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A study published in Nature Medicine looks at whole-genome risk prediction of common diseases in human preimplantation embryos.
Prof Joyce Harper, Head of the Reproductive Science and Society Group, UCL Institute for Women’s Health, UCL, said:
“In this paper, the authors report a preclinical study examining the feasibility of using preimplantation genetic testing to examine the genome sequence for 12 common conditions on 110 embryos with the aim of using this for couples wishing to prevent these common diseases in their children. Currently in the UK, the use of this technology would not be allowed as the Human Fertilisation and Embryology restricts the use of PGT for ‘serious’ inherited conditions.
“The authors discuss some of the issues this method has. Genetics is not that simple, and as they conclude – ‘the clinical utility of using PRS to reduce disease risk in preimplantation embryos remains to be proven.’ And as the authors state, the majority of genetics has been studied in those of European ancestry and current diagnostic techniques are not open to those of non-European decent, which may exacerbate the view that IVF is seen as a white, middle class treatment. Another practical problem is that the diseases the authors wish to measure are polygenic, meaning that they are affected by genetics and the environment. How the person lives can affect their chance of getting the disease. For example, for the BRAC gene, having the mutated gene does not mean you will definitely get breast cancer.
“Currently PGT is mainly limited to those experiencing infertility and those who carry a serious genetic disease. Even then, since PGT was first performed in 1989, it has not become the common treatment for patients carrying a serious genetic disease as it is not easy going through IVF as it is emotionally and financially draining. But the use of polygenetic risk scoring has the potential to open up IVF to those who are fertile, who can afford it, and want to do all they can to ensure their children are genetic healthy. It certainly has the potential to expand the demographics of those going through IVF. I am sure I am not alone in feeling uncomfortable with this future technology.”
Prof Darren Griffin, Professor of Genetics, University of Kent, said:
“This paper provides data for the use of PGT-P (preimplantation genetic testing for polygenic disease) and gives an evaluation for its future use. The study is robust, rigorous and interesting, but raises more questions than it answers.
“Those of use who practice PGT are used to definitive diagnoses. By and large, recessive diseases such as cystic fibrosis and sickle cell anaemia have consistent person to person symptoms, and two mutant copies gives a reasonable prediction of clinical outcome. With dominant diseases such as hypercholesterolemia, tuberous sclerosis and neurofibromatosis then the situation is more complex as only a single copy of the disease gene is required (usually present already in one parent) but the severity of the disease can vary. The situation complicates further PGT-P.
“Diseases globally of most worry are polygenic ones, with a complex, genetic component such as cancer, schizophrenia, diabetes and heart disease. More than one gene is involved in the pathology and environmental factors (diet, radiation exposure, smoking, exercise etc.) are also involved. We all carry a risk, but the point of PGT-P is to screen embryos for which these odds are significantly skewed.
“A “PRS” (polygenic risk score) is a calculated percentage that an embryo will develop into someone with a polygenic disease like cancer, diabetes or schizophrenia. Assigning a PRS to an embryo is possible because scientists have studied large data sets of people with each disease. PRS are already used in adult populations to advise people of lifestyle choices, effects of certain medicines etc. but the crux of the emotive question raised by this paper is their application on human embryos.
“There are already examples of PGT being performed for gene variants that carry a high risk of breast cancer (BRCA1 and 2 genes) and there are PRS that embryos could be assigned, via PGT-P, that near give ~100% prediction that this disease will develop. Proponents of PGT-P (including in this paper) argue that this represents improved diagnosis on the status quo and one of the prime examples why PGT-P should be justified. They also argue that, in any PGT cycle, it is always necessary to rank the embryos, so adding a PRS is only another means of facilitating selection, and that, for some diseases, when an embryo carries a dominant disease gene, we don’t know whether the subsequent child will be affected, and with what severity. By extension therefore PGT-P is not such a big next step. A final argument is that, if PGT-P were practiced widely, it could relieve the burden on health systems, as people with lower risks of e.g. heart disease or cancer would result from the process.
“There are nonetheless a series of potential downsides to PGT-P:
· If it is not free at the point of delivery, richer families are therefore inevitably more likely to benefit from it, and the process could lead to exploitation of families desperate to have children, exposing them to another IVF treatment with no proven clinical benefit.
· The opportunity for using PGT-P for reasons less clearly associated with health, becomes more likely (“slippery slope”). While PGT for any perceived “cosmetic” reasons we not be sanctioned in most countries (including the UK), often a tenuous health benefit can be assigned to some traits.
· If parents are “safe” in the knowledge that their child are in a genetically lower risk group, would they be less likely to encourage them follow a healthier lifestyle?
· There are many genetic variants of which we do not fully know the clinical significance. Many of these will be revealed through PGT-P, without proper knowledge or evaluation. Provided with incredible amounts of genomic information that even the experts find it difficult to interpret, there is a genuine risk of obsessive patient over-interpretation of the PRS, placing unreasonable burdens on genetic counsellors and clinicians.
· The datasets are based on current people’s lifestyles that will inevitably change by the time the disease develops (or not) in the current embryo.
· There may be more effective treatments for these diseases by the time that they become an issue.
· Although it will be possible to ascertain that the child will have the same genomic sequence as the original diagnosis in the embryo, it really will not be practicable to establish, for most polygenic disorders, whether PGT-P has significantly reduced the chances of the diseases developing. Follow up of cases could take decades and some children will inevitably get the disease for which they were diagnosed a low PRS.
“The question therefore needs to be asked, how much benefit would we create in comparison to the risks involved? In order to establish PGT-P as routine, significant time and effort would need to be invested. There may be a limited number of conditions and a limited number of families for which, under strict regulation, PGT-P may be appropriate (e.g. BRCA1 and 2). For each disease however, a case will need to be made, as will a justification that the family involved will actually benefit. This might be more work than the cost justifies.
“PGT-P is an interesting medical, technical and ethical challenge in the light of new technology and the historical success of PGT. In addition to proper regulation, advertising standards are a consideration: to what extent can clinics claim to be reducing the risk of disease when they have little evidence that they are so doing?
“In other words, how pointless is PGT-P? When we have used PGT to eliminate the chromosomally abnormal embryos, how many will be left in the IVF cycle to look at PRS, and how much will each embryo be different the next? What mad pursuit will it be to be in a situation where we are agonising over e.g. 55% vs 50% PRS compared to the many other differences that contribute to overall IVF success?”
Prof Alison Murdoch, Former Head of Newcastle Fertility Centre at Life, Newcastle University, said:
“Understanding the genetic basis of disease is important but a role for PRS (Polygenic Risk Scores) in relation to successful prevention of mature onset disease remains unproven. Nonetheless, such controversial tests are publicly available in adults for diagnosis. Extension of PRS to preimplantation embryos implies embryo selection not diagnosis and the additional ethical challenges are obvious.
“Aneuploidy testing of the embryo for implantation potential (PGT-A), which is not yet proven to be effective, has already been prematurely adopted into routine practice (in the UK, it is available in some IVF clinics but the HFEA have given it a red light status, meaning there is no evidence from RCTs to show that it is effective at improving the chances of having a baby for most fertility patients). Kumar et al have described a “preclinical research study” implying a following clinical study. But without evidence of disease reduction after PRS in adult testing, this is misleading. This study does not support the adoption of PRS into clinical embryology practice.
“The genetics of preimplantation embryo development is poorly understood and studies that add knowledge are welcomed and must be encouraged. The scientific imperative is to understand the causes of human reproductive failure and the clinical aim is to improve IVF outcome.”
Dr Helen O’Neill, Lecturer in Reproductive and Molecular Genetics, UCL, said:
“This study looks at the application of risk profiling (or screening) of embryos for multiple genetic conditions at once, known as polygenic risk scoring. This study outlines three areas of note; the first is in the utility of computational reconstruction of an embryonic genome using parental and embryonic DNA to predict susceptibility across common conditions. This method (called whole genome reconstruction) is a more reliable method than current methods of whole genome amplification and increased resolution of genetic information gained from the biopsy of an embryo alone. The second is the further proof of better predictive power from later stage biopsy (day 5) than earlier (day 3), which for many years had been debated. The third is the benefit of using DNA from babies born in addition to their biopsied embryo material to enable a more robust comparison of a small amount of biopsied DNA from an embryo with that of a baby (the authors took DNA from 10 born children to compare their DNA with the previously taken embryonic DNA to contrast the risk profiles) which is a very necessary quality control check.
“The authors outline the limitations of the study, stating that Polygenic Risk Scores have limited effectiveness in non-European populations, due to the lack of representation in genome sequencing databases. Given this well known limitation, it would have been good to quantify this limitation by including a diverse set of embryonic and parental genomes in the study.”
Prof Ewan Birney, Deputy Director General of the European Molecular Biology Laboratory (EMBL), said:
“Scientists from a commercial company in the US offering clinical genomics services have shown that a pre-implementation based readout of a genome, done in the context of in vitro fertilisation (IVF treatment) is very concordant with a genome from the resulting children. In particular they show that if you generate a statistical model of a risk score (polygenic risk score – PRS) for risk of a disease, the score you generate is the same at the early embryo stage as it is post birth. This is an important technical check for the complex process of single or small number of cell genomics but is expected – we have known for a long time that single gene tests performed at the embryo stage are consistent with later life, and indeed this is the basis for pre-implantation genetic diagnosis which has been used for the last two decades.
“It is important to stress that this study does not shed light on the most important aspect of using Polygenic risk scores (PRSs) for embryo selection from IVF, where there are fundamental questions of both the statistical validity of the PRS in this setting and also the ethical appropriateness of procedure.
“Taking the ethics first, selecting embryos for implantation by PRS would be a large extension of the choices of parents in the outcome of their children. In the UK such a procedure would have to be authorised by the Human Fertilisation and Embryo Authority (HFEA) which takes evidence from leading scientists in a committee which has a majority of non-scientific experts, including experts from ethics and religious groups. In contrast in the US these procedures are self regulated by the clinicians who provide them.
“In both settings an unanswered scientific question is whether selection from a limited number of embryos which is generated from two parents is actually useful; polygenic risk scores are constructed across many individuals in a population (e.g., the ~500,000 volunteers to UK BioBank) which is a very different setting in terms of the diversity of genetic components and environments to a mother and father wishing to conceive.
“In my view as a statistical geneticist this has not been shown and it is not clear that a PRS employed for embryo selection would perform as designed.
“Furthermore as a citizen I am uncomfortable about a wide set of traits that could be considered in polygenic risk scores and I don’t think society is well served by allowing parents apparent control over these aspects, whilst supporting that parents can have the choice for severe genetic disease where there is not the same statistical concern and the impact on the child and family is clear cut.
“Clearly one needs a good framework to make these decisions both at the individual and societal level and I am reassured by the framework set up by legislation in the UK under the HFEA.”
Prof Dusko Ilic, Professor of Stem Cell Science, King’s College London, said:
“In this study, the scientists from three Silicon Valley-based companies, MyOme, Spring Fertility, and Natera, enhanced accuracy of whole-genome reconstruction (WGR) by integrating parental genome sequencing and embryo genotyping, to predict the inherited genome sequence of an embryo. They used 110 embryos from 10 couples to compute polygenic predictors across 12 medical conditions such as Type 2 diabetes, breast and/or prostate cancer. The reconstructed genome and polygenic predictions for the embryos were compared to those generated from a tissue sample of the corresponding born children. The authors conclude that 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 IVF.
“It is easy to conceive that in no time, such “predictive” tests will be offered to prospective parents in IVF clinics worldwide.
“In general, for future parents the proposed testing might sound seductive, and they could easily be tempted to spend extra cash to assure that their child lives a healthier life. However, the money would be wasted. Even though the methods used, and data provided in this study are more robust than in other studies, none of the predictions can actually exclude disease and guarantee that a child will remain free of these medical conditions. So, what is the point?”
Dr Francesca Forzano, Chair of the European Society of Human Genetics Public and Professional Policy Committee; Consultant in Clinical Genetics, Guy’s & St Thomas’ NHS Foundation Trust; and Honorary Senior Lecturer, Faculty of Life Sciences & Medicine, King’s College London, said:
“To begin with, the press release accompanying this paper is misleading. It confuses the accuracy of the method used in detecting the genetic variants (analytical validity) with its accuracy in predicting the later development of disease (clinical validity and clinical utility). These are very different things.
“Referring to the paper itself, the data presented, as well as the conclusions, are incomplete and need further clarification. Which genes were analysed for the PRS calculation? What was the sex of the embryos tested (this is very relevant for, e.g., cancers, cardiovascular disorders, and autoimmune disorders)? What is the relation between the genetic findings and the actual disease risk (no calculations are included in the paper)? What were the integrated results of all Polygenic Risk Scores (PRSs) calculated for each embryo, which would be the typical situation in real life? And these are just a few examples.
“The authors list numerous limitations in the use of PRSs in embryos, and from these alone it is clear that it is impossible to calculate the extent of their analytic validity in PGT-P (Preimplantation Genetic Testing; the P stands for Polygenic Risk Scores). But the most important issue – the ethics of the practice – is glossed over and dismissed as something to be handled in a counselling session with a medical geneticist. This is major buck passing. A session of genetic counselling does not equate to an endorsement of any test, particularly one which is inappropriate.
“As the accompanying Comment says: “Genetic tests in reproductive medicine should be based on rigorous science, be transparent about efficacy, and be properly regulated.” At present, none of these prerequisites can be said to even begin to apply to PRSs for PGT-P.
“In general there is a lot of hype around about PRS. It would be worrying if respected journals publish studies that do not adequately examine the many problems that surround its clinical use.”
Prof Alastair Sutcliffe, Professor of General Paediatrics, UCL, said:
“Professor Alan Handyside invented PGD and there have been efforts to rebrand it with various other names ever since (seemingly).
“Here in this study the researchers looked at complex polygenically inherited conditions and worked out the hereditary risk in a variety of IVF conceived embryos, using gene testing and computer modelling.
“They then did ‘quality checks’ on born children selected on this basis to be at lower risk of the polygenic diseases of study.
“The group did this to demonstrate proof of principle and appear to have done so validly.
“This study does raise some broader issues. The couples involved were counselled, however, did they for example get informed that an increased polygenic risk score for other conditions might be a side effect of the decreased risk for the ten disorders studied? It’s possible that other polygenic conditions not looked at could have a higher prevalence in the residual embryos, a law of unintended consequences. When a family is traumatised by a strong family risk of X (e.g. breast cancer) they will focus on that potentially irrationally and thus counselling will simply wash over.
“Fortunately most embryos are naturally conceived and thus are not eligible for this kind of approach.
“The authors stress that this technique is experimental. Whilst it may be of value for some niche families, it is not much of an advance on the use of PGD for single gene defects.”
Prof Karen Sermon, ESHRE Chair-elect; and geneticist in the Reproduction & Genetics Research Group, Vrije Universiteit Brussel, said:
Are polygenic risk scores robust and reliable?
“No, they are not, and the authors themselves discuss the shortcomings in the larger part of the discussion in their paper.
How does this work fit with the existing evidence?
“This work brings together previous studies including PRS in populations, and single cell genomics as applied to preimplantation embryos. Once the difficulty to perform whole genome sequencing, or other large-scale genomic analysis at the single cell level is overcome the data obtained from embryos can be used in the same way as those obtained from postnatal samples within families.
Have the authors accounted for confounders? Are there important limitations to be aware of?
“Yes, the authors outline the limitations to their work in the larger part of their discussion.
What are the implications in the real world? Is there any overspeculation?
“ESHRE issued a statement in February (https://www.eshre.eu/Europe/Position-statements/PRS) cautioning against the use of PRS in embryos. The complexity of obtaining these results (whole genome sequencing, highly complex bioinformatics) relative to the scant additional information about the embryo limits the clinical utility of PRS in the setting of embryo selection and it cannot be supported in clinical practice.”
‘Whole-genome risk prediction of common diseases in human preimplantation embryos’ by Akash Kumar et al. was published in Nature Medicine at 16:00 UK time on Monday 21 March 2022.
DOI: 10.1038/s41591-022-01735-0
Declared interests
Prof Alison Murdoch: “I have no conflict of interest.”
Dr Helen O’Neill: “No conflicts.”
Prof Ewan Birney: “I am a consultant and shareholder to Oxford Nanopore, a DNA sequencing company and a consultant to Dovetail, a DNA library company.”
Prof Dusko Ilic: “I have no conflict of interest to declare.”
Dr Francesca Forzano: “I do not have any conflicts of interest.”
Prof Karen Sermon: “ESHRE and the experts that supported these comments do not have any conflicts of interest with regards to PRS.”
None others received.