A collaborative team of scientists have developed a new whole-genome sequencing technique to detect spontaneous mutations in IVF embryos. [3dmentat/Fotolia]
Credit: 3dmentat/Fotolia

The European Society for Human Genetics (ESHG) has made a strong statement against the use of polygenic risk scores (PRS) for pre-implantation genetic testing of embryos generated for use in in vitro fertilization (IVF).

In a viewpoint paper published in the European Journal of Human Genetics and presented to the press in a briefing in London this week, the authors state this is an “unproven, unethical practice” that “raises many concerns.”

PRS’s have advanced enormously in recent years and are now well on their way to becoming an established part of modern medicine. They involve testing a person for many small mutations linked to disease, often single nucleotide polymorphisms (SNPs), instead of simply looking for one disease causing genetic variant.

Use of these scores is most useful when trying to assess how likely someone might be to develop a common, polygenic disease such as cancer or cardiovascular disease, because multiple genetic variants contribute to the risk of developing these conditions. A good PRS can help assess how likely someone is to need extra screening to reduce their risk for disease, or early treatment to improve their prognosis.

However, they are not infallible. Their accuracy and applicability rely considerably on having a large and diverse source population to create the score—PRSs are based on genetic association study data, which are largely carried out in white, European populations. The PRS test population needs to match the population the score is being used to test to be truly accurate.

At present, PRSs are primarily set up to test adults and assess their risk for developing one type of disease. This is an important distinction to make, as they are not diagnostic tests, but instead give a prediction of how likely someone is to go on to develop a disease.

“Even if you can provide a very good, grounded and solid PRS in an adult, it will still not be a diagnosis,” Francesca Forzano, first author of the viewpoint article, told Inside Precision Medicine.  “This is a test which is absolutely inadequate to be offered for use in embryos.”

Forzano is a consultant in clinical genetics at the Guys and St Thomas NHS Foundation Trust in London, an honorary senior lecturer at Kings College London, and is currently chairing the Public and Professional Policy Committee of the ESHG.

Pre-implantation genetic testing (PGT) to help with embryo selection is something that is offered widely to parents with a family history of serious genetic disease who are undergoing IVF. For example, to test for cystic fibrosis or chromosomal disorders such as Down’s syndrome. But these are diagnostic tests and can tell prospective parents whether or not a specific embryo will have a genetic disease with a high degree of accuracy.

The ESHG are concerned that prospective parents may misunderstand how PRS are used and treat them as diagnostic tests. “We’re obviously not against polygenic risk scores per se. We feel that this is an incredibly complex and promising field for the future. But it has to be used in an appropriate way,” says Forzano.

“It will not be beneficial for parents, because they will have a false assurance that what they have decided about those embryos will mean that those children will not have some disease, and this is not actually true.”

While use of PRS’s for embryo selection is not approved for public use in the U.K., which has fairly strict regulations compared with some European countries, they are more widely used in the U.S. and are offered to prospective parents by companies, such as Genomic Prediction and Orchid Health, as well as private clinics.

Forzano and colleagues are concerned that private clinics could be offering these tests in Europe or that European couples could be traveling to countries where they are more widely offered, such as the U.S., to undergo IVF and pre-implantation testing. They want to make sure prospective parents understand the utility of these tests before agreeing, and often paying large amounts of money, to have them.

There are clear questions about how useful these tests are for embryo selection, but some feel they could be useful. Shai Carmi, an associate professor in statistical and population genetics at the Hebrew University of Jerusalem, recently published a paper analyzing the accuracy of polygenic risk scores like those used by Genomic Prediction for embryo selection.

He also has reservations about widespread rollout, but thinks this method could be useful for embryo selection in some circumstances.

Commenting on the ESHG statement, he told Inside Precision Medicine that he shares concerns about “the possible inconsistency between ranking embryos by PRS and ranking them by other parameters, and the questionable validity of the PRS in the next generation,” as well as other factors.

“However, I disagree with their statement that ‘the utility of a PRS in this respect is severely limited’,” he adds. “We showed in our recent paper [Lencz et al, eLife, 2021] that under optimistic, yet feasible, conditions, relative risk reduction for diseases such as schizophrenia or Crohn’s disease can reach nearly 50%. It can be argued that the absolute risk reduction would be small (e.g., less than 0.5 percentage point), but I would not categorically call 50% risk reduction ‘severely limited’.”

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