P-742 Universal genome-wide haplotyping-based preimplantation genetic testing: a systematic seven-year experience at a single center
Authors: Tšuiko O , Melotte C , Peeraer K , Vanhie A , Denayer E , Vermeesch J , Dimitriadou E , Debrock S 
Published: June 2023

Study question

To record the outcome and clinical benefit of universal genome-wide haplotyping-based preimplantation genetic testing (PGT).

Summary answer

Universal PGT allows for standardization of protocols and reduces turnaround time. Apart from accurate genetic diagnosis, it also provides chromosome information, improving embryo selection strategies.

What is known already

Developments in genome-wide technologies leveraged the implementation of universal PGT that combines haplotyping and copy number typing across the whole genome. Universal PGT provides diagnosis for any familial monogenic disorder (PGT-M) or structural rearrangement (PGT-SR), and allows for concurrent aneuploidy screening (PGT-A) in PGT-M/SR cycles, all using the same generic protocol and the same biopsy. For this reason, various universal PGT approaches have been developed in the last 2-3 years and are increasingly making their way to the clinic worldwide.

Study design, size, duration

Universal PGT as a first-tier test was implemented at UZ Leuven mid-2014, using in-house developed algorithm (siCHILD/haplarithmisis). This is a retrospective analysis of universal PGT data, collected between 1 January 2015 and 31 December 2022. Data on PGT indication, PGT cycles and biopsy results was extracted. Implantation rate (IR; with IU/EU fetal sac) per embryo transfer was calculated from frozen embryo transfer (FET) cycles for patients with known result by the end of 2021.

Participants/materials, setting, methods

By the end of 2022, 718 couples have successfully finalized preclinical PGT workup. At the time of writing, 573 couples (80%) have further proceeded with PGT cycles. In total, 1264 PGT cycles were performed with day-3 (D3) cleavage-stage (n = 3344) or trophectoderm (TE) biopsies (n = 1524). For 403 patients with known outcome from 954 FET cycles, IR per embryo transfer was calculated per biopsy type and embryo ranking, considering genome-wide chromosome information.

Main results and the role of chance

Couples were referred to PGT due to various autosomal dominant (AD, 65%), autosomal recessive (AR, 14%) and X-linked disorders (XL, 10%). Various PGT-M indications encompassed &gt;200 genes in total, but almost 20% of couples enrolled due to inherited BRCA1/BRCA2 mutations. PGT-SR was indication in 7% of cases, mainly for familial microduplications/deletions (64%). For all PGT cycles, approximately 15% and 18% of all performed D3 and TE biopsies, respectively, were scored as abnormal largely due to meiotic errors in the embryo. All unaffected embryos were further ranked as R1 (euploid) or R2 (mosaic), and the number of R2 embryos was expectedly higher after D3 biopsies, compared to TE biopsies (250/1063, 23.6% vs 37/510, 7.3%, p&lt;0.001). In accordance with inheritance mode, the number of unaffected embryos suitable for transfer was significantly lower in AD PGT cycles, compared to AR (32.3% (1116/3455) vs 44.0% (262/596) ; p&lt;0.0001)). For 403 patients with FET cycles, IR was higher in R1 vs R2 embryos after D3 biopsy (231/590, 39.2% vs 30/159, 18.9 %, p &lt;0.0001), whereas no difference was observed between R1 and R2 embryos after TE biopsy, although low number of R2 embryos after TE biopsy was transferred (85/142, 59.9% vs 7/12, 58.3%, p=ns).

Limitations, reasons for caution

The analyzed data is derived from a single center and the clinical outcome may not reflect the experience of other IVF/PGT centers due to confounding factors, such as PGT indication, used PGT technology and IVF lab practice.

Wider implications of the findings

The current dataset provides a comprehensive overview on general trends and outcome of universal PGT practice. Apart from accurate genetic diagnosis, universal PGT provides information on chromosomes, which improves embryo selection for transfer. This in turn impacts clinical counselling, interpretation and reporting of the results, and embryo transfer policies.

Trial registration number

Not applicable