Posted on November 15th, 2021by Dr. Jenna Friedenthalin Research

Novel Insights into the Phenomenon of Embryonic Mosaicism

One of the greatest advances in the field of assisted reproductive technology is the advent of comprehensive chromosomal screening of embryos, known today as preimplantation genetic testing for aneuploidy (PGT-A). PGT-A entails a 5-6 cell biopsy of the trophectoderm (the cells that will become the placenta) from a human embryo at the blastocyst stage. These cells are then sent for genetic testing to determine which embryos have the highest chance of being chromosomally normal (euploid) or abnormal (aneuploid). However, with the increasing sensitivity of PGT testing platforms, the diagnosis of embryonic mosaicism has become an important area of discussion and research with significant clinical implications.

Embryonic mosaicism is defined as the coexistence of more than one genetically distinct cell line (e.g. chromosomally normal and abnormal cells) within a single embryo. Traditional theories hold that viable human embryos result from the faithful cloning and cell division of the original embryonic cell after fusion of the egg and sperm. However, chromosomal analysis of embryos grown in vitro and biopsied may also identify embryonic mosaicism that is likely the result of errors occurring after the initial fertilization and cell division.

Interestingly, the true incidence of embryonic mosaicism remains unknown. Although extended culture to the blastocyst stage has enabled embryologists to perform trophectoderm biopsy and PGT-A, this genetic analysis is only based on a select portion of the embryo obtained via biopsy; as such, does this biopsy represent the embryo as a whole?

To truly be able answer this question and gain a better understanding of the incidence of embryonic mosaicism in human embryos, embryos would need to be dissociated into individual cells and genetic testing would need to be performed on the single-cell level in every single cell. Such an experiment was unable to be performed with modern PGT-A platforms in human blastocysts – until now.

In a landmark study performed by RMA of New York’s Dr. Jenna Friedenthal, Dr. Friedenthal isolated and sequenced every cell from 9 dissociated human blastocysts in order to define the precise chromosomal composition of human embryos and determine the true incidence of human embryonic mosaicism. The study, which was the first of its kind, found that PGT-deemed ‘normal’ (euploid) and ‘abnormal’ (aneuploid) embryos behave very differently. Almost all aneuploid embryos were found to be 100% abnormal on single cell analysis. These findings are reassuring and suggest that embryos deemed aneuploid by PGT labs truly are entirely abnormal, and thus their chances of leading to a pregnancy and live birth are extremely low.

On the other hand, all embryos that were determined to be euploid by PGT-A were found to have some amount of aneuploid cells present, with an average rate of 26.5% mosaicism. These findings suggest for the first time that, in blastocysts likely to lead to a pregnancy and live birth (i.e. PGT-deemed euploid embryos), some degree of embryonic mosaicism may be a part of normal human development. At RMA of New York, patients may be offered a mosaic embryo transfer if euploid embryos are not available; the current study supports this practice and may lead modern PGT labs to redefine embryonic mosaicism in the clinical setting. This research was a two-time prize-winning abstract presented at the 2021 Conjoint Meeting of the American Society for Reproductive Medicine.

Dr. Friedenthal is a passionate and compassionate physician-scientist who has dedicated her career to the study of reproductive science with the goal of improving clinical outcomes for her patients.

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