What's new in guidance? Scientific Impact Paper summary

Expanded carrier screening (ECS) is a genetic test carried out by analysing a blood or a saliva sample. It can be used to detect whether an individual carries gene variants associated with common genetic conditions. Everyone carries several gene variants that may cause autosomal recessive disease in their offspring if their partner also carries a variant in the same gene, but carrying a gene variant does not mean that the individual would present with any symptoms associated with disease. Currently, genetic tests for specific conditions are available either before or during pregnancy for prospective parents who have a family or personal history of a genetic condition, or for those from ethnic backgrounds where certain conditions – such as haemoglobinopathies – are common, prompting a referral to a clinical genetics department. ECS is often offered privately to provide preconception information, including when IVF with or without gamete donors are considered. Indeed, many sperm and egg banks perform blanket ECS on their donors. Although the Human Fertilisation and Embryology Authority (HFEA) provides some advice to UK fertility clinics about donor screening, there is currently inequity of access to ECS as there is no specific national guidance on this particular topic. ECS may test for several conditions via various gene panels (comprising 250–600 genes on average). Some panels test for genes that do not cause serious disease, or cause diseases that occur later in life; others test for genes that cause severe conditions in childhood. There is no agreement or guidance as to which panel of genes should be tested, and dealing with the results can be complicated, raising technical, legal, ethical and social questions as prospective parents can use this information for reproductive decision making when both are carriers of the same disease. The laboratories involved in ECS are not always accredited or subject to quality control. In the UK, the NHS England (NHSE) National Genomic Test Directory states that testing for partners of known carriers should only be offered if the carrier frequency is higher than 1 in 70 in the general population; where the gene is suitable for carrier testing (excluding pseudogenes and/or high rates of benign variants); and/or where the identification of an affected fetus would have a sufficiently predictable effect to allow actionable reproductive choices. ECS may be of value to consanguineous couples, where it has been reported that 12–28% may carry likely pathogenic or pathogenic variants not previously known to them. The benefit of using ECS is that it is more accurate than using self-reported ethnicity and ethnicity-based panels. ECS results are, however, not always clear and reliable regarding how identified variants (pathogenic, likely pathogenic or uncertain significance) have been classified. Some countries may exclude donors who have been found to be carriers, which could in time lead to reduced available donors as well as increase in waiting time and cost of treatment. Various options are available to prevent the birth of an affected child, such as prenatal testing, IVF using donor gametes or preimplantation genetic testing (PGT) of the embryos accepting the risk, or deciding not to have children. Couples or donors screened via ECS should be made aware that regardless of any screening results, there remains a residual risk. If only the recipient or the donor are found to be carriers of a pathogenic or likely pathogenic variant, any offspring conceived will then have a 50:50 chance of being a carrier, which will need to be shared with them at the appropriate age, particularly if it is a condition with a high carrier frequency. The European Society of Human Genetics (ESHG) recommends that the provision of genetic information and counselling as well as testing should be provided by appropriately trained professionals. However, what is appropriate genetic counselling and how much genomics knowledge would be needed to provide this are not defined. This highlights the importance of continuing professional education regarding genetics and carrier screening for those providing fertility care, as well as working in a multidisciplinary environment comprising genetics clinicians. Interpretation of ECS results needs to be approached with caution and carried out by appropriately trained healthcare professionals with sufficient genetics knowledge, who are able to provide appropriate counselling, pre and post testing. Further work is needed to determine which genes are appropriate to be included in ECS panels, considering population and ethnicity variations, as well as balancing the benefit to patients and their future offspring with the risk of unnecessary screening and anxiety.