Researchers call for more regulation to prevent the use of donated sperm with a cancer-causing genetic mutation, according to results presented at the annual conference of the European Society of Human Genetics.
A case in which a sperm donor was found to be carrying a cancer-causing pathogenic variant in his gametes has highlighted some of the problems of regulating gamete donation at the European and international levels. The lack of cross-border regulation in Europe can result in the use of gametes within the same family, risking inbreeding and the dissemination of inherited diseases.
In 2023, Dr. Edwige Kasper, a specialist in genetic predisposition to cases from the Rouen University Hospital, France, became aware of a situation where a patient received a letter from a private sperm bank located in Europe, alerting her to the presence of the TP53 (tumour protein 53) gene her donor’s gametes. TP53 provides instructions for making a tumour suppressor protein, keeping cells from growing and dividing too fast or uncontrolled. The donor remained in good health, but his biological children had a high risk of developing Li-Fraumeni syndrome, a rare inherited disorder that predisposes to the development of cancers. In fact, some of these children had already developed leukaemia and non-Hodgkin’s lymphoma, which led to any use of the donor’s gametes being definitively blocked.
“I analysed the variant using population and patient databases, computer prediction tools, and the results of functional trials, and came to the conclusion that the variant was probably cancer-causing and that children born from this donor should receive genetic counselling,” said Dr Kasper.
A number of Genetics and Paediatric Departments across Europe were also investigating their own cases, leading to 67 children from 46 families in eight European countries being tested, with the variant being found in 23 of them and cancer found in ten to date.
Some mutations in the TP53 gene cause Li-Fraumeni syndrome, where carriers have one of the most severe inherited predispositions to cancer, typically at an early age. The affected children, born between 2008 and 2015, are being closely monitored to detect any signs of cancers. “The follow-up protocol involves whole-body MRI scans, MRI scans of the brain and, for adults, of the breast, ultrasound examination of the abdomen, and a clinical examination by a specialist. This is heavy and stressful for carriers, but we have seen its effectiveness in that it has enabled early detection of tumours and thus improved patients’ chances of survival,” said Dr Kasper. “Because animal models of Li-Fraumeni syndrome have shown that exposure to genotoxic chemotherapy or X-rays accelerated tumour development, these children should avoid radiation-based imaging techniques such as mammography and PET scans, if possible.”
The search continues for other children born from the same donor. “Although the variant would have been practically undetectable in 2008 when the individual started to donate sperm, there are many things that could have been and still need to be improved,” said Dr Kasper. “Some fertility clinics have refused to provide information to the families concerning the variant because they wanted the children to be tested in their own laboratories. There is a major issue here concerning a lack of harmonised regulation across Europe.”
At the moment, laws on sperm donation differ from one European country to another. For example, the law in France sets a limit of ten births per donor; it can go up to 15 births in Germany and Denmark, and in the UK, the same donor may be used for 12 families.
“My advice to French parents would be to favour a medically assisted procreation procedure in France, where donation is voluntary, anonymous, and free,” said Dr Kasper. In this country, gamete donation is medically supervised for both donors and recipients, and any suspicion of a genetic disorder is promptly investigated. Above all, each donor is limited to a maximum of ten births, and the import or export of gametes may only be requested by an approved centre and is subject to authorisation from the Agence de la Biomédecine. “The fact that the case in point is very rare does not mean that it will not reoccur, and gonadal mosaicism – where one or more groups of cells possess a different genetic makeup – has previously been reported in a sperm donor with reference to neurofibromatosis type 1. We need proper regulation at the European level to try to prevent it happening again and to implement measures to ensure a worldwide limit on the number of offspring conceived from the same donor.”
“While current legislation on assisted reproduction usually does not cross borders, this is a good example of why wider oversight is needed,” said Chair of the conference Professor Alexandre Reymond. “What we learn in genetics in one country can help future parents everywhere.”