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TO THE EDITOR: We would like to thank the authors for their letter addressing our recent policy paper on PGT-P, as this provides us with an additional opportunity to clarify our position.

Tellier et al. criticise the selection of papers we have cited, considering them not sufficiently representative of the wealth of literature on this subject, so that, according to them, we

have not correctly represented the ‘scientific consensus’ and ‘potential utility’ of the technology. It is important to emphasise that our paper does not aim to address the research

underlying polygenic risk scores (PRSs) in general, nor the full range of potential screening and clinical applications, but only those PRSs applied to embryo selection and ranking

(so-called PGT-P). We would like to reassure Tellier et al. that we have considered a much larger body of literature than just the papers we have referred to. As one might expect, we

selected the papers that are the most relevant and important for the very specific scope of our policy paper. We are quite puzzled, however, by the view expressed by the authors of the

letter about a ‘scientific consensus’ regarding the clinical application of PRSs to embryo selection. Indeed, if a consensus can be said to exist, it seems to us to be very much contrary to

the views of Tellier et al. In 2021 and 2022, the European Society of Human Genetics [1], the American College of Medical Genetics [2], the European Society of Human Reproduction and

Embryology [3], the International Society of Psychiatric Genetics [4] and the Polygenic Risk Score Task Force of the International Common Disease Alliance [5] all released statements

concordant in their opinion that preimplantation or prenatal testing for common disorders using PRSs is not yet appropriate for clinical use. While we agree with the authors that PGT-P might

be able to identify some ‘risk outliers’ among sibling IVF embryos, we disagree with their claim that the differences among sibling IVF embryos will be, on average, significant enough to

enable meaningful, clinically useful selection or ranking. The lack of any likely substantial net effect on traits such as duration of education is indeed one of the key points made by

Turley et al. [6]. The latter is cited by Tellier et al. as if it supports their own views, but we read it very differently from them. Even the paper they cite by Lello et al. (whose

authorship overlaps with the letter), while demonstrating some ability to distinguish PRSs of siblings, fails to produce convincing evidence that this would be of any clinical utility in

testing embryos [7]. Nor would there be any path to determine the accuracy of any ‘predictions’ made on the basis of such claims. Furthermore, it is quite strange that yet another paper

cited in their letter [8] concludes that ‘screening human embryos for polygenic traits has limited utility’. Tellier et al. are maybe striving to cite the literature fairly, even if it

undermines their position. Of course, if selection based on PRSs were to be applied for more than one trait at the same time, any reason to believe it could be employed in a useful way

becomes even more remote in most family-specific circumstances. Another point where we disagree with the authors is their statement that the selection they can achieve would confer a disease

risk reduction comparable to that of embryo selection for monogenic disease. We disagree with this for two reasons. First, such large effects of PRSs are not usually available within a

single nuclear family [6], nor does the paper by Lello et al. support this [7]. Second, what would be at stake is a relative increase or reduction of risk compared with the general

population for a common disorder, though it will never be possible to exclude the development of that condition in the chosen embryo. Conflating the calculation of risks for common

multifactorial disorders with that for rare monogenic disorders, even where they have a reduced penetrance, is both mistaken and misleading. The authors use as a supportive argument for the

use of PGT-P the fact that ‘roughly 50% of US IVF embryos undergo some form of genetic screening today’. We hope that the authors would concur that performing one form of screening does not

automatically entail endorsing the use of a second, particularly if it has not been adequately assessed. Though aneuploidy screening in preimplantation embryos (PGT-A) has been introduced in

many (private) clinics, this screening is not without its critics. In fact, a relatively recent Cochrane review [9] has concluded that the currently available evidence is insufficient to

support PGT-A in routine clinical practice. This apparent conundrum highlights yet further our still limited knowledge of embryo physiology and development, and the differences in testing an

early embryo as compared to a foetus or a newborn. We are glad to know that the authors would welcome an open scientific discussion on the merits of PGT-P, and we would hope this would, at

the same time, include addressing the relevant ethical issues, such as ramping up false expectations as to what can be achieved through the application of unevaluated new technologies, which

might lead to ill-advised management of the couple’s reproductive journey and potentially to financial exploitation. We strongly support this call for a frank debate, with the caveat that

this should precede, and not follow, the introduction of this test in the clinic. CHANGE HISTORY * _ 19 DECEMBER 2022 A Correction to this paper has been published:

https://doi.org/10.1038/s41431-022-01263-y _ REFERENCES * Forzano F, Antonova O, Clarke A, de Wert G, Hentze S, Jamshidi Y, et al. The use of polygenic risk scores in pre-implantation

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ESHG on embryo selection based on polygenic risk scores. 2022. https://www.eshre.eu/Europe/Position-statements/PRS. * ISPG Board Advisory on the use of Polygenic Risk Scores to screen

embryos for adult mental health conditions. 2021. https://ispg.net/ethics-statement/. * Polygenic Risk Score Task Force of the International Common Disease Alliance. Responsible use of

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AR, et al. Problems with using polygenic scores to select embryos. N Eng J Med. 2021;385:78–86. Article  Google Scholar  * Lello L, Raben TG, Hsu SDH. Sibling validation of polygenic risk

scores and complex trait prediction. Sci Rep. 2020;10:13190. Article  CAS  PubMed  PubMed Central  Google Scholar  * Karavani E, Zuk O, Zeevi D, Barzilai N, Stefanis NC, Hatzimanolis A, et

al. Screening human embryos for polygenic traits has limited utility. Cell. 2019;179:1424–35. Article  CAS  PubMed  PubMed Central  Google Scholar  * Cornelisse S, Zagers M, Kostova E,

Fleischer K, van Wely M, Mastenbroek S. Preimplantation genetic testing for aneuploidies (abnormal number of chromosomes) in in vitro fertilisation. Cochrane Database Syst Rev.

2020;9:CD005291. Download references FUNDING IP has received funding from the World Cancer Research Fund (WCRF UK) and World Cancer Research Fund International (2017/1641), the European

Union’s Horizon 2020 research and innovation programme (LONGITOOLS, H2020-SC1-2019-874739), Agence Nationale de la Recherche (PreciDIAB, ANR-18-IBHU-0001), the European Union through the

“Fonds européen de développement régional” (FEDER), the “Conseil Régional des Hauts-de-France” (Hauts-de-France Regional Council), and the “Métropole Européenne de Lille” (MEL, European

Metropolis of Lille). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Clinical Genetics Department, Guy’s and St Thomas NHS Foundation Trust, London, UK Francesca Forzano * Department of

Medical Genetics, Medical University of Sofia, Sofia, Bulgaria Olga Antonova * Division of Cancer and Genetics, School of Medicine, Cardiff University, Cardiff, Wales, UK Angus Clarke *

Maastricht University, Maastricht, The Netherlands Guido de Wert * Practice for Human Genetics, Heidelberg, Germany Sabine Hentze * Genetics Research Centre, Molecular and Clinical Sciences

Institute, St George’s University of London, London, UK Yalda Jamshidi * University of Leuven ESAT-STADIUS, B-3001, Leuven, Belgium Yves Moreau * Finnish Institute for Health and Welfare

(THL), Biomedicum 1, Haartmaninkatu 8, 00290, Helsinki, Finland Markus Perola * Department of Clinical & Experimental Medicine, University of Surrey, Guildford, UK Inga Prokopenko * UMR

8199 – EGID, Institut Pasteur de Lille, CNRS, University of Lille, F-59000, Lille, France Inga Prokopenko * People-Centred Artificial Intelligence Institute, University of Surrey, Guildford,

UK Inga Prokopenko * Centre for Genomic Medicine, St Mary’s Hospital, M13 0JH, Manchester, England Andrew Read * Center for Integrative Genomics, University of Lausanne, CH- 1015, Lausanne,

Switzerland Alexandre Reymond * Department of Genetics and Molecular Medicine, Landspitali University Hospital, Reykjavik, Iceland Vigdis Stefansdottir * Section Community Genetics,

Department of Clinical Genetics and Amsterdam Public Health Research Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands Carla van El * UOC Genetica Medica,

Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy Maurizio Genuardi & Maurizio Genuardi * Sezione di Medicina

Genomica, Dipartimento di Scienze della Vita e Sanità Pubblica, Università Cattolica del Sacro Cuore, Rome, Italy Maurizio Genuardi & Maurizio Genuardi * Clinical Institute for Genomic

Medicine, University Medical Center Ljubljana, Ljubljana, Slovenia Borut Peterlin & Karin Writzl * Institute of Molecular Pathology and Immunology of the University of Porto (Ipatimup),

University of Porto, PT, Porto, Portugal Carla Oliveira * Department of Pathology, Faculty of Medicine, University of Porto, PT, Porto, Portugal Carla Oliveira * Instituto de Investigação e

Inovação em Saúde (i3S), University of Porto, PT, Porto, Portugal Carla Oliveira * Department of Medical Genetics, Haukeland University Hospital, 5021, Bergen, Norway Gunnar Douzgos Houge *

Department of Genetics, SYNLAB Suisse SA, Chemin d’Entre Bois 21, 1018, Lausanne, Switzerland Christophe Cordier * Medical Ethics, Lund University, Uppsala, Sweden Heidi Howard * Chalmers

University (part of GENIE initiative), Uppsala, Sweden Heidi Howard * Department of Biology and Medical Genetics, 2nd Faculty of Medicine, Charles University and Motol University Hospital, V

Uvalu 84, Prague, CZ15006, Czech Republic Milan Macek * Department of Medical Genetics, University of Pécs, Szigeti 12., H-7624, Pécs, Hungary Béla Melegh * UnIGENe and Centre for

Predictive and Preventive Genetics, IBMC—Institute for Molecular and Cell Biology, i3S—Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal Alvaro Mendes *

Laboratory for Molecular Biology, Institute of Molecular Genetics and Genetic Engineering, University of Belgrade, Belgrade, Serbia Dragica Radojkovic * CERPOP, UMR 1295, Inserm, Université

de Toulouse-Université Paul Sabatier-Toulouse III, Responsable Equipe BIOETHICS: Trajectoires d’innovations en santé:enjeux bioéthiques et sociétaux, Toulouse, France Emmanuelle Rial-Sebbag

* Plateforme Sociétale “Génétique et Société, GIS Genotoul, Génopole Toulouse Midi-Pyrénées, 37, allées Jules Guesde, 31073, Toulouse Cedex, France Emmanuelle Rial-Sebbag * Manchester Centre

of Health Psychology, Division of Psychology and Mental Health, School of Health Sciences, Manchester Academic Health Science Centre, University of Manchester, Coupland Street, Manchester,

M13 9PL, UK Fiona Ulph Authors * Francesca Forzano View author publications You can also search for this author inPubMed Google Scholar * Olga Antonova View author publications You can also

search for this author inPubMed Google Scholar * Angus Clarke View author publications You can also search for this author inPubMed Google Scholar * Guido de Wert View author publications

You can also search for this author inPubMed Google Scholar * Sabine Hentze View author publications You can also search for this author inPubMed Google Scholar * Yalda Jamshidi View author

publications You can also search for this author inPubMed Google Scholar * Yves Moreau View author publications You can also search for this author inPubMed Google Scholar * Markus Perola

View author publications You can also search for this author inPubMed Google Scholar * Inga Prokopenko View author publications You can also search for this author inPubMed Google Scholar *

Andrew Read View author publications You can also search for this author inPubMed Google Scholar * Alexandre Reymond View author publications You can also search for this author inPubMed 

Google Scholar * Vigdis Stefansdottir View author publications You can also search for this author inPubMed Google Scholar * Carla van El View author publications You can also search for

this author inPubMed Google Scholar * Maurizio Genuardi View author publications You can also search for this author inPubMed Google Scholar CONSORTIA EXECUTIVE COMMITTEE OF THE EUROPEAN

SOCIETY OF HUMAN GENETICS * Maurizio Genuardi * , Borut Peterlin * , Andrew Read * , Alexandre Reymond * , Carla Oliveira * , Karin Writzl *  & Gunnar Douzgos Houge PUBLIC AND

PROFESSIONAL POLICY COMMITTEE OF THE EUROPEAN SOCIETY OF HUMAN GENETICS * Francesca Forzano * , Angus Clarke * , Christophe Cordier * , Guido de Wert * , Sabine Hentze * , Heidi Howard * , 

Milan Macek * , Béla Melegh * , Alvaro Mendes * , Yves Moreau * , Markus Perola * , Inga Prokopenko * , Dragica Radojkovic * , Emmanuelle Rial-Sebbag * , Vigdis Stefansdottir * , Fiona Ulph

* , Carla van El * , Olga Antonova *  & Yalda Jamshidi CONTRIBUTIONS FF drafted the paper. All the co-authors have contributed to implementing and finalising the draft. All the members

of the Exec Committee and of the PPPC have reviewed and endorsed the manuscript. CORRESPONDING AUTHOR Correspondence to Francesca Forzano. ETHICS DECLARATIONS COMPETING INTERESTS The authors

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ARTICLE Forzano, F., Antonova, O., Clarke, A. _et al._ Reply to Letter by Tellier et al., ‘Scientific refutation of ESHG statement on embryo selection’. _Eur J Hum Genet_ 31, 279–281

(2023). https://doi.org/10.1038/s41431-022-01241-4 Download citation * Received: 03 November 2022 * Accepted: 08 November 2022 * Published: 01 December 2022 * Issue Date: March 2023 * DOI:

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