Preimplantation genetic testing (PGT) can be used in IVF to assess and select the genotype of embryos in order to avoid passing specific genetic disorders on to future children. Such testing is offered when a patient or couple has a high risk of having children affected with a condition caused by abnormalities in a single gene (a monogenic disorder) or of the chromosomes (a chromosomal disorder). Almost all of these are rare disorders, and such tests are for specific conditions. In such cases, the disease has a single genetic cause and the ability of the test to predict its development in any offspring is high.
Recently, some private fertility clinics have begun selling polygenic risk score (PRS) analyses of embryos to prospective parents – so-called PGT-P (preimplantation genetic testing using polygenic risk scores). This practice raises many concerns, to the extent that three eminent scientific societies – the European Society of Human Genetics (ESHG) the European Society of Human Reproduction and Embryology (ESHRE) and the American College of Medical Genetics (ACMG) – have released statements advising against the implementation of this test in clinical practice, as it is not considered appropriate for clinical use.
Why such strong reactions?
PRSs are estimates of an individual's genetic susceptibility to a specific common trait or common disease – for instance diabetes, some cancers, and cardiovascular disorders. They are assessed by integrating a great number of genetic variants, each of which has a small individual effect. Still, PRSs can only capture a part of the genetic component. For risks to be calculated as accurately as possible, PRSs should be combined with the effects of non-genetic factors from an individual's life history such as environment, nutrition, and physical activity.
Even if a PRS for a trait was to perform very well in assessing the relative risk for a condition, its value in calculating the absolute risk for the condition would still be very small. As an example, if a trait is present in one percent of the population, a PRS showing a 50 percent risk reduction for that trait would mean that the absolute risk for that trait would be 0.5 percent.
PRS studies have multiple layers of complexity
To begin with, our knowledge about how PRSs interact with the environment in which we live is still limited. PRSs should be calculated using their effects from the ethnic group the individual belongs to, and for the majority of ethnicities these data are lacking. Some people may also not be aware of their exact ethnic background. Moreover, the data available from these studies relate to adult populations, and very little information is available on their performance in young children.
Furthermore, the effects of the genetic factors may interact with each other, as well as with changes in lifestyle and clinical risk factors throughout an individual's life, and these interactions may be difficult to account for when calculating the PRS – even more so if multiple traits are being investigated at one time, as different genetic variants might have opposite effects on different traits.
Finally, the concomitant occurrence of rare genetic variants of major effect, whose presence might be unknown, can mislead hugely the calculation of the PRS.
Although this is an extremely complex field, it is very promising for the future development of personalised medicine, providing that it is deployed in an appropriate way and with adequate clinical oversight.
PRSs have not been devised to assess the interaction of the genotype of an embryo with its current or future environment (in vitro or in utero), an interaction which is not yet understood. At present, there is no evidence that PRSs can reliably predict the relative risk of an embryo of developing a certain trait or disease.
Moreover, when multiple PRSs are being calculated for each individual embryo, we can easily predict that there will be instances of conflicting results, where an embryo will have an allegedly higher risk for some conditions and an allegedly reduced risk for others. Also, we do not know if the combination of variants that might be considered riskier for a particular trait in an adult, and due to which an embryo might be discarded, might have important functions in the embryo development.
With a limited genetic variability within an individual family, and a very limited number of embryos among which to choose, how can PRSs be useful for a couple in determining the choice of one embryo over another?
There are no perfect human beings, and embryos are no exceptions
Discarding embryos for a couple undergoing IVF without a sound reason will ultimately reduce their chances of having a child. Offering PGT-P is neither appropriate nor clinically useful, and it is unethical.
It is imperative that evidence of safety, effectiveness and clinical utility should be produced before introducing new interventions into clinical practice. This evidence can only be acquired by robust research protocols, with adequate ethical oversight and informed consent. Such studies would be very challenging to perform in embryos, as it would be necessary to wait decades for the predicted disorder to appear – or not.
It is also important that unbiased information on the risks and limitations of this practice are provided to prospective parents and the public. We urge that a societal debate takes place before any potential application of PRSs in embryo selection. Without proper public engagement and oversight, this practice could lead to discrimination and the stigmatisation of certain conditions. What would society consider acceptable regarding the selection of individual traits, for instance intelligence or neurodiversities (see BioNews 1113)?
For all these reasons, the ESHG – as well as ESHRE and ACMG – are clear in their statements that performing a PRS test for embryo selection is not appropriate for clinical use.