Researchers Discover 8 New Epilepsy Genes

November 10, 2017

MONTREAL -- November 10, 2017 -- A recent study examining 200 children with epileptic encephalopathy and their parents could lead to the development of a more rational antiepileptic treatment strategy.

Researchers identified 8 new genes involved in this type of epilepsy thanks to their use of whole-genome sequencing, which had never been done before in an epileptic study of this scope.

“By learning about the pathophysiology of the genes involved, we hope to move towards a more appropriate treatment and decrease the amount of time spent on cumbersome medical assessments,” said Jacques Michaud, MD, CHU Sainte-Justine, and Université de Montréal, Montréal, Québec.

The findings, published in the American Journal of Human Genetics, not only validate the systematic approach to whole-genome sequencing in clinics, they also demonstrate that de novo mutations, otherwise known as spontaneous mutations not inherited by parents, are the main cause of this severe type of epilepsy.

“We were able to identify the specific genetic change that led to epileptic encephalopathy in 32% of our subjects, which is quite remarkable,” said Dr. Michaud. “These children underwent extensive medical assessments, but no one could find the main cause. If we had conducted this analysis earlier, before all the medical tests were performed, it is possible the yield would have been even greater.”

Dr. Michaud believes that using whole-genome sequencing in a clinical setting has added value compared with the more conventional approach based on the exome, which represents less than 2% of the genome.

“Thanks to whole-genome sequencing, we were able to identify a larger number of mutations,” he said. “In the future, the development of new methods for analysing whole-genome sequencing data will make it possible to improve diagnostic performance.”

The researchers performed whole-genome sequencing in 197 individuals with unexplained developmental and epileptic encephalopathy and pharmaco-resistant seizures and in their unaffected parents. They focused their attention on de novo mutations (DNMs) and identified candidate genes containing such variants. They also sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with developmental and epileptic encephalopathy and by mining various sequencing datasets.

By combining these strategies, the researchers were able to provide a causal link between developmental and epileptic encephalopathy and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25.

The main cause of developmental and epileptic encephalopathy in these individuals was de novo point mutations (53 of 63 solved cases), followed by inherited mutations (6 of 63 solved cases).

In the context of epilepsy de novo mutations seem to involve mechanisms of gene disruption that are unlike those involved in intellectual disability.

“Mutations in epilepsy tend to affect specific areas of the gene, whereas mutations associated with intellectual disability are more often distributed throughout the entire gene,” said Dr. Michaud. “This pattern suggests that mutations in epilepsy impart specific properties to their corresponding proteins, which may then manifest as a decrease or increase in protein activity. In intellectual disability, mutations will simply deactivate the gene.”

Knowledge of these mechanisms of action is crucial for the development of personalised epilepsy treatments. However, much more work is needed before these treatments can be harmonised with patients’ genetic profiles.

Reference: http://dx.doi.org/10.1016/j.ajhg.2017.09.008

SOURCE: University of Montreal

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