Department of Genome Sciences, University of Washington School of Medicine, 15th Avenue NE, Seattle, WA, 98195, USA.
Current affiliation: Center of Innovation for Veteran-Centered and Value-Driven Care, VA Puget Sound Health Care System, S Columbian Way, Seattle, WA, 98108, USA.
Genome Med. 2019 Dec 20;11(1):85. doi: 10.1186/s13073-019-0698-7.
Variants of uncertain significance represent a massive challenge to medical genetics. Multiplexed functional assays, in which the functional effects of thousands of genomic variants are assessed simultaneously, are increasingly generating data that can be used as additional evidence for or against variant pathogenicity. Such assays have the potential to resolve variants of uncertain significance, thereby increasing the clinical utility of genomic testing. Existing standards from the American College of Medical Genetics and Genomics (ACMG)/Association for Molecular Pathology (AMP) and new guidelines from the Clinical Genome Resource (ClinGen) establish the role of functional data in variant interpretation, but do not address the specific challenges or advantages of using functional data derived from multiplexed assays. Here, we build on these existing guidelines to provide recommendations to experimentalists for the production and reporting of multiplexed functional data and to clinicians for the evaluation and use of such data. By following these recommendations, experimentalists can produce transparent, complete, and well-validated datasets that are primed for clinical uptake. Our recommendations to clinicians and diagnostic labs on how to evaluate the quality of multiplexed functional datasets, and how different datasets could be incorporated into the ACMG/AMP variant-interpretation framework, will hopefully clarify whether and how such data should be used. The recommendations that we provide are designed to enhance the quality and utility of multiplexed functional data, and to promote their judicious use.
不确定意义的变体对医学遗传学来说是一个巨大的挑战。多重功能检测，其中同时评估数千个基因组变体的功能影响，越来越多地产生可以用作变体致病性的额外证据。这种检测方法有可能解决不确定意义的变体，从而提高基因组检测的临床实用性。美国医学遗传学与基因组学学院 (ACMG)/分子病理学协会 (AMP) 的现有标准和临床基因组资源 (ClinGen) 的新指南确立了功能数据在变体解释中的作用，但并未解决使用来自多重检测的功能数据的具体挑战或优势。在这里，我们在这些现有指南的基础上，为实验人员提供了关于生产和报告多重功能数据的建议，以及为临床医生提供了关于评估和使用此类数据的建议。通过遵循这些建议，实验人员可以生成透明、完整且经过充分验证的数据集，为临床应用做好准备。我们向临床医生和诊断实验室提出的关于如何评估多重功能数据集质量以及如何将不同数据集纳入 ACMG/AMP 变体解释框架的建议，有望阐明是否以及如何应该使用此类数据。我们提供的建议旨在提高多重功能数据的质量和实用性，并促进其合理使用。
