, Jonathan S.
随着基因组测序技术的进步，报道的基因与疾病关系的数量迅速增加。然而，支持这些主张的证据差异很大，从而混淆了临床环境中基因组变异的准确评估。尽管迫切需要区分临床上有效的关系与证据不足的关系，但目前尚不存在此类评估的标准指南。美国国立卫生研究院 (NIH) 资助的临床基因组资源 (ClinGen) 开发了一个框架来定义和评估各种孟德尔疾病的基因-疾病对的临床有效性。在这篇手稿中，我们描述了一个拟议的框架，用于评估支持或反驳基因-疾病关系的相关遗传和实验证据，以及使用一组代表性基因-疾病对对该框架的后续验证。该框架为基因与疾病关系的证据强度提供了半定量测量，该证据强度与定性分类相关：“明确”、“强”、“中等”、“有限”、“无报告证据”或“冲突证据”。在 ClinGen 结构内，根据相应疾病专家的临床专业知识对从此框架得出的分类进行审查、确认或调整。我们的网站上提供了使用该框架和访问管理界面的详细指南。这种评估基因与疾病关系强度的基于证据的系统方法将有助于在临床和研究环境中更明智地利用基因组变异。
With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.