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Download PDF Correspondence Open access Published: 01 December 2022 Reply to Letter by Tellier et al., ‘Scientific refutation of ESHG statement on embryo selection’ Francesca Forzano  ORCID:

orcid.org/0000-0001-5632-00521, Olga Antonova  ORCID: orcid.org/0000-0003-3123-48302, Angus Clarke  ORCID: orcid.org/0000-0002-1200-92863, Guido de Wert  ORCID:

orcid.org/0000-0002-0410-49024, Sabine Hentze5, Yalda Jamshidi  ORCID: orcid.org/0000-0003-0151-64826, Yves Moreau7, Markus Perola8, Inga Prokopenko9,10,11, Andrew Read12, Alexandre Reymond

  ORCID: orcid.org/0000-0003-1030-832713, Vigdis Stefansdottir  ORCID: orcid.org/0000-0003-4451-312614, Carla van El  ORCID: orcid.org/0000-0003-2201-232015, Maurizio Genuardi  ORCID:

orcid.org/0000-0002-7410-835116,17, Executive Committee of the European Society of Human Genetics & Public and Professional Policy Committee of the European Society of Human GeneticsShow

authors European Journal of Human Genetics volume 31, pages 279–281 (2023)Cite this article

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A Correction to this article was published on 19 December 2022

This article has been updated

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.

A Correction to this paper has been published: https://doi.org/10.1038/s41431-022-01263-y

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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 informationAuthors 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

AuthorsFrancesca ForzanoView author publications You can also search for this author inPubMed Google Scholar

Olga AntonovaView author publications You can also search for this author inPubMed Google Scholar

Angus ClarkeView author publications You can also search for this author inPubMed Google Scholar

Guido de WertView author publications You can also search for this author inPubMed Google Scholar

Sabine HentzeView author publications You can also search for this author inPubMed Google Scholar

Yalda JamshidiView author publications You can also search for this author inPubMed Google Scholar

Yves MoreauView author publications You can also search for this author inPubMed Google Scholar

Markus PerolaView author publications You can also search for this author inPubMed Google Scholar

Inga ProkopenkoView author publications You can also search for this author inPubMed Google Scholar

Andrew ReadView author publications You can also search for this author inPubMed Google Scholar

Alexandre ReymondView author publications You can also search for this author inPubMed Google Scholar

Vigdis StefansdottirView author publications You can also search for this author inPubMed Google Scholar

Carla van ElView author publications You can also search for this author inPubMed Google Scholar

Maurizio GenuardiView author publications You can also search for this author inPubMed Google Scholar

Genuardi, Borut Peterlin, Andrew Read, Alexandre Reymond, Carla Oliveira, Karin Writzl & Gunnar Douzgos HougePublic and Professional Policy Committee of the European Society of Human

GeneticsFrancesca 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 JamshidiContributions

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.

The authors declare no competing interests.

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About this articleCite this 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

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Received: 03 November 2022

Accepted: 08 November 2022

Published: 01 December 2022

Issue Date: March 2023

DOI: https://doi.org/10.1038/s41431-022-01241-4

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