A study at the University of Montreal (Quebec, Canada) has examined 200 children with epileptic encephalopathy and their parents. Utilizing whole-genome sequencing, a technique never before used in epileptic studies of this scale, the team discovered eight novel genes involved in the epilepsy type. The study was published in the American Journal of Human Genetics.
Approximately 30% of children do not respond to anti-epileptic drugs, leaving neurologists without a clear way to approach treatment. Often the only option is to attempt to find a working combination through trial and error. This already arduous task is compounded by variable mutations from child to child, creating epilepsy symptoms which do not clearly reflect their cause.
In this trial, however, it was demonstrated that de novo mutations are the primary cause of epileptic encephalopathy. Where epilepsy is concerned, authors, Jacques Michaud (University of Montreal), suggested that de novo mutations seem to involve differing gene-disruption mechanisms from those found in intellectual disability: Genes involved in epileptic mutations affected specific areas of the genes. In contrast, mutations involved with intellectual disability permeated the entire gene, simply deactivating them rather than impacting particular proteins.
The results have also validated the systematic approach to whole-genome sequencing in clinics. Michaud is an advocate for using whole-genome sequencing, believing that it has added value in a clinical setting when compared to conventional exome-based approaches. Knowledge of the genetic mechanisms could be crucial for development of personalized epilepsy treatments, though further work is necessary before treatments can be attuned to individual genetic profiles.
Michaud summarized: “Thanks to whole-genome sequencing, we were able to identify a larger number of mutations. In the future, the development of new methods for analyzing whole-genome sequencing data will make it possible to improve diagnostic performance.”
Sources: Michaud JL, Minassian BA, Rossignol E et al. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies. Am. J. Hum. Genet. 101(5), 664–685 (2017); www.eurekalert.org/pub_releases/2017-11/uom-rde110617.php