Contributing to the on-going debate around the clinical application of preimplantation embryo selection based on polygenic risk scores (PGT-P)

The article by Siermann et al. [1] in this issue presents the findings of a questionnaire-based survey of 31 health care professionals (HCPs) involved in Preimplantation Genetic Testing (PGT), representing one of the main groups of stakeholders potentially involved in the routine application of PGT-P. The questionnaires took the form of interviews performed over a 6-month period, and the results reported in this article cover the HCPs’ views relating to the potential validity of the PGT-P technology, the clinical utility, the limitations and consequences of using PGT-P, as well as potential benefits.

The introduction of a new indication for PGT has often created a lively debate amongst HCPs, other professional groups and the wider public. The reasons principally stem from concerns of the safety of procedures, their clinical validity and utility, and the overall ethical implications for society. Several such applications have initially been received with resistance from HCPs, although the trend is subsequent acceptance (e.g. PGT to exclude a variety of monogenic diseases or chromosome aneuploidy, PGT-M or PGT-A, respectively) while others, for example sex-selection for social rather than medical reasons, have been legally banned in many countries. The potential of introducing new PGT applications into clinical practice is primarily technology-driven, and often involves only limited studies towards an evidenced-based clinical practice. In this issue the article by Siermann et al. [1], presents an empirical study of the views of healthcare professionals towards investigating ethical aspects of applying preimplantation genetic testing for complex traits, through Polygenic Risk Score (PRS) calculation, otherwise referred to by the acronym PGT-P.

Polygenic Risk Scores (PRSs) have various definitions, but the consensus is that they represent a way to stratify the risk that an individual may have for developing complex traits (usually common complex diseases), based on an estimation of the genetic component. For each disease tested, the result is usually represented either as a risk-fold difference compared to the general population, or as an absolute risk. These estimations of risk have been somewhat supported by Genome Wide Association Studies (GWAS), but it is only recently that the estimation of PRS has shown promise for clinical utility, expedited by the collation of sufficiently large data sets from both patients and controls, along with the development of novel algorithms. It is foreseen that PRSs could be applied for a wide variety of purposes, ranging from relatively targeted groups of patients (e.g. cancer patients to evaluate their risk of developing a second tumour), to the entire adult population (e.g. as a screening test for identifying individuals at higher risk of developing coronary heart disease).

PGT-P is already offered by private companies and the article by Siermann et al. [1], contributes to a continuing debate between advocates of PGT-P who demonstrate the feasibility and scientific accuracy of PRS in PGT, and those who argue against the practice based on an evaluation of clinical validity, utility and ethical considerations [2–6]. Siermann et al. [1] aimed to obtain the views of HCPs who work in reproductive medicine and genetics and have a professional experience with PGT. The data collected presents the views of 31 HCPs who agreed to be interviewed. Although a small group, it represents HCPs in both the USA (23%) and Europe (77%), men (39%) and women (61%) and includes geneticists (52%), reproduction specialists (35%) and genetic counsellors (13%). After analysis the authors show that across all interviewees, the principal theme was that of caution in all the aspects related to the use of PGT-P, both ethical and scientific as summarized in Table 2 of the article by Siermann et al, namely: validity, utility, choices of the future parents, limitations in understanding PGT-P and potential benefit.

As far as the clinical validity and utility of PGT-P are concerned, we also consider that these two points are essentially self-evident. Currently there are no guidelines for the clinical application of PRSs for any disease in either adult or paediatric populations. Considering the universal lack of knowledge relative to the potential outcomes of applying PRSs in adults for the prevention of common complex traits, the promotion of their use for predicting complex traits in the embryo, and furthermore using them for the selection of embryos, becomes highly problematic, as eloquently reflected in the title of the paper from the Public and Professional Policy Committee of the European Society of Human Genetics (ESHG) “The use of polygenic risk scores in pre-implantation genetic testing: an unproven, unethical practice.” [2]

The other themes presented in the paper are grouped under the limited choices offered to the future parents who elect to use of PGT-P, the difficulties in explaining PGT-P to them and finally the potential benefits from its use. Limited choices include the fact that PGT-P is offered in the context of IVF as an embryo selection tool, often in combination with other PGT indications, and usually the number of embryos that can be tested and eventually selected for transfer is small. Additionally, the interviewees expressed concern about an understanding of the basic principles of heredity and genetics in so far as the embryos will have similar traits to their parents anyway (a specific and thus limited “gene pool”, otherwise referred to as a “genetic bottleneck”), and also that the PGT-P results are likely to reveal conflicting risks for complex diseases both within the same embryo and between embryos (“there is no ideal embryo”). An understanding of the basic concepts of PGT-P by the future parents is also raised as a crucial point, as without this understanding, informed decision-making becomes void. Finally, with respect to the potential benefits of PGT-P, the reproductive autonomy and a potential reduction of disease risk were highlighted, but the latter requires a clear understanding of a PGT-P result, while the concept of reproductive autonomy is closely influenced by and reflected in the accepted norms of society, which tend to evolve over time.

During the second half of the 20^th century, all advances and goals in medical genetics have been firmly directed towards understanding, treating, and preventing human diseases. With respect to preventing genetic diseases, it is generally accepted that the diseases targeted should fulfill certain criteria, key amongst which are an early onset and severe clinical course. In a preconception or prenatal setting for severe monogenic disorders, the final decision is left to the future parents following their non-directive counselling, with a principal consideration of reproductive autonomy. But despite best efforts made by geneticists when informing and counselling prospective parents, it is often misunderstood that preconception and prenatal care does not guarantee the birth of a healthy baby, but only offers future parents the possibility of eliminating any additionally identified risk.

The reproductive autonomy as promoted within PGT-P is quite different as it promises the birth of “healthier babies”. This promise appeals to one of the most basic dispositions of humans, which is to protect life and ensure life quality, particularly that of our offspring. An ongoing RCT called the “Embryo Health Study” (clinical trial identifier NCT04528498) intends to determine the perception and motivation of parents relative to obtaining additional information about the risks of their preimplantation embryos with respect to polygenic disorders. The scientists involved in this RCT have so far reported [7] that over half of couples elect to obtain additional information on their embryos. Additionally, in a recent poll of public opinion, most individuals expressed an acceptance to undergo PGT-P not only for improved health outcomes but also for a promise of (even minimally) improved academic achievements in their offspring [8].

The main conclusion of the study by Siermann et al. [1] reinforces the caution expressed by most HCPs, also conveyed by the Public and Professional Policy Committee of the ESHG [2], that the use of PGT-P today is premature. PGT-P risks introducing an era of “designer babies” where reproductive autonomy does not concern the birth of children with a health risk equivalent to that of the general population, but the birth of “healthier” and even “smarter” or “prettier” babies. As the authors state, further research is required concerning specifically the implementation and regulation of PGT-P among HCPs and all involved stakeholders. We would also add that HCPs, have a responsibility to ensure that they only practice “evidenced-based medicine” and disseminate any evidence that they generate to all other HCPs, and crucially, also to the public. Overall, the article by Siermann et al. [1] in this issue of the journal, makes a valid contribution to the on-going and important debate on the highly controversial use of PGT-P, another IVF/PGT “add-on” that should not be introduced prematurely.

Author contributions

PM, GK and JTS wrote the manuscript; TM and CV provided feedback and editing.

Funding

The “Comment” had no specific funding.

Competing interests

The authors declare no competing interests.