Abstract：
BACKGROUND: Although in general prenatal exome sequencing only reports (likely) pathogenic variants, in some cases a variant of uncertain significance (VUS) is disclosed. The aims of this retrospective study were to evaluate the types of VUS that have been reported to prospective parents, possible reclassification and to design a standard flow chart to determine which types of VUS could be considered for reporting in prenatal settings. Furthermore, we investigated what the crucial elements are to facilitate rapid management of uncertain results in a prenatal setting.
METHODS: We reviewed exome results from 451 pregnancies performed in 2019-2021. We analyzed which factors that were taken into account by the multidisciplinary team (MDT) contributed towards decision making on reporting VUS after prenatal exome sequencing.
RESULTS: In 9/451 (2%) pregnancies tested with exome sequencing using a broad panel analysis a VUS was reported. After birth 3/9 VUS could be reclassified to likely pathogenic variants based on new clinical follow up data. We considered reporting VUS in genes: 1) matching the fetal phenotype, 2) associated with a severe disorder when a functional test is available or 3) possibly associated with a disorder where early post-partum diagnosis and treatment are crucial for a better prognosis. Two flowcharts were designed to guide first the laboratory specialist and then the MDT in decisions on reporting VUS. The crucial elements that enabled timely decisions on VUS disclosure were regular meetings, appropriate expertise, professional connections with other experts and psychological safety within the MDT.
CONCLUSIONS: In this study three out of nine VUS could be re-classified as likely pathogenic after clinical follow-up. In order to protect pregnant couples from the burden of uncertain results, the genetic professionals have to take the responsibility to limit the reporting of VUS. This can be done not only by automated filtering of data, by following professional guidelines and by building standardized decision flows, but also by discussing individual cases considering personal situations and the involved disease and by sharing professional experience and responsibility in a multidisciplinary prenatal team setting.
METHODS: We reviewed exome results from 451 pregnancies performed in 2019-2021. We analyzed which factors that were taken into account by the multidisciplinary team (MDT) contributed towards decision making on reporting VUS after prenatal exome sequencing.
RESULTS: In 9/451 (2%) pregnancies tested with exome sequencing using a broad panel analysis a VUS was reported. After birth 3/9 VUS could be reclassified to likely pathogenic variants based on new clinical follow up data. We considered reporting VUS in genes: 1) matching the fetal phenotype, 2) associated with a severe disorder when a functional test is available or 3) possibly associated with a disorder where early post-partum diagnosis and treatment are crucial for a better prognosis. Two flowcharts were designed to guide first the laboratory specialist and then the MDT in decisions on reporting VUS. The crucial elements that enabled timely decisions on VUS disclosure were regular meetings, appropriate expertise, professional connections with other experts and psychological safety within the MDT.
CONCLUSIONS: In this study three out of nine VUS could be re-classified as likely pathogenic after clinical follow-up. In order to protect pregnant couples from the burden of uncertain results, the genetic professionals have to take the responsibility to limit the reporting of VUS. This can be done not only by automated filtering of data, by following professional guidelines and by building standardized decision flows, but also by discussing individual cases considering personal situations and the involved disease and by sharing professional experience and responsibility in a multidisciplinary prenatal team setting.
摘要：
背景：尽管通常产前外显子组测序仅报告（可能）致病变异，在一些情况下,公开了不确定显著性(VUS)的变体。这项回顾性研究的目的是评估已报告给准父母的VUS类型，可能的重新分类，并设计一个标准流程图，以确定哪些类型的VUS可以考虑在产前设置报告。此外，我们调查了在产前环境中促进不确定结果的快速管理的关键因素。
方法：我们回顾了2019-2021年451例妊娠的外显子组结果。我们分析了多学科团队（MDT）考虑的哪些因素有助于产前外显子组测序后报告VUS的决策。
结果：在9/451（2％）妊娠中，使用广义组分析进行了外显子组测序，报告了VUS。出生后3/9VUS可以根据新的临床随访数据重新分类为可能的致病变异。我们考虑在基因中报告VUS：1）与胎儿表型相匹配，2）当可以进行功能测试时与严重疾病相关，或者3）可能与产后早期诊断和治疗对于更好的预后至关重要的疾病相关。设计了两个流程图，以首先指导实验室专家，然后指导MDT决定报告VUS。能够及时决定VUS披露的关键因素是定期会议，适当的专业知识，MDT内与其他专家的专业联系和心理安全。
结论：在这项研究中，在临床随访后，9个VUS中有3个可能被重新分类为可能的致病性。为了保护怀孕夫妇免受不确定结果的负担，遗传专业人员必须承担限制VUS报告的责任。这不仅可以通过自动过滤数据来完成，通过遵循专业准则和建立标准化的决策流程，而且还通过讨论考虑个人情况和所涉及的疾病的个别病例，并通过在多学科的产前团队环境中分享专业经验和责任。
方法：我们回顾了2019-2021年451例妊娠的外显子组结果。我们分析了多学科团队（MDT）考虑的哪些因素有助于产前外显子组测序后报告VUS的决策。
结果：在9/451（2％）妊娠中，使用广义组分析进行了外显子组测序，报告了VUS。出生后3/9VUS可以根据新的临床随访数据重新分类为可能的致病变异。我们考虑在基因中报告VUS：1）与胎儿表型相匹配，2）当可以进行功能测试时与严重疾病相关，或者3）可能与产后早期诊断和治疗对于更好的预后至关重要的疾病相关。设计了两个流程图，以首先指导实验室专家，然后指导MDT决定报告VUS。能够及时决定VUS披露的关键因素是定期会议，适当的专业知识，MDT内与其他专家的专业联系和心理安全。
结论：在这项研究中，在临床随访后，9个VUS中有3个可能被重新分类为可能的致病性。为了保护怀孕夫妇免受不确定结果的负担，遗传专业人员必须承担限制VUS报告的责任。这不仅可以通过自动过滤数据来完成，通过遵循专业准则和建立标准化的决策流程，而且还通过讨论考虑个人情况和所涉及的疾病的个别病例，并通过在多学科的产前团队环境中分享专业经验和责任。
