Secondary findings (SFs) from genomic sequencing can have significant impacts on patient health, yet existing practices guiding their clinical investigation are inconsistent. We systematically reviewed existing SFs policies to identify variations and gaps in guidance. We cataloged and appraised international policies from academic databases (n = 5, inception-02/2022) and international human genetic societies (n = 64; inception-05/2022), across the continuum of SFs selection, analysis, and clinical management. We assessed quality using AGREE-II and interpreted results using qualitative description. Of the 63 SFs policies identified, most pertained to clinical management of SFs (98%; n = 62; primarily consent and disclosure), some guided SFs analysis (60%; n = 38), while fewer mentioned SFs selection (48%; n = 30). Overall, policies recommend (1) identifying clinically actionable, pathogenic variants with high positive predictive values for disease (selection), (2) bioinformatically filtering variants using evidence-informed gene lists (analysis), and (3) discussing with affected individuals the SFs identified, their penetrance, expressivity, medical implications, and management (clinical management). Best practices for SFs variant analysis, clinical validation, and follow-up (i.e., surveillance, treatment, etc.) were minimally described. Upon quality assessment, policies were highly rated for scope and clarity (median score, 69) but were limited by their rigor and applicability (median scores, 27 and 25). Our review represents a comprehensive international synthesis of policy guiding SFs across the continuum of selection, analysis, and clinical management. Our synthesis will help providers navigate critical decision points in SFs investigation, although significant work is needed to address gaps in SFs analysis, clinical validation, and follow-up processes and to support evidence-based practice.

中文翻译：

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指导基因组测序次要结果的选择、分析和临床管理的国际政策： 系统评价


基因组测序的次要发现 （SF） 可能对患者健康产生重大影响，但指导其临床研究的现有做法并不一致。我们系统地审查了现有的 SFs 政策，以确定指南的变化和差距。我们对来自学术数据库 （n = 5， inception-02/2022） 和国际人类遗传学会 （n = 64;inception-05/2022） 的国际政策进行了编目和评估，涵盖 SFs 选择、分析和临床管理的连续体。我们使用 AGREE-II 评估质量，并使用定性描述解释结果。在确定的 63 项 SFs 政策中，大多数与 SFs 的临床管理有关 （98%;n = 62;主要是同意和披露），一些指导性 SFs 分析 （60%;n = 38），而较少提及 SFs 选择 （48%;n = 30）。总体而言，政策建议 （1） 识别对疾病具有高阳性预测值的临床可操作的致病性变异（选择），（2） 使用循证基因列表（分析）进行生物信息学过滤变异，以及 （3） 与受影响的个体讨论识别的 SFs、它们的外显率、表现度、医学意义和管理（临床管理）。对 SFs 变异分析、临床验证和随访 （即监测、治疗等） 的最佳实践进行了最低限度的描述。在质量评估中，政策的范围和清晰度受到高度评价（中位数为 69），但受到其严谨性和适用性的限制（中位数为 27 和 25）。我们的综述代表了指导 SF 在选择、分析和临床管理的连续体中的政策的综合国际综合。 我们的综合将帮助提供者在 SF 调查中导航关键决策点，尽管需要做大量工作来解决 SFs 分析、临床验证和随访过程中的差距并支持循证实践。