Preimplantation Genetic Testing for More Than One Genetic Condition

Clinical and Ethical Considerations and Dilemmas

V. van der Schoot; W. Dondorp; J.C.F.M Dreesen; E. Coonen; A.D.C Paulussen; G. deWert; C.E.M. de Die-Smulders


Hum Reprod. 2019;34(6):1146-1154. 

In This Article

Abstract and Introduction


Study Question: Which clinical and ethical aspects of preimplantation genetic testing for monogenic disorders or structural rearrangements (PGT-M, PGT-SR) should be considered when accepting requests and counselling couples for PGT when applied for more than one condition (combination-PGT; cPGT-M/SR)?

Summary Answer: cPGT is a feasible extension of the practice of PGT-M/SR that may require adapting the criteria many countries have in place with regard to indications-setting for PGT-M/SR, while leading to complex choices that require timely counselling and information.

What is Known Already: Although PGT-M/SR is usually performed to prevent transmission of one disorder, requests for PGT-M/SR for more than one condition (cPGT-M/SR) are becoming less exceptional. However, knowledge about implications for a responsible application of such treatments is lacking.

Study Design, Size, Duration: Retrospective review of all (40) PGT-M/SR applications concerning more than one genetic condition over the period 1995–2018 in the files of the Dutch national PGT centre. This comprises all relevant national data since the start of PGT in the Netherlands.

Participants/Materials, Setting and Methods: Data regarding cPGT-M/SR cases were collected by means of reviewing medical files of couples applying for cPGT-M/SR. Ethical challenges arising with cPGT-M/SR were explored against the background of PGT-M/SR regulations in several European countries, as well as of relevant ESHRE-guidance regarding both indications-setting and transfer-decisions.

Main Results and the Role of Chance: We report 40 couples applying for cPGT-M/SR of which 16 couples started their IVF treatment. Together they underwent 39 IVF cycles leading to the birth of five healthy children. Of the couples applying for cPGT, 45% differentiated between a primary and secondary condition in terms of perceived severity. In the light of an altered balance of benefits and drawbacks, we argue the 'high risk of a serious condition' standard that many countries uphold as governing indications-setting, should be lowered for secondary conditions in couples who already have an indication for PGT-M/SR. As a consequence of cPGT, professionals will more often be confronted with requests for transferring embryos known to be affected with a condition that they were tested for. In line with ESHRE guidance, such transfers may well be acceptable, on the condition of avoiding a high risk of a child with a seriously diminished quality of life.

Limitations, Reasons for Caution: We are the first to give an overview of cPGT-M/SR treatments. Retrospective analysis was performed using national data, possibly not reflecting current trends worldwide.

Wider Implications of the Findings: Our observations have led to recommendations for cPGT-M/SR that may add to centre policy making and to the formulation of professional guidelines. Given that the introduction of generic methods for genomic analysis in PGT will regularly yield incidental findings leading to transfer requests with these same challenges, the importance of our discussion exceeds the present discussion of cPGT.

Study Funding/Competing Interest(s): The research for this publication was funded by the Dutch Organization for Health Research and Development (ZonMw), project number: 141111002 (Long term safety, quality and ethics of Preimplantation Genetic Diagnosis). None of the authors has any competing interests to declare.


Over the past decades, preimplantation genetic testing for monogenic disorders (PGT-M) or structural rearrangements (PGT-SR) has become an established technique allowing couples at high risk of having affected offspring to avoid the birth of a child with a serious genetic disorder or of losing the pregnancy as a result of an unbalanced chromosomal abnormality. PGT as offered for these indications (PGT-M/SR) comprises an in vitro fertilization (IVF)-treatment combined with a blastomere biopsy at the cleavage stage or trophectoderm (TE) biopsy at the blastocyst stage of the in vitro embryo. The cell or cells thus obtained are tested for the relevant mutation(s) and/or chromosomal anomalies. This then allows for the selective transfer of embryos in which the targeted genetic condition is absent, thereby enabling at risk couples to reproduce with confidence (Harton et al., 2011). Although usually performed to avoid the transmission of a single disease, PGT-M/SR allows for simultaneous testing for more disorders. Nowadays, it is no longer rare for centres to be confronted with applicants asking for such 'combination PGT' (cPGT-M/SR). Two case reports describe cPGT-M for Tay–Sachs and Gaucher disease and a cPGT-M/SR for a reciprocal translocation and alfa-thalassemia (Altarescu et al., 2007; Lee et al., 2014). Kuliev et al. (2014) listed a small series of cPGT-M treatments including combinations of single-gene disorders like Charcot–Marie–Tooth and Fabry disease; HBOC (hereditary breast and ovarian cancer) and SMA (spinal muscular atrophy) and HBOC and MEN1 (multiple endocrine neoplasms type 1). Rechitsky et al. (2013) reported 11 cycles of combined testing for cystic fibrosis (CF) mutations and another monogenic disorder.

Several factors may have led to a growing number of requests for cPGT-M/SR, including an increased familiarity with the role of genetics in disease, and a greater awareness of personal reproductive risks as a result of more frequent genomic testing in families. The possible future introduction of a routine offer to the general population of expanded preconception carrier screening for recessive disorders may further add to this effect (Henneman et al., 2016; Sallevelt et al., 2017). Finally, possibilities to diagnose genetic disorders at a single-cell level are expanding. For instance, comprehensive methods such as genome wide single nucleotide polymorphism (SNP) haplotyping (karyomapping) or next generation sequencing (NGS)-based techniques (Natesan et al., 2014; Zamani et al., 2015) enable simultaneous testing for multiple or even an unlimited number of genetic disorders without the need for extensive customization of PGT protocols.