Study Traces Hypermutation in Children to Fathers’ Sperm

Researchers in the UK have traced cases of hypermutation in children to a higher rate of random mutations in their biological fathers’ sperm cells, caused either by chemotherapy prior to conception or to rare genetic defects in DNA repair.

Scientists from the Wellcome Sanger Institute and their collaborators analyzed data from over 20,000 UK families with children with suspected genetic conditions who participate in the Deciphering Developmental Disorders and 100,000 Genomes projects. From this, they identified 12 children with between two to seven times more mutations than the general population. The team linked the majority of these to increased mutations in the sperm of the biological father.

The research, published in Nature, shows that just under half of these fathers had been treated with certain types of chemotherapy earlier in life, which could be linked to the increased number of mutations in their sperm cells.

While these cases of hypermutation in children are rare, and in the vast majority of children will not lead to genetic disorders, hypermutation will increase the risk of a child having a rare genetic disorder. If further research confirms an impact of chemotherapy, patients could be offered the opportunity to freeze their sperm before treatment.

Most genetic disorders only occur when both copies of an important gene are damaged, resulting in a recessive disease. If only one copy is damaged, for example, by a new mutation, the remaining functioning copy of the gene will be able to prevent disease. However, a minority of genetic disorders, known as dominant disorders, occur when only one copy of a gene is damaged. It is these dominant disorders that can be caused by a single, random mutation.

One of the main factors influencing mutation rate is the age of the parents, with mutations increasing by 1.3 mutations per year in the fathers and 0.4 mutations per year in mothers. If there is a higher number of germline mutations, there is a higher risk of a child being born with a dominant disorder. However, hypermutation in children does not always mean they will have a dominant disorder. 

The current study found that children with hypermutation were rare among the participating families. As the number of children with hypermutations was only 12 out of around 20,000, these rates of increased mutations could not have been caused by common exposures, such as smoking, pollution, or common genetic variation.  For eight of these children, the excess mutations could be linked to their father’s sperm. It was possible to investigate in detail seven of the families, where the excess mutations came from the biological father. Two of the fathers had rare recessive genetic variants that impaired DNA repair mechanisms.

The other five men had all previously been treated with chemotherapy before conceiving a child. Three of these children had a pattern of mutations characteristic of chemotherapy using platinum-based drugs and the fathers of the other two children had both received chemotherapy with mustard-derived alkylating agents. It is currently unclear why these types of chemotherapies seem to impact the sperm more than the egg cells.  Linking the genetic data to anonymized health data did show, however, that most fathers and all mothers who had received chemotherapy prior to conceiving a child did not have children with a notable excess of mutations.

 “These findings could really help people with cancer consider family planning,” says Sir Mark Caulfield, from Queen Mary University of London, and former Chief Scientist at Genomics England.

The study also underscores the value of linking nationwide genetic data and routine clinical records in secure, anonymized and trustworthy ways to provide unique insights into unanticipated, but important, questions.