In a new study on children with severe forms of epilepsy, researchers have found the genetic copying mistake that causes the severe epilepsy in children can be found in their parents who do not have epilepsy.

“The research findings are important for reproductive counseling because these young parents are often in the middle of forming their families,” says one of the researchers Associate Professor Lynette Sadleir, from the University of Otago, Wellington.

The study, a collaborative research project between the University of Washington, University of Melbourne, and University of Otago, Wellington, has just been published in New England Journal of Medicine.

“Our collaborators in Seattle studied the genes in blood from parents of New Zealand and Australian children with severe epilepsies,” explains Sadleir.

Severe neurological conditions in children, including epilepsy and autism, are increasingly recognized to be due to de novo disease-causing genetic variants. De novo means the genetic copying mistake occurs in the child and is not found in either of their parents.

“Parents with a child with a de novo variant are informed that they have 1% chance of having a second child with the neurological disorder,” she says.

The researchers found that in around 8% of apparent de novo cases, one of the parents is actually ‘mosaic’ for the genetic change. Mosaicism is when the genetic change is not in every cell in the body but rather in a very low proportion of the cells.

“Mosaicism occurs when the copying mistake in the gene happens later in fetal development. If the genetic copying error is in the cells of the reproductive organs but not the brain, the parent does not clinically have any neurological problems, but can pass on the genetic copying error to 50% of their children,” says Sadleir.

“In this study, we looked at children with severe epilepsies and apparent de novo genetic mutations as based on standard clinical type testing,” she says.

“These severe epilepsies, known as epileptic encephalopathies, occur in normal children who start to have many seizures at a young age and lose developmental skills.”

“One in four of these children will die within 20 years of seizure onset and surviving children are left with significant cognitive, behavioral, and movement difficulties.”

“Our collaborators in Seattle used a technique that was able to find low levels of the genetic change not detectable on standard clinical testing. Usual parental clinical testing looks for the child’s genetic changes in at least 30 copies of the gene in their parent.”

"But this method looks at over 200 copies of the gene so can detect very low levels of the genetic change in the parent.”

This finding radically changes reproductive decision-making for parents, and likely applies to other severe genetic human diseases.

“Our study suggests that this kind of mutational analysis for parental mosaicism should be routine for families undergoing reproductive counseling,” says Sadleir.

“If the parent is ‘mosaic’; ie, has the genetic change in a very low proportion of the cells, the risk of having another affected child jumps up to 50%. In New Zealand, a finding of mosaicism in a parent could mean a family will qualify for pre-implementation genetic testing, allowing them to select an embryo without the mutation.”