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Preimplantation Genetic Testing Could be Informed by Whole-Genome Reconstruction, Study Shows

Human embryo

NEW YORK – The ability to assess disease-related polygenic scores and rare variants in preimplantation embryos may be improved through whole-genome reconstruction (WGR) informed by embryo genotypes and parental genome sequences, according to new research by a team from MyOme, Natera, the Columbia University Irving Medical Center, and Spring Fertility.

The researchers turned to statistical methods and molecular clues to do WGR on up to 110 embryos from 10 families, using array-based genotyping profiles on embryos and high-coverage genome sequencing for both parents in each family. From there, they compared the predicted variant patterns with those found in 10 children born to these families after undergoing preimplantation genetic testing (PGT).

Their findings, published in Nature Medicine on Monday, suggested that genotyping predictions at some 5.4 million to 6.4 million variants — including disease PRS-related sites — jumped from a range of 97.2 percent to 99.1 percent to a range of 99 percent to 99.4 percent in biopsy samples obtained from day 5 embryos compared to day 3 embryo samples.

With these reconstructed sequences, the team also looked at the possibility of assessing variants linked to polygenic risk scores previously generated with data from the UK Biobank effort for a dozen common conditions. There, the group considered polygenic risk score variability between sibling embryos, alongside differences in predicted and absolute risk in relation to disease type.

"In this preclinical research study, we demonstrated that WGR for embryos is feasible and enables accurate calculation of PRS when compared with results from genomic samples from 10 born children," the authors reported, noting that "[w]e observed variability in polygenic disease risk across embryos of different families and among the sibling embryos within families."

By bringing in rare variant predictions from synthetic long read sequencing-based rare variant phasing in four of the families, meanwhile, they identified additional variation between sibling embryos that went beyond the disease clues possible with PRS alone.

Within a breast cancer-affected family, for example, the team tracked down pathogenic BRCA1 variants in 13 of 20 preimplantation embryos that had been classified as euploid. Those insights were combined with polygenic modeling and BRCA2 variant data to predict variable breast cancer risk across the sibling embryos, before extending breast cancer analyses to sibling embryos from other families.

Beyond the ethical and practical issues raised by their research, the researchers cautioned that there are remaining questions around the clinical utility of PRSs, which also tend to be skewed toward individuals with European ancestry. And they noted that the WGR-based approach does not provide clues to de novo variants that are not inherited from parents, or PRSs in embryos with mosaic or aneuploid features.

Even so, the authors suggested, "[a]s our understanding and the predictive power of PRSs improves and sequencing technology becomes more cost effective, this approach may be used to reliably infer inherited genome sequence and model predicted genetic risk in embryos of couples with a personal and/or family history of common disease undergoing [in vitro fertilization]."

In a related commentary article in Nature Medicine, investigators from the US, Austria, and Israel cautioned that additional scrutiny is needed to evaluate not only PRS validity but also the assumptions that go into preimplantation genetic screening and embryonic aneuploidy testing, in general.

"Genetic tests in reproductive medicine should be based on rigorous science, be transparent about efficacy, and be properly regulated," they wrote.

For an accompanying News and Views piece, Hastings Center researchers Josephine Johnston and Lucas Matthews pointed to the importance of taking non-genetic disease contributors into account, rather than focusing on genetic risk and related testing alone.

"[P]RS-informed PGT may further de-emphasize environmental and social determinants of common diseases," they wrote, "drawing public attention away from structural solutions to health and disability challenges and toward individual responsibility for managing disease risk."