Let the data do the talking: the need to consider mosaicism during embryo selection

Viotti, Manuel; Griffin, Darren K.; Spinella, Francesca; Greco, Ermanno; Madjunkov, Mitko; Madjunkova, Svetlana; Librach, Clifford L.; Victor, Andrea; Barnes, Frank L.; Zouves, Christo

doi:10.1016/j.fertnstert.2021.09.008

Cited by 26 publications

(20 citation statements)

References 52 publications

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“…Understanding the origins and consequences of mosaic aneuploidies may provide insight into the causes of human pregnancy loss and improve the success of assisted reproduction technology (ART) 50 . Indeed, the exclusion of mosaic aneuploid embryos from patient treatment is not advisable 17 , 18 .…”

Section: Discussionmentioning

confidence: 99%

The first mitotic division of human embryos is highly error prone

et al. 2022

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Human beings are made of ~50 trillion cells which arise from serial mitotic divisions of a single cell - the fertilised egg. Remarkably, the early human embryo is often chromosomally abnormal, and many are mosaic, with the karyotype differing from one cell to another. Mosaicism presumably arises from chromosome segregation errors during the early mitotic divisions, although these events have never been visualised in living human embryos. Here, we establish live cell imaging of chromosome segregation using normally fertilised embryos from an egg-share-to-research programme, as well as embryos deselected during fertility treatment. We reveal that the first mitotic division has an extended prometaphase/metaphase and exhibits phenotypes that can cause nondisjunction. These included multipolar chromosome segregations and lagging chromosomes that lead to formation of micronuclei. Analysis of nuclear number and size provides evidence of equivalent phenotypes in 2-cell human embryos that gave rise to live births. Together this shows that errors in the first mitotic division can be tolerated in human embryos and uncovers cell biological events that contribute to preimplantation mosaicism.

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Section: Discussionmentioning

confidence: 99%

The first mitotic division of human embryos is highly error prone

et al. 2022

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“…With regards to the analytical validity of using intermediate copy number to determine the presence of mosaic chromosome abnormalities in TE biopsy specimens, technical/experimental noise, such as aneuploid TE biopsies with DNA contamination, as well as biological factors, such as polyploid embryos with extra/missing chromosomes, have been documented to complicate the designation of a mosaic result. Still, performing recommended validation experiments using mixtures of different ratios of normal and aneuploid cells to mimic mosaicism seems to provide an acceptable evaluation of technical accuracy ( ESHRE PGT-SR/PGT-A Working Group et al , 2020 ; Viotti et al , 2021a ). In a clinical setting, variability arises owing to the characteristics of TE biopsies of different cellularity/quality, changing reagent batches and shipping conditions.…”

Section: Discussionmentioning

confidence: 99%

ESHRE survey results and good practice recommendations on managing chromosomal mosaicism

Rycke

Capalbo²,

Coonen

et al. 2022

Human Reproduction Open

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STUDY QUESTION How should ART/preimplantation genetic testing (PGT) centres manage the detection of chromosomal mosaicism following PGT? SUMMARY ANSWER 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. WHAT IS KNOWN ALREADY 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. STUDY DESIGN, SIZE, DURATION 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. MAIN RESULTS AND THE ROLE OF CHANCE 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. LIMITATIONS, REASONS FOR CAUTION 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. WIDER IMPLICATIONS OF THE FINDINGS 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 INTEREST(S) 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. DISCLAIMER This Good Practice Recommendations (GPR) document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and are based on the scientific evidence available at the time of preparation. ESHRE GPRs should be used for information and educational purposes. They should not be interpreted as setting a standard of care or be deemed inclusive of all proper methods of care, or be exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgement to each individual presentation, or variations based on locality and facility type. Furthermore, ESHRE GPRs do not constitute or imply the endorsement, or favouring, of any of the included technologies by ESHRE.

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“…Mitotic errors occurring during early postzygotic divisions will spread to a larger proportion of daughter cells [ 2 ]. Data from mosaic embryo transfers may represent indirect clinical evidence for self-correction by a mechanism of clonal depletion, which may alter this ratio [ 28 ]. Nevertheless, we cannot ignore the information provided by PGT-A, including mosaic level and type, based on the results of 1000 mosaic embryo transfer study [ 29 ].…”

Section: Discussionmentioning

confidence: 99%

Comparison of chromosomal status in reserved multiple displacement amplification products of embryos that resulted in miscarriages or live births: a blinded, nonselection case–control study

Yang

Zeng

et al. 2022

BMC Med Genomics

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Objective To analyze chromosomal status in reserved multiple displacement amplification (MDA) products of embryos that result in miscarriages or live births. Methods Patients who underwent preimplantation genetic testing for monogenic disorders (PGT-Ms) without aneuploidy screening were included. The case group included 28 cycles that resulted in miscarriages. Controls included 56 cycles with live births. Comprehensive chromosomal screening (CCS) using next-generation sequencing (NGS) was performed on reserved MDA products from previous blastocyst trophectoderm biopsies. The incidence and type of chromosomal abnormalities in embryos resulting in miscarriages or live births were analyzed. Results Of 28 embryos resulting in miscarriages in the case group, the rate of chromosomal abnormalities was 53.6%, which was significantly greater than 14.3% for those resulting in live births in control group (P < 0.001). Whole-chromosome aneuploidy was not found in the control group but was noted in 25.0% of embryos in the case group. Although the rates of segmental abnormality and mosaicism were also greater in the case group, no significant differences were detected. One chaotic embryo in the control group progressed to live birth. Conclusion Chromosomal abnormalities were the main reason leading to early pregnancy loss. However, abnormalities, such as segmental aneuploidy and mosaicism, should be managed cautiously, considering their undermined reproductive potential.

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Let the data do the talking: the need to consider mosaicism during embryo selection

Cited by 26 publications

References 52 publications

The first mitotic division of human embryos is highly error prone

The first mitotic division of human embryos is highly error prone

ESHRE survey results and good practice recommendations on managing chromosomal mosaicism

Comparison of chromosomal status in reserved multiple displacement amplification products of embryos that resulted in miscarriages or live births: a blinded, nonselection case–control study

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