O-117 Advances in PGT diagnostics - technologies beyond copy number
Authors: Ottolini C S 
Published: July 2024

Genetic abnormalities are well recognised as the main factor contributing to the high rate of infertility, pregnancy loss and congenital abnormalities in humans. A prime example of this can be seen from recent studies showing that embryos identified as uniformly aneuploid following PGT-A have little to no reproductive potential. However, embryos shown to have no gross chromosomal abnormalities after PGT are not a guarantee of healthy pregnancy and many other undetected genetic issues are likely to influence embryo competence.

Developments in both sample preparation and methods for DNA analysis are driving ever-increasing data yield from PGT platforms, permitting not only DNA quantitation, but also allowing qualitative evaluation of genotyping data in parallel. This opens the door to the possibility of overcoming some of the previous limitations of PGT, leading to a more comprehensive assessment of the genetic health and reproductive potential of embryos.

How to use this increasing amount of information, and if it can tangibly improve test accuracy and clinical outcomes, remains open to debate. There is, for instance, no consensus on how to interrogate genotyping data for better distinction of clinically relevant aneuploidy as well as genome wide (ploidy) abnormalities and exogenous DNA contamination, which could impact the correct reporting of PGT results. There is also no consensus on the potential benefit of genotyping data to be used for the accurate distinction of meiotic recombination by linkage analysis, nor for fingerprinting of embryos to identify rare, but catastrophic, lab error events as a routine part of treatment. Finally, there is no clear path on how to utilise these improvements in embryo genotyping, to detect sub-chromosomal de novo genetic abnormalities that could impact embryo viability beyond the scope of current testing for chromosomal abnormalities alone.

The aim of this presentation is therefore to focus on the current state of the ART and address the current and potential future uses of genotyping in PGT. Topics covered will include identification of biopsy sample contamination to determine the truth from the noise, through to how we can rescue embryos by utilising PGT as a molecular fertilisation check and how fingerprinting of embryo can be an invaluable tool in the clinic. The origin of aneuploidy will be explored and how genotyping is reshaping our understanding of aneuploidy landscape of the preimplantation embryo. From a more basic science perspective, the potential of genotyping to identify meiotic recombination will be discussed and how this fundamental element of human reproduction could be an important biomarker for reproductive competence. Lastly future perspectives on how the evolution of PGT technologies can bring us closer to the accurate detection of de novo genomic changes will be explored and how this is taking PGT-A beyond just aneuploidy detection.

It is no secret that PGT for embryo selection continues to be a controversial area of reproductive medicine, and the field of PGT-A especially continues to show disquieting inconsistency in data analysis and reporting. This new era of genotyping brings with it information that can be used as a standardization tool helping to focus and facilitate improvements in the field of PGT for better and more consistent clinical reporting and outcomes.