Each year, tens of thousands of babies are born in the US alone as the result of IVF (in-vitro fertilization) – where several eggs are fertilized outside the mother’s body and then an embryo is selected for transfer into her womb. 

The first successful cases of preimplantation genetic diagnosis (PGD) in humans were performed in 1988. This is a technique used to identify genetic defects in embryos created through in vitro fertilization (IVF) before pregnancy. It has been used when one or both genetic parents has a known genetic abnormality and testing is performed on an embryo to determine if it also carries a genetic abnormality. 

However, the development and acceptance of PGD since then has been slow, mainly due to the time necessary to develop and learn single-cell diagnostic techniques and to the costs involved.

For a number of years now, it has been possible for prospective parents to screen their embryos for rare genetic defects such as cystic fibrosis or Tay-Sachs disease, which is always fatal in infants. But new technical advances now make it possible for parents to have their embryos screened for genetic risk factors for diseases such as cancers, diabetes, heart disease, or psychiatric disorders such as schizophrenia.  

Polygenic risk scores (PRSs) have been offered since 2019 to screen in vitro fertilization embryos for genetic liability to adult diseases, despite a lack of comprehensive modeling of expected outcomes. In such cases, only a single mutation on a specific gene is responsible for the disease, and consequently, these diseases are known as monogenic. However, most adult diseases are polygenic – affected by a large number, sometimes thousands, of different genes and variants, each having a small effect on the risk of developing a particular disease. Polygenic risk scores combine genetic variants in these numerous genes to estimate the risk of an individual. 

This has major ethical implications. It has not been clear if screening actually reduce the probability that an embryo will develop one of these diseases. Hebrew University of Jerusalem (HUJI) and New York researchers looked into this. 

Prof. Shai Carmi and Prof. Or Zuk at the Hebrew University of Jerusalem (HUJI) and Prof. Todd Lencz at the Feinstein Institutes for Medical Research in New York published a statistical-analysis study on this in eLife under the title “Utility of polygenic embryo screening for disease depends on the selection strategy.” In their new study, there was one key question that needed addressing: Can screening actually reduce the probability that an embryo will develop one of these diseases? 

They analyzed scenarios where parents are provided with the risk scores of their embryos for one given disease. These parents would then be faced with two selection strategies – to eliminate embryos with a particularly high score for an undesirable disease and then randomly choose one of the remaining embryos for implantation or to select the embryo with the lowest predicted risk score.

With this new method, genetic testing provides each embryo with a risk score – an estimate of the chances of the given embryo to develop a particular disease. After studying the scores, parents can then select the embryo they want implanted. 

The first strategy has the advantage of eliminating some ethical issues, because no single embryo is selected as the “best” of the group, but the researchers showed this choice did not substantially reduce the risk of developing a disease.  

In fact, it was much better to select the embryo with the lowest risk score. The team’s analysis was confirmed when they ran simulations for “virtual parents” based on real genomes from studies of the gastroenterological disorder Crohn’s disease and schizophrenia.  The researchers emphasized that screening embryos based on polygenic scores does not offer any guarantees about the health of the baby; it only reduces the risk. In addition, they found that the achieved risk reduction may be smaller than expected; it depends on several factors such as the specific disease screened, the ancestry of the parents and their age.

Given the complexities, the team urged all those involved – doctors, IVF patients, prospective parents, professional societies and lawmakers – to “keep our study results in mind and carefully consider the limitations of polygenic embryo screening, along with its ethical, legal, and social implications,” Carmi suggested. “Overall, it’s imperative that the debate on polygenic embryo screening be a well-informed one.”

The scientists hope to go forward with their research in two major directions. “The first will involve interviews with parents and clinicians to better understand their views on the use of risk scores when selecting embryos. The second is to consider the possibilities and outcomes when parents screen their embryos for more than one disease,” Carmi concluded.