Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Renaissance Computing Institute, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
Genome Med. 2019 Nov 29;11(1):77. doi: 10.1186/s13073-019-0683-1.
The 2015 American College of Medical Genetics and Genomics (ACMG) and the Association for Molecular Pathology (AMP) guidelines for clinical sequence variant interpretation state that "well-established" functional studies can be used as evidence in variant classification. These guidelines articulated key attributes of functional data, including that assays should reflect the biological environment and be analytically sound; however, details of how to evaluate these attributes were left to expert judgment. The Clinical Genome Resource (ClinGen) designates Variant Curation Expert Panels (VCEPs) in specific disease areas to make gene-centric specifications to the ACMG/AMP guidelines, including more specific definitions of appropriate functional assays. We set out to evaluate the existing VCEP guidelines for functional assays.
We evaluated the functional criteria (PS3/BS3) of six VCEPs (CDH1, Hearing Loss, Inherited Cardiomyopathy-MYH7, PAH, PTEN, RASopathy). We then established criteria for evaluating functional studies based on disease mechanism, general class of assay, and the characteristics of specific assay instances described in the primary literature. Using these criteria, we extensively curated assay instances cited by each VCEP in their pilot variant classification to analyze VCEP recommendations and their use in the interpretation of functional studies.
Unsurprisingly, our analysis highlighted the breadth of VCEP-approved assays, reflecting the diversity of disease mechanisms among VCEPs. We also noted substantial variability between VCEPs in the method used to select these assays and in the approach used to specify strength modifications, as well as differences in suggested validation parameters. Importantly, we observed discrepancies between the parameters VCEPs specified as required for approved assay instances and the fulfillment of these requirements in the individual assays cited in pilot variant interpretation.
Interpretation of the intricacies of functional assays often requires expert-level knowledge of the gene and disease, and current VCEP recommendations for functional assay evidence are a useful tool to improve the accessibility of functional data by providing a starting point for curators to identify approved functional assays and key metrics. However, our analysis suggests that further guidance is needed to standardize this process and ensure consistency in the application of functional evidence.
2015 年美国医学遗传学与基因组学学院（ACMG）和分子病理学协会（AMP）的临床序列变异解读指南指出，“成熟”的功能研究可作为变异分类的证据。这些指南阐述了功能数据的关键属性，包括检测应反映生物环境并具有分析学意义；然而，如何评估这些属性的细节留给了专家判断。临床基因组资源（ClinGen）在特定疾病领域指定变异管理专家小组（VCEP），对 ACMG/AMP 指南进行基因中心规范，包括对适当功能检测的更具体定义。我们着手评估现有的 VCEP 功能检测指南。
我们评估了六个 VCEP（CDH1、听力损失、遗传性心肌病-MYH7、PAH、PTEN、RASopathy）的功能标准（PS3/BS3）。然后，我们根据疾病机制、一般检测类别以及主要文献中描述的特定检测实例的特征，为评估功能研究建立了标准。使用这些标准，我们广泛研究了每个 VCEP 在试点变异分类中引用的检测实例，以分析 VCEP 建议及其在功能研究解释中的应用。
不出所料，我们的分析突出了 VCEP 批准的检测的广泛多样性，反映了 VCEP 之间疾病机制的多样性。我们还注意到，不同 VCEP 之间在选择这些检测的方法以及指定强度修饰的方法以及建议的验证参数方面存在很大差异。重要的是，我们观察到 VCEP 指定为批准检测实例所需的参数与试点变异解释中引用的个别检测中这些要求的满足之间存在差异。
功能检测的错综复杂的解释通常需要对基因和疾病的专家级知识，当前的 VCEP 功能检测证据建议是提高功能数据可及性的有用工具，为鉴定人员提供了识别批准的功能检测和关键指标的起点。然而，我们的分析表明，需要进一步的指导来规范这一过程，并确保功能证据的应用一致性。
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