Detecting mosaic variation in parents improves genetic counseling

Postscript

April 25, 2018

Detecting mosaic variation in parents improves genetic counseling

Mosaic variations in the cells of a parent may explain why childhood epilepsy strikes twice in some families

Advances in genetic testing offer new insights to parents who have a child with a rare but serious form of epilepsy, epileptic encephalopathy (EE), found in one of about every 2,000 births and characterized by developmental disabilities as well as horrible seizures. Previously, it was thought that EE occurred at random, but it is now known that EE is often caused by a new genetic mutation in the child. These mutations are rarely present in the parents, so they are counseled that it is unlikely that they will have a second child with EE.

New ways of sequencing the human genome mean geneticists and genetic counselors have much more to say to parents who wonder if future children might carry the disease, says Dr. Heather Mefford, associate professor of pediatrics (genetic medicine) at the University of Washington School of Medicine and deputy scientific director of the Brotman Baty Institute for Precision Medicine. She is the co-senior author of findings published this week in the New England Journal of Medicine.

These advances offer insights for all of us because they are part of the growing study of what scientists call mosaicism. Many of us do not have just one genome in us. We are made of cells that may have different genotypes buried deep within us.

“A mosaic mutation happens sometime after fertilization when cells are dividing, which requires copying all of the DNA. If one of those cells makes a copying error, that introduces a mutation. All the cells that come from that cell will carry the same mutation. So you end up with a mosaic pattern where some cells have the mutation and some cells don’t. That’s the mosaic,” Mefford said.

graphic showing effectiveness of test
Before advanced gene testing, parents were often told a chance of having a second child with epilepsy was 1 percent. Scientists announced this week that new testing allows them to identify mosaic mutations that were previously not discoverable inside parents. So now we know a small percentage of parents with these mutations account for a high percentage of instances where a second child could have epilepsy.

The fact that, say, 10 percent of your cells scattered throughout your body might be different than other cells may be completely unimportant. But if 10 percent of your sperm or oocytes have a disease-causing mutation, that could be a big problem if the mutation is passed on to one or more children.

A big question from any parent of a child with epilepsy is: What are the odds that our other children might have this condition? For decades, parents whose child had epilepsy were told there’s a 1 to 5 percent chance that other children might inherit the mutation. This was based on clinical evidence – the numbers of reoccurrences physicians saw in the clinic.

But armed with more precise testing, the geneticists found parental mosaicism that wasn’t easily detected before in about 10 percent of families of children with EE, putting these families at higher risk of passing the mutation to another child. What this means in practical terms is that this small group probably accounts for most of the reoccurrences. Thus, for some parents, there’s good news. If this parental mosaicism was not detected, the odds of having another such child with EE could be much less than 1 percent.

“We have the technology to pick out mosaic cells in a sea of otherwise normal cells. The percentage of families where we can identify mosaicism in the parent is higher than most of us thought it would be. While the overall recurrence risk (across all families) is about 1 percent,  for those families where we can find the mosaic mutation in the parents, it’s not a 1 percent risk. It’s much higher than that. And we now have the tools to help give them that information, and help them with better family planning and decision-making down the road,” Mefford said.

“Our study focused on patients with severe epilepsy. But the finding that 10 percent of the parents have mosaicism may actually apply to a broad range of other disorders that are apparently due to new genetic mutations, including autism and intellectual disability." Mefford said.

Other UW Medicine co-authors of the publication include: lead author Candace MyersAlison Muir, Zoe Thuesmunn, Allison KnuppAmy Lacroix and Michele Mehaffey.

Media contact: Contact Walter Neary (wneary@uw.edu) to speak with one of the authors.

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