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Hypermutation in children linked to mutations in father’s sperm cells, Wellcome Sanger Institute finds

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Researchers have found that some rare cases of higher genetic mutation rates in children, known as hypermutation, could be linked to the father receiving certain chemotherapy treatments.

Studying genetic information from more than 20,000 families, the scientists at the Wellcome Sanger Institute and their collaborators identified 12 children with between two to seven times more mutations than the general population.

Dr Joanna Kaplanis, Wellcome Sanger Institute. Picture: Wellcome Sanger Institute
Dr Joanna Kaplanis, Wellcome Sanger Institute. Picture: Wellcome Sanger Institute

They linked eight of these to increased mutations in the sperm of the biological father.

And studying seven of the families in greater detail, the researchers found five of the men had previously been treated with chemotherapy before conceiving a child, which could be linked to the increased number of mutations in their sperm cells.

The other two had rare recessive genetic variants that impaired DNA repair mechanisms.

Hypermutation does not lead to genetic disorders for the vast majority of children with it, but it does increase the risk.

The scientists suggest that if further research confirms the impact of chemotherapy, it could in future lead to patients being offered the opportunity to freeze their sperm before treatment.

Dr Joanna Kaplanis, first author and post-doctoral fellow at the Wellcome Sanger Institute, said: “Hypermutation in children, where they have between two and seven times more random mutations than the general population, is rare and therefore cannot be caused by common carcinogens or exposures.

“Our research analyses over 20,000 families and highlights new causes of these mutations, linking them back to germline mutations in the father’s sperm as well as identifying a new mutational signature. Understanding the impact of these germline mutations in the sperm could help us uncover why some people are more likely to have children with these high rates of random mutations, and help protect against these if they cause disease.”

The research, supported by HDR UK Cambridge, was published in Nature.

John Danesh, director of HDR UK Cambridge, who supported the research, said: “Hypermutation in children is an uncommon but important phenomenon that increases the risk of life-altering genetic diseases. By bringing together genetic data at scale, and linking this with routine clinical data like the hospital records of parents, the team has identified new risk factors that may influence future healthcare decisions. This work elegantly demonstrates how work in Health Data Research UK's Understanding the Causes of Disease Programme is helping to link nationwide genetic data and clinical records in secure, anonymised and trustworthy ways that provide unique insights into unanticipated, but important questions.”

Sir Mark Caulfield, from Queen Mary University of London, and former chief scientist at Genomics England, said: “These findings were only possible due to access to whole genomes and linked health record data on the family members from the 100,000 Genomes Project. These findings could really help people with cancer consider family planning.”

Prof Matthew Hurles
Prof Matthew Hurles

Prof Matthew Hurles, senior author and head of human genetics at the Wellcome Sanger Institute, added: “Chemotherapy is an incredibly effective treatment for many cancers, but unfortunately it can have some damaging side effects. Our research found a plausible link between two types of chemotherapy and their impact on sperm in a very small number of men.

“These results require further systematic studies to see if there is a causal link between chemotherapy and sperm mutations, and if there is a way of identifying individuals at risk prior to treatment so they could take family planning measures, such as freezing their sperm prior to treatment. I would also like to thank the families that donated their genetic and health information to make this research possible.”

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