Two clinical case reports of embryonic mosaicism identified with PGT-A persisting during pregnancy as true fetal mosaicism

Abstract

The health risks associated with transferring embryos classified as mosaic by preimplantation genetic testing for aneuploidies (PGT-A) are currently unknown. Such embryos produce PGT-A results indicating the presence of both euploid and aneuploid cells and have historically been deselected from transfer and grouped with uniformly aneuploid embryos as ‘abnormal’. In recent years, numerous groups have reported the intentional transfer of mosaic embryos in the absence of uniformly euploid embryos, largely observing births of seemingly healthy babies. However, it remains to be understood whether the embryonic mosaicism invariably becomes resolved during the ensuing pregnancy, or whether the placenta and/or fetal tissues retain aneuploid cells, and if so to what potential clinical effect. Here, we report two cases of mosaicism persisting from the embryonic stage to the established pregnancy. Case 1 involved an embryonic low-level segmental mosaic loss in Chromosome (Chr) 1, which was confirmed in amniocentesis as well as in brain tissue of the products of conception. This pregnancy was terminated due to the chromosomal pathologies associated with 1p36 deletion syndrome, such as severe intellectual disability. Case 2 involved a low-level mosaic Chr 21 trisomy, which was confirmed with chorionic villus sampling and amniocentesis. The ensuing pregnancy was terminated after ultrasound identification of severe abnormalities in the placenta and fetus. Together, these two cases should be taken into account for risk-benefit assessments of prospective mosaic embryo transfers.

Associations between the artificial intelligence scoring system and live birth outcomes in preimplantation genetic testing for aneuploidy cycles

“…In addition, our research supports the notion that mosaic embryos can, especially for patients without any available euploid embryos, be considered for transfer, albeit with caution regarding potential risks and undesired negative effects. Similar to previous reports, the results indicate that types of embryonic mosaicism may affect clinical outcomes in mosaic ET cycles [ 22 ], but most LB babies are healthy and have a low risk of abnormal ploidy [ 21 , 27 – 29 ]. Moreover, advanced embryo analysis software accompanied by TL annotations can be used to effectively rank euploid blastocysts by their implantation potential [ 20 , 30 ].…”

“…The dataset also exhibited a skewed distribution of embryo data, with a concentration of AI scores ≥ 8.0 (75.3%, 363/482), which may have led to an underestimation of the predictive ability of iDAScore. Although this study, along with our previous study [ 21 ], confirmed that healthy live births could be delivered from mosaic embryo transfers, these results should be interpreted with caution because several studies have revealed that embryonic mosaicism can persist during pregnancy, leading to the development of mosaic fetuses [ 29 ] and even babies with mosaicism [ 28 ]. Therefore, patients should receive adequate and comprehensive genetic counseling before ET on the possible outcomes of transferring mosaic embryos.…”

Meiotic and mitotic aneuploidies drive arrest of in vitro fertilized human preimplantation embryos

“…Nevertheless, mosaic aneuploidies, typically affecting one or few chromosomes, are detected in a smaller proportion of blastocyst-stage embryos by PGT-A and are potentially compatible with healthy birth [ 48 ] (though see [ 49 ] for how this may depend on the features of mosaicism), posing a dilemma regarding their clinical management. While numerous forms of pathogenic mosaic aneuploidy and structural variation have been identified in clinical studies [ 50 ], current evidence suggests that mosaic aneuploidies identified in blastocyst-stage embryos are rarely detected at later stages of pregnancy or at birth, though exceptions have been reported [ 51 , 52 ]. This observation is consistent with a model of selection against aneuploid cells within mosaic embryos during peri- and post-implantation development, as supported by data from mouse and human embryo models [ 53 – 55 ], as well as analyses of single-cell genomic data from human embryos [ 56 , 57 ].…”

Mosaic results after preimplantation genetic testing for aneuploidy may be accompanied by changes in global gene expression

“…Intermediate chromosome copy-number values in trophectoderm (TE) biopsies are often interpreted as evidence of chromosomal mosaicism (Paulson and Treff, 2020). Embryos with putative diploid-aneuploid mosaicism, which originates from mitotic errors after fertilization, have the potential to develop into healthy offspring (McCoy, R. C., 2017;Treff and Marin, 2021;Greco et al, 2023). However, the clinical management of these embryos remains the subject of an intense debate.…”

“…Importantly, these studies agree that transferring a mosaic embryo entails a low risk of confirming the abnormal karyotype in the ensuing pregnancy. In fact, reports on this matter are limited (Kahraman et al, 2020;Schlade-Bartusiak et al, 2022;Greco et al, 2023).…”