O-153 Clinical utility of preimplantation genetic testing for aneuploidy origin (PGT-AO) to enhance embryo selection for monogenic disorders: a retrospective pan-country integrative genomic and clinical study
Authors: Essers R , Biglari S , Janssen A , Stevens S  J C , Dreesen J , Van Buul-van Zwet M  L , Pieters M  H E , Van Zomeren K , Van Echten-Arends J , Derijck A , Mastenbroek S , Van den Wijngaard A , Coonen E , Paulussen A , Zamani Esteki M 
Published: July 2024

Abstract

Study question
What is PGT-AO’s impact on implantation and pregnancy rate per embryo transfer, by determining the prevalence and effect of (mosaic) aneuploidies and their segregational origin?

Summary answer
PGT-AO potentially enhances the efficiency of PGT and increases the pregnancy rate per embryo transfer by minimizing transfers with poor outcomes and improving implantation rates.

What is known already
Demographic factors such as advanced parental age increases risk of aneuploid offspring, driving demand for advanced PGT. Randomized controlled trials revealed that PGT-A does not increase live birth rates after IVF. PGT-A, the most frequent form of PGT, overlooks the mosaic nature and segregational origin of aneuploidies in IVF embryos. This possibly leads to avoiding the transfer of mosaic embryos and reduces the pregnancy rate per cycle. Prompting this study, five embryos transferred based on PGT-M, led to trisomic pregnancies terminated following invasive prenatal diagnosis. Subsequent genome haplarithmisis revealed that these embryos carried (meiotic) trisomies not previously detected by PGT-M.

Study design, size, duration
In this retrospective study, we included 1944 embryos (816 PGT-M embryos, 323 couples, 224 indications). Currently, 284 have been processed by genome haplarithmisis-based PGT-AO and analyzed to assess if (mosaic) aneuploidies and segregational origin would have altered transfer decisions and subsequent clinical outcomes. We evaluated our novel PGT- A approach, termed PGT-AO, providing a nuanced understanding of early embryonic development in clinical practice and more responsible PGT-A, potentially leading to viable mosaic embryo transfer.

Participants/materials, setting, methods
The couples were counseled by clinical geneticists at Dutch University Medical Centers (UMCs), in Maastricht, Amsterdam, Utrecht, and Groningen, and enrolled in the diagnostic PGT-M procedure after signing an informed consent form. Embryos (n = 816) eligible for transfer based on absence of the monogenic aberration of interest by PGT-M were analyzed by haplarithmisis-based PGT-AO including parental information. This information allows for the detection of (mosaic) chromosomal abnormalities and their parental and segregational origin.

Main results and the role of chance
Of 816 included embryos (323 couples, 224 indications), 284 were found to be suitable for transfer by PGT-M and were analyzed by PGT-AO. Of these, 183 were transferred. Of the transferred embryos, 65 (35.5%) had a positive HCG and 48 (26.3%) resulted in a liveborn. 14.6% (7/48) carried abnormalities following our PGT-AO approach. These abnormalities consisted of mitotic mosaic trisomies, mosaic monosomies, and mosaic duplications and a deletion. Of the transferred embryos, 132 (72.1%) did not result in a liveborn and 115 (62.8%) had negative HCG tests. Of the transferred embryos with negative HCG, 38.3% (44/115) contained a total of 90 abnormalities, consisting of 37 monosomies, 35 trisomies, 12 deletions, 2 duplications, 2 UPD and 1 ring chromosome. The 35 trisomies occurred in 20 embryos, of which 9 were of meiotic origin and 5 of mitotic origin, 1 of both meiotic and mitotic, and 5 could not be determined. Based on these preliminary results, PGT-AO can avoid the transfer of embryos with aneuploidy of meiotic origin and non-mosaic status. In contrast, embryos with aneuploidy of mitotic origin are often mosaic and the abnormality may not be uniformly distributed throughout the blastocyst and could potentially be considered for transfer.

Limitations, reasons for caution
Haplarithmisis relies on the inclusion of parental DNA to phase the embryonic genome and thus determine the segregational origin of aberrations. Additionally, mitosis and meiosis II trisomies cannot be discerned where a crossover event is absent for a chromosome with trisomy.

Wider implications of the findings
Implementation of PGT-AO will re-define the current embryo selection system. This enhances PGT by increasing pregnancy rate per embryo transfer and minimizing transfers with poor outcomes, disposal of potentially viable embryos, spontaneous pregnancy losses, and termination of aneuploid pregnancies. This reduces the emotional and financial burdens on families and healthcare.

Trial registration number
Not applicable