Gene variant could protect against ultra-rare seizure disorder, fruit fly research finds microbiologystudy

One in 10 Americans live with a rare disease, which often lacks effective treatments. Such is the case for PIGA-CDG, an ultra-rare genetic disease that causes seizures and developmental delays. Treatments for the disease are limited to symptom management.

The severity of PIGA-CDG symptoms varies widely, hinting that multiple genes might influence symptoms. Knowing which genes are involved could lead to better treatments, but the very small number of PIGA-CDG patients makes many standard genetic analysis techniques impossible.

Now, a team of University of Utah Health researchers led by first author Holly Thorpe and senior author Clement Chow, Ph.D., has used a combination of pedigree analysis and fruit fly genetics to identify a gene variant that may protect against PIGA-CDG.

The results are published in The American Journal of Human Genetics.

Everyone with PIGA-CDG has a change in a gene called PIGA. But the scientists had noticed that in one family that included people with the disease, some members were perfectly healthy—despite having the same change in the PIGA gene as their affected relatives.

The researchers looked for secondary genetic changes that only the unaffected family members had, then made a shortlist based on the predicted function of the genes involved.

Then, they approximated those genetic changes in fruit flies. Flies that have reduced PIGA function in their neurons have seizures and difficulty moving. But flies that have reduced PIGA function and reduced function of one of the shortlist candidate genes move more readily and have less severe seizures.

This gene, called CNTN2, is altered in family members who have a change in PIGA but do not have symptoms of PIGA-CDG.

The researchers believe that changes to CNTN2 likely protect people against the disease. This finding could eventually lead to better therapies for PIGA-CDG.

Chow, associate professor of genetics in the Spencer Fox Eccles School of Medicine at University of Utah Health, also says that the approach of combining pedigree analysis with fruit fly genetics could be very valuable for rare disease research more generally.

“If we can use this strategy more broadly, I think we can help address the problem of phenotypic variation in rare diseases,” he says. “I am hoping that this will be used as a roadmap moving forward.”