De Rycke Martine, Capalbo Antonio, Coonen Edith, Coticchio Giovanni, Fiorentino Francesco, Goossens Veerle, Mcheik Saria, Rubio Carmen, Sermon Karen, Sfontouris Ioannis, Spits Claudia, Vermeesch Joris Robert, Vermeulen Nathalie, Wells Dagan, Zambelli Filippo, Kakourou Georgia
Centre for Medical Genetics, UZ Brussel, Reproduction and Genetics, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
JUNO Genetics, Rome, Italy.
Hum Reprod Open. 2022 Nov 7;2022(4):hoac044. doi: 10.1093/hropen/hoac044. eCollection 2022.
How should ART/preimplantation genetic testing (PGT) centres manage the detection of chromosomal mosaicism following PGT?
Thirty good practice recommendations were formulated that can be used by ART/PGT centres as a basis for their own policy with regards to the management of 'mosaic' embryos.
The use of comprehensive chromosome screening technologies has provided a variety of data on the incidence of chromosomal mosaicism at the preimplantation stage of development and evidence is accumulating that clarifies the clinical outcomes after transfer of embryos with putative mosaic results, with regards to implantation, miscarriage and live birth rates, and neonatal outcomes.
This document was developed according to a predefined methodology for ESHRE good practice recommendations. Recommendations are supported by data from the literature, a large survey evaluating current practice and published guidance documents. The literature search was performed using PubMed and focused on studies published between 2010 and 2022. The survey was performed through a web-based questionnaire distributed to members of the ESHRE special interest groups (SIG) Reproductive Genetics and Embryology, and the ESHRE PGT Consortium members. It included questions on ART and PGT, reporting, embryo transfer policy and follow-up of transfers. The final dataset represents 239 centres.
PARTICIPANTS/MATERIALS SETTING METHODS: The working group (WG) included 16 members with expertise on the ART/PGT process and chromosomal mosaicism. The recommendations for clinical practice were formulated based on the expert opinion of the WG, while taking into consideration the published data and results of the survey.
Eighty percent of centres that biopsy three or more cells report mosaicism, even though only 66.9% of all centres have validated their technology and only 61.8% of these have validated specifically for the calling of chromosomal mosaicism. The criteria for designating mosaicism, reporting and transfer policies vary significantly across the centres replying to the survey. The WG formulated recommendations on how to manage the detection of chromosomal mosaicism in clinical practice, considering validation, risk assessment, designating and reporting mosaicism, embryo transfer policies, prenatal testing and follow-up. Guidance is also provided on the essential elements that should constitute the consent forms and the genetic report, and that should be covered in genetic counselling. As there are several unknowns in chromosomal mosaicism, it is recommended that PGT centres monitor emerging data on the topic and adapt or refine their policy whenever new insights are available from evidence.
Rather than providing instant standardized advice, the recommendations should help ART/PGT centres in developing their own policy towards the management of putative mosaic embryos in clinical practice.
This document will help facilitate a more knowledge-based approach for dealing with chromosomal mosaicism in different centres. In addition to recommendations for clinical practice, recommendations for future research were formulated. Following up on these will direct research towards existing research gaps with direct translation to clinical practice. Emerging data will help in improving guidance, and a more evidence-based approach of managing chromosomal mosaicism.
STUDY FUNDING/COMPETING INTERESTS: The WG received technical support from ESHRE. M.D.R. participated in the EQA special advisory group, outside the submitted work, and is the chair of the PGT WG of the Belgian society for human genetics. D.W. declared receiving salary from Juno Genetics, UK. A.C. is an employee of Igenomix, Italy and C.R. is an employee of Igenomix, Spain. C.S. received a research grant from FWO, Belgium, not related to the submitted work. I.S. declared being a Co-founder of IVFvision Ltd, UK. J.R.V. declared patents related to 'Methods for haplotyping single-cells' and 'Haplotyping and copy number typing using polymorphic variant allelic frequencies', and being a board member of Preimplantation Genetic Diagnosis International Society (PGDIS) and International Society for Prenatal Diagnosis (ISPD). K.S. reported being Chair-elect of ESHRE. The other authors had nothing to disclose.
辅助生殖技术/植入前基因检测（PGT）中心应如何处理PGT后染色体嵌合体的检测？
制定了30条良好实践建议，ART/PGT中心可将其作为制定自身“嵌合”胚胎管理政策的基础。
全面染色体筛查技术的应用提供了发育植入前阶段染色体嵌合发生率的各种数据，且越来越多的证据阐明了移植推定嵌合结果胚胎后的临床结局，包括着床率、流产率、活产率及新生儿结局。
本文件依据ESHRE良好实践建议的预定义方法制定。建议得到了文献数据、一项评估当前实践的大型调查及已发表指导文件的支持。文献检索使用PubMed进行，重点关注2010年至2022年发表的研究。调查通过向ESHRE生殖遗传学和胚胎学特别兴趣小组（SIG）成员以及ESHRE PGT联盟成员分发的网络问卷进行。问卷包括关于ART和PGT、报告、胚胎移植政策及移植随访的问题。最终数据集代表239个中心。
参与者/材料设置方法：工作组（WG）由16名在ART/PGT过程及染色体嵌合方面具有专业知识的成员组成。临床实践建议基于工作组的专家意见制定，同时考虑了已发表数据和调查结果。
对三个或更多细胞进行活检的中心中，80%报告存在嵌合体，尽管所有中心中只有66.9%验证了其技术，其中仅61.8%专门针对染色体嵌合的判定进行了验证。在回复调查的各中心中，指定嵌合体的标准、报告和移植政策差异显著。工作组制定了关于在临床实践中如何处理染色体嵌合体检测的建议，包括验证、风险评估、指定和报告嵌合体、胚胎移植政策、产前检测及随访。还提供了关于构成知情同意书和基因报告的基本要素以及基因咨询应涵盖内容的指导。由于染色体嵌合存在若干未知因素，建议PGT中心监测该主题的新出现数据，并在有新证据提供新见解时调整或完善其政策。
这些建议并非提供即时标准化建议，而是应帮助ART/PGT中心在临床实践中制定自身针对推定嵌合胚胎管理的政策。
本文档将有助于促进不同中心以更具知识基础的方法处理染色体嵌合问题。除了临床实践建议外，还制定了未来研究建议。跟进这些建议将引导研究针对现有研究空白，并直接转化为临床实践。新出现的数据将有助于改进指导，并采用更基于证据的方法管理染色体嵌合。
研究资金/利益冲突：工作组获得了ESHRE的技术支持。M.D.R.在提交的工作之外参加了EQA特别咨询小组，并且是比利时人类遗传学会PGT工作组主席。D.W.宣称从英国Juno Genetics获得薪资。A.C.是意大利Igenomix的员工，C.R.是西班牙Igenomix的员工。C.S.获得了比利时FWO的研究资助，与提交的工作无关。I.S.宣称是英国IVFvision Ltd的联合创始人。J.R.V.宣称拥有与“单细胞单倍型分型方法”和“使用多态性变异等位基因频率进行单倍型分型和拷贝数分型”相关的专利，并且是植入前基因诊断国际协会（PGDIS）和国际产前诊断协会（ISPD）的董事会成员。K.S.报告是ESHRE当选主席。其他作者无利益冲突声明。
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