The expanding role of genomics in preconceptional ‘personalised’ medicine

genomic medicine

Published 23 December 2020

A well attended online Campus course staged by the SIG Reproductive Genetics heard that the expansion of sequencing analysis is poised to push forward the development of cost-effective preconception tests able to identify several underlying genetic causes of infertility

The everyday implications of preconceptional medicine have so far been largely evident in lifestyle advice conducive to successful pregnancy, but a well attended online Campus meeting staged in December suggests that genomic medicine has an increasingly important role to play. Sessions at the meeting not only covered the much debated subject of genetic risk assessment by expanded carrier screening, but explored the application of genome-wide sequencing in recurrent miscarriage, in predicting ART outcomes from parental genome analysis, and even in explaining the different responses to ovarian stimulation with gonadotrophins. Such subjects, especially expanded carrier screening, are not without their ethical problems, notably in the disclosure (or not) of secondary findings, so it was also appropriate at this meeting to hear a preview of ESHRE’s forthcoming recommendations on expanded carrier screening in ART.

In his opening lecture Stéphane Viville, a former coordinator of ESHRE’s SIG Reproductive Genetics, said that known genetic and chromosomal factors account for around 20% of all infertility cases, with three additional (and relatively unknown) phenotypes now moving into ‘active research’: POI, oocyte maturation defect, and preimplantation embryonic lethality, all of which were covered at this meeting. Viville added that so far at least 21 genes have been implicated in POI and advised that genetics is now ‘getting more and more into IVF labs’ and no longer confined to chromosomal aberrations or microdeletions on the Y chromosome.

Much of the content of this Campus course has been explored in detail in a recent Human Reproduction Update review, whose first author, Antonio Capalbo, is deputy of ESHRE’s SIG Reproductive Genetics and an organiser of this course.(1) In the review, as was repeatedly implied at this meeting, Capalbo et al note that the expansion of sequencing analysis may enable the development of cost-effective preconception tests capable of identifying underlying genetic causes of infertility, which until now have largely been defined as idiopathic.

One such step in this move towards a more positive and personalised approach to preconceptional medicine is in genetic risk assessment by expanded carrier screening, which occupied a large section of this meeting. James Goldberg, prominent in the development of ECS, said its availability now steps beyond the disparities and restrictions of ethnicity-specific screening and aims to inform couples about their risk of having children with autosomal recessive and X-linked recessive disorders and thereby to support informed decision making. Nevertheless, two of the current guidance statements on ECS cited by Goldberg – both from the USA – are largely based on ethnicity screening with an emphasis on cystic fibrosis and spinal muscular dystrophy. ECS, said Goldberg, represents ‘a more equitable approach’ to identifying risk. Such risk assessment – in both the general population and IVF couples - will allow identification of those who carry recessive mutations, and thereby provide increased reproductive autonomy to couples deemed at risk and where PGT is available for embryo selection.

However, when a publicly provided ECS programme was set up in Amsterdam offering a test panel of 50 genes (at a cost of 650 euro per test) and following the guidance of the European Society of Human Genetics, there was a relatively quiet response (20%) from the ‘general risk’ population, and higher (80%) from the high risk population.(2) Nevertheless, assessment of the programme, began in 2016, appeared to raise more questions than answers, and no clear resolution of how such a programme might be best provided. Capalbo and his fellow Update reviewers concluded that ‘ECS represents one of the most effective and advanced applications of preconception genomic medicine worldwide today’ and is expected to grow in application in coming years.

The preview of recommendations from ESHRE’s Ethics Committee was specifically about ECS ahead of ART (and not just involving gamete donors). Thus, asked Dutch bioethicist Guido de Wert, would the offer of ECS to all such applicants be proportionate, and if so, for what kinds of disorders and under what conditions? Applying the three ethicists’ principles of proportionality, respect for autonomy and justice, De Wert firstly noted that any possible benefits should ‘clearly’ outweigh any possible harms, that ECS should still be embedded in a research framework, and that a couple’s access to ECS should only be ‘on condition that they take preventive measures and apply for PGT, donor gametes, or, maybe, prenatal diagnosis’.

Even the outcome of fertility treatments may well be affected by genetic mutations, and such extreme outcomes as oocyte maturation failure and embryonic developmental arrest are now investigated as a genetic cause of infertility. Indeed, Semra Kahraman from the Istanbul Memorial Hospital reported that variants in more than 2000 genes are now predicted to be involved in various infertility pathways. She described her own study in which 22 IVF patients whose repeated failure was attributed to oocyte maturation failure and embryo development arrest and who were investigated using whole exome sequencing panels. Family history analysis had also identified infertility and early menopause in the family of nine of the subjects. The analysis identified genomic variants in eight of the 22 subjects, including four genes known to be ‘lethal’ at the embryonic stage.

With ovarian ageing identified as one of today’s most frequent causes of infertility, John Berry, an MRC investigator from Cambridge, reported in a keynote lecture that ten years ago population studies had identified four common genetic variants associated with menopause. Today, he added, there are now more than 300 loci identified, which explain ‘around 10%’ of the heritable component. Too few to be clinically useful? he asked. Again, there appeared more questions than answers, notably if POI can be explained ‘solely’ by monogenic alleles and if menopausal age can indeed be predicted by genetics.

The conclusions from this meeting, as well as the increasing number of genes and variants identified, suggest that genomic assessment ahead of conception may have real clinical benefits at both the individual (in identifying genetic risks in the male and female partner) and the couple level (in allowing a specific reproductive prognosis). Information at this early stage may thus lay the basis for personalised interventions, and certainly make at-risk couples better informed of their reproductive choices.


1. Capalbo A, Poli M, Riera-Escamilla A, et al. Preconception genome medicine: current state and future perspectives to improve infertility diagnosis and reproductive and health outcomes based on individual genomic data, Hum Reprod Update 2020; doi:10.1093/humupd/dmaa044

2. Henneman L, Borry P, Chokoshvili D, et al. Responsible implementation of expanded carrier screening. Eur J Hum Genet 2016; 24: e1-e12. doi:10.1038/ejhg.2015.27

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