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Rare cases of high genetic mutation linked to fathers’ chemotherapy

A study published in Nature by scientists from the Wellcome Sanger Institute and elsewhere, indicates that some rare cases of high genetic mutation rates in children — known as hypermutation — are linked to the father receiving chemotherapy.

A child typically has around 60 to 70 mutations that their biological parents don’t have. These mutations are responsible for genetic variation and many genetic diseases. Parental age explains a large proportion of genetic variance, but little is known about individuals with a large number of germline hypermutations.

To better understand the cause of extreme mutation rates, the scientists analysed the genome-wide sequences of over 20,000 families with rare genetic diseases to identify children that had unusually high mutation rates.

Chemotherapy-induced hypermutation is rare

The study found that children with hypermutation (between two and seven times higher than average) were rare among the families; only 12 children out of around 20,000 had an increased rate of mutations, and these were not due to common exposures, such as smoking or pollution, or common genetic variation.

In most families (9 out of 12), the excess mutations came from the father. Two fathers had rare recessive genetic variants that impaired DNA repair mechanisms. In five of the families, the father had been treated with chemotherapy before conceiving a child. Three of the children had a pattern of mutations characteristic of platinum-based chemotherapy and the fathers of the other two children had received chemotherapy with mustard-derived alkylating agents.

Hypermutation does not lead to genetic disease

By linking the genetic data to anonymised health data, the researchers showed that most fathers and all mothers who had received chemotherapy before conceiving a child did not have children with a notable excess of mutations.

“Our results suggest that the germline is well-protected from mutagenic effects, hypermutation is rare, the number of excess mutations is relatively modest and most individuals with a hypermutated genome will not have a genetic disease,” they write in the manuscript.

The authors note that only a few individuals receive chemotherapy before having children, so exposure to chemotherapy cannot explain a large proportion of the remaining variation in germline-mutation rates. To better comprehend the implications of these findings for patients who receive chemotherapy before having children, the next steps of research will involve targeted studies (such as cancer survivor cohorts) to evaluate the effects of different chemotherapeutic agents on germline mutations.

Written by Charlotte Harrison, Science Writer

Image Credit: Canva