Expanded carrier screening: Reflections on new guidance

Yesterday, the British Fertility Society (BFS) issued new guidance which provides direction on genetic testing in gamete donation in the UK. In a landscape with many gaps and uncertainties, this provides welcome and much-needed guidance on the use of expanded carrier screening (ECS).

This topic has been the focus of the PRECAS Project, which has investigated the emergence, commercialisation and implications of ECS in the UK over the last three years.

ECS is a genetic test usually used before conception, either by couples conceiving together or by donors and recipients. It is frequently called expanded carrier screening because, unlike targeted screening, it screens for the presence of often hundreds of disease-causing pathogenic recessive genetic variants that may be passed on to children. Most people are carriers of between one and seven variants, and if parents carry the same disease-causing variant, there is a 25 percent chance that the child will be affected.

Despite its widespread use in countries such as the USA and Spain, and its adoption by donor banks in the USA and Denmark, ECS is currently not offered within the NHS. Consequently, uptake in the UK has been largely driven by commercial providers. When looking at the routes to the use of ECS, we found that it was most often used by recipients of donated gametes, who selected a donor with preexisting test results. Although this trend initially emerged through the use of imported gametes, some UK clinics and donor banks are now also using ECS to test UK donors.

In this comment piece, we reflect on three key points of the guidance that, in our view, represent welcome improvements but would benefit from further clarification: the use of carrier-positive donors, the eligibility criteria for genetic testing of recipients, and the consistency of information and support provided to recipients, donors and donor-conceived people.

A first important development is the BFS guidance's recognition that donors known to be carriers of autosomal recessive variants should not be excluded, stating that exclusion of all carrier-positive donors 'has no medical basis in most circumstances'. This is because most people carry one or more pathogenic variants, although their frequency and severity vary considerably.

For the vast majority of autosomal recessive conditions, carrier status has no health implications for the individual (with notable exceptions, such as sickle cell trait), and if the recipient is not a carrier of a pathogenic variant in the same gene, the risk of having an affected child is generally considered to be very low. This clarification will be welcomed by fertility and genetics professionals, many of whom, in our interviews, expressed concern about the lack of clarity on this issue in existing guidance for clinical scientists.

Additionally, the BFS guidance includes a series of recommendations to support informed decision-making about the use of carrier-positive donors. These include informing recipients that carrier screening does not cover all genetic conditions, and offering appropriate genetic testing for the variants identified in the donor (with recommended eligibility criteria).

This guidance was developed in light of the recently revised Medical and Laboratory Procurement and Use of Sperm, Egg and Embryo Donors guidelines on donor testing. While these guidelines do not recommend ECS for donors or the use of carrier-positive donors, stating that 'donors should not ordinarily be heterozygous for an autosomal recessive gene', they also acknowledge that 'a recessive gene disorder is not an absolute contraindication to donation'. Although this position is expressed somewhat ambiguously, it recognises that the use of carrier-positive donors may be appropriate in some circumstances and that recipients require support with informed decision-making and, where indicated, access to genetic testing.

Secondly, the BFS Guidance recommends a carrier frequency threshold of one in 70 for determining eligibility for recipient carrier testing. Under this recommendation, recipients should be offered testing when a donor is known to carry a pathogenic variant associated with an autosomal recessive condition that meets this threshold. This figure is drawn from the National Genomic Test Directory for NHS-funded genetic testing, aligning donor recipients with existing eligibility criteria for couples in which one partner is a known carrier.

This is a pragmatic and consistent approach that will undoubtedly reassure fertility patients. However, it should be noted that other carrier screening panels determine inclusion based not only on carrier frequency, but also on the severity of the associated condition. Moreover, given that 75 percent of fertility treatment in the UK takes place outside the NHS, where the National Genomic Test Directory does not determine access to genetic testing, it remains to be seen how widely this recommendation will be adopted in practice.

Lastly, another key contribution of the BFS Guidance is to recommend that recipients should systematically be offered appropriate support and information to help them understand ECS, the associated transmission risks and the implications of test results.

The guidance provides clear and useful recommendations on how this can be achieved, including an example information leaflet to support informed decision-making. However, comparable guidance on the information and support that should be offered to donors is absent.

We suggest that greater consideration of donors' informational and support needs would strengthen the implementation of ECS, especially given that some UK clinics and donor banks have already introduced donor testing. Donors also need to be prepared for and supported in understanding the results of their own genetic testing, as the identification of pathogenic variants may have important implications for their own reproductive choices, as well as those of their existing or future children.

The BFS guidance also recognises the importance of ECS results for the future reproductive decision-making of donor-conceived people, but does not address some of the practical challenges of ensuring access to this information. Future guidance should therefore consider how donors' carrier status could be stored securely and made accessible – when needed – to donor-conceived people later in life.

The introduction of these guidelines is timely. We welcome the BFS's first set of recommendations on the use of ECS and carrier-positive donors, which provide an important framework for professional practice in the UK. Considerable effort and time have clearly been invested in producing guidance that is both practical and inclusive, equipping fertility professionals to support patients in making informed decisions.

We hope these recommendations will also serve as a foundation for future guidance on the use of ECS for prospective parents more broadly.