Purpose

To review cases of couples presented to our PGT-unit with copy number variants (CNVs) classified as variants of uncertain significance (VUS) in order to better understand their needs.

Methods

Retrospective cohort study conducted in a tertiary medical-center, 2014–2019. We reviewed files of all couples applying for genetic counseling with CNVs classified as VUS. The main outcomes measured: number of VUS findings and their description, PGT-M procedures planned and performed, IVF cycles, clinical pregnancy, and live birth rates (LBR). VUS were classified according to the American-College of Medical-Genetics and Genomics classification at time of first consultation, and updated—December 2018.

Results

Twenty-four couples presented with a total of 30 VUS. Twelve couples (50%) had isolated VUS and 12 (50%) had VUS diagnosed in addition to a pathogenic mutation. Initially, nine findings (30%) were defined as VUS; eight (27%) as likely benign (b-VUS); and 13 (43%) as likely pathogenic (p-VUS). PGT-M was recommended for 17/30 CNVs (56.6%), 12 (70%) of which, isolated VUS. No couple had other indications for IVF. To date, nine couples performed PGT-M for isolated VUS; LBR per-couple—55.5%. Five couples performed PGT-M for both pathogenic findings and VUS, LBR—80%. After reviewing VUS classifications, 30% remained unchanged, 20% were more severely defined, and 50% less severely defined.

Conclusion

The genomic era enables detection of VUS whose definition is subject to change as additional information becomes available. The uncertainty of variants’ clinical significance and changes in VUS definition over time complicates genetic counseling. Revised guidelines for VUS interpretation and reevaluation of patient counseling before each pregnancy must be practiced when counseling them regarding the justification of PGT-M for their diagnosed VUS.

中文翻译：

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基因组时代不确定意义的拷贝数变异（CNV-VUS）的植入前基因检测（PGT）：做还是不做？

目的

审查提交给我们的 PGT 单位的夫妇的案例，其中拷贝数变异 (CNV) 被归类为具有不确定意义的变异 (VUS)，以便更好地了解他们的需求。

方法

2014-2019 年在一家三级医疗中心进行的回顾性队列研究。我们审查了所有申请遗传咨询的夫妇的文件，其中 CNV 被归类为 VUS。测量的主要结果：VUS 发现的数量及其描述、计划和执行的 PGT-M 程序、IVF 周期、临床妊娠和活产率 (LBR)。VUS 在首次咨询时根据美国医学遗传学和基因组学学院分类进行分类，并于 2018 年 12 月更新。

结果

24 对夫妇共提交了 30 个 VUS。12 对夫妇 (50%) 分离出 VUS，12 对 (50%) 除了致病性突变外还诊断出 VUS。最初，9 个发现 (30%) 被定义为 VUS；8 个（27%）可能为良性（b-VUS）；和 13 (43%) 为可能致病 (p-VUS)。PGT-M 推荐用于 17/30 CNV (56.6%)，其中 12 (70%) 是孤立的 VUS。没有夫妇有其他 IVF 适应症。迄今为止，9 对夫妇为孤立的 VUS 进行了 PGT-M；每对夫妇的 LBR——55.5%。五对夫妇对致病性发现和 VUS、LBR-80% 进行了 PGT-M。在审查 VUS 分类后，30% 保持不变，20% 定义更严格，50% 定义不那么严格。

结论

基因组时代能够检测 VUS，其定义会随着其他信息的可用而发生变化。变异的临床意义的不确定性和 VUS 定义随时间的变化使遗传咨询变得复杂。在就诊断出的 VUS 进行 PGT-M 的正当性进行咨询时，必须实施修订后的 VUS 解释指南和每次怀孕前对患者咨询的重新评估。