A sperm donor fathers 67 children. Then it turns out that he carries a risk gene, and ten of his children have already developed cancer. How could this happen?

It was the end of 2023 when Edwige Kasper first heard about the problem with TP53. The abbreviation stands for a gene in which the young geneticist specializes at the University Hospital in Rouen, France. And it was the focus of a letter forwarded to her by a colleague.

In it, a Copenhagen-based sperm bank operating throughout Europe informs one of its former fertility clients that a "variant of unknown significance" in the TP53 gene has been discovered in the sperm of her child's biological father. The European Sperm Bank supplies up to 75 families with donor sperm. Kasper can therefore guess that the woman is unlikely to be the only recipient of such a letter.

"Variant of unclear clinical significance" – this actually means: The gene's letter code contains an error compared to the common variant, but the consequences are still unclear. However, TP53 is one of the genes in which one would least want to have an error. It plays such a central role in the body's cells that researchers have given it its own honorary title: "Guardian of the Genome."

TP53 contains the blueprint for the protein p53, a so-called tumor suppressor that slows the division and growth of cells when their genetic material has been damaged. This gives the cell time to either repair the damage or eliminate itself through "programmed cell death." In other words: p53 prevents cancer.

Although each cell contains a paternal and a maternal copy of this gene, the loss of even one of these copies due to a mutation leads to insufficient tumor suppressor production. As a result, budding tumor cells are no longer effectively combated; the risk of developing cancer before the age of 30 increases by a factor of 50.

This congenital susceptibility to numerous different types of cancer is called Li-Fraumeni syndrome, and it often manifests in childhood. The only countermeasure is close monitoring of those affected to detect and treat tumors early.

Kasper quickly realizes from the letter that the mutation in the Danish donor's case is not harmless: The man himself is in good health, it states, but cases of blood cancer have already occurred among his children. Further use of this donor's sperm has since been stopped. It also points out that the mutation is found in less than half of all the man's sperm—retrospectively, sperm donation becomes a lottery.

Over the next year, Kasper embarked on a detective-like search for genetic clues. She analyzed the previously unknown variant using computer-based predictive models and scoured relevant study results. At the same time, colleagues across Europe investigated cases in their own countries.

Kasper presented the research results two weeks ago at the annual congress of the European Society of Human Genetics in Milan. They confirmed the suspicion: The variant is likely cancer-causing. They identified 67 children of the donor from 46 families, all born between 2008 and 2015.

The cases are spread across eight European countries, 51 in Belgium alone. The remaining children apparently live in France, Germany, Denmark, Sweden, Spain, Greece, and the United Kingdom. The defective gene variant was found in 23 of these children, ten of whom have already developed cancer, according to Kasper's report.

These sobering figures are devastating news for the families affected. The question arises whether and how this suffering could have been prevented.

Based on everything known about this specific case, however, neither the donor nor the sperm bank can be accused of misconduct. This specific case is a very special one: The mutation is a so-called germ cell mosaic.

This means that the donor did not inherit the genetic defect from a parent, explains Sven Cichon, a human geneticist at the University Hospital of Basel. Rather, the mutation arose spontaneously during the man's early childhood development in one of the precursor cells from which sperm are ultimately formed. "It was then passed on to all cells that developed from this precursor – and thus also to the sperm produced later. Depending on how early or late the mutation occurred, the proportion of mutated sperm is higher or lower."

Because only certain cells in the testicle are affected, the mutation cannot be detected in blood or saliva samples. This also explains why the man himself apparently does not suffer from Li-Fraumeni syndrome. "That's probably why he wasn't even noticed during the medical history and routine diagnostics. That's the crux of the matter with germ cell mosaics," says Cichon.

What else do such standard checks cover? The first step is always the quality control of the prospective donor sperm, says reproductive medicine specialist Gideon Sartorius, a sperm donation expert at the Fertisuisse fertility center in Basel and Olten. Only one in ten men who present themselves has sperm in sufficient numbers and with sufficient vitality. The standards are very high to ensure that, after the wasteful freezing in liquid nitrogen, sufficient viable gametes remain for successful fertilization.

Only once this hurdle has been overcome do tests follow to rule out a hereditary predisposition. "There are no fixed requirements for this in Switzerland or most European countries; Swiss law simply requires that we ensure that healthy children are conceived," says Sartorius.

In practice, a thorough medical history is crucial, including reviewing the patient's personal medical history and possible family predispositions. If this raises suspicions of a hereditary disease, these are immediately investigated. In addition, a blood count and tests for pathogens such as HIV are usually performed. Genetic testing is limited to relatively common diseases such as cystic fibrosis or spinal muscular atrophy, which are inherited recessively.

Such recessive diseases only become apparent when both parents pass a defective copy of the gene to a child. In carriers with only one diseased gene, the defect remains hidden and can therefore skip many generations in the family history.

Dominantly inherited diseases such as TP53-related Li-Fraumeni syndrome, on the other hand, occur in carriers with only one defective copy. This makes them almost impossible to miss in the family history—with the rare exception of a completely new mutation.

In the case of the Danish sperm donor, this could not have been detected by any realistic testing scenario, the experts interviewed agree. However, there is considerable debate among experts about the extent to which preliminary tests for possible risk genes could be meaningfully expanded. Theoretically, several options are possible, including sequencing the entire donor genome.

Sven Cichon calls the idea of ​​such comprehensive tests without any concrete evidence of suspicion a "bottomless pit." "The more you test, the more unclear variants you will find, whose relevance to the carrier is difficult to assess." And his colleague Markus Nöthen from the University Hospital Bonn clarifies: "In the end, there wouldn't be a single sperm donor left."

However, Nöthen certainly advocates for a reasonable expansion of existing tests, for example by offering genetic testing for both donors and recipients in order to predict the possible occurrence of even rarer recessive gene variants.

But concerns aren't just about the enormous effort required to obtain difficult-to-interpret test results. "This is also an ethical question: Do donors have to be healthier than the population average? This enters the sensitive area of ​​eugenics," says reproductive medicine specialist Gideon Sartorius.

There is, however, consensus on the demand for a stricter cap on the number of children fathered by a single donor. In Switzerland, the total number of offspring is already limited to eight. The European Sperm Bank, on the other hand, has set the limit at 75 families that may be provided with sperm from a single donor. In this specific case, this led to the large number of affected children.