Genetic Mutation Identification Expands Epilepsy Phenotypes

Mutations were identified in 7 genes, including one for the first time.

PHILADELPHIA – Several newly-identified genes have been linked to epileptic encephalopathies through whole exome resequencing.

Data was presented at the 2015 American Epilepsy Society Annual Meeting.

Candace Myers, PhD, of the University of Washington, and colleagues sought to expand on the results of a previous study that identified 329 de novo mutations in 305 genes in 264 familial trios consisting of an affected child and unaffected parents.

In this study, Dr. Myers and colleagues performed targeted high throughput resequencing of 27 genes in which a de novo mutation was previously identified in one or more proband with infantile spasms or Lennox-Gastaut syndrome in 537 patients with diverse epileptic encephalopathies (EEs).

Sixteen patients were found to have de novo mutations in 7 of the previously identified genes, including ALG13, CACNA1A, DNM1, GABRB3, GNAO1, IQSEC2, and SLC1A2. The results establish a genetic diagnosis for approximately 3% of patients. Recurrent mutations accounted for 44% of pathogenic variants identified, with GABR3 accounting for the majority (n=6/537), explaining approximately 1% of the cohort.

“The first step in precision medicine is identifying the molecular cause of the disease, which will eventually allow us to treat the cause of disease rather than the symptoms. Often in the EEs, the diagnosis can evolve overtime, so it is very beneficial to have a molecular diagnosis for this patients,” Dr. Myers told Neurology Advisor

The resequencing also revealed two parents with mosaic germline mutations in two independent families with multiple people affected, an important finding with implications for family planning, Dr. Myers said.

With this genetic information, “you can start to get a good idea of phenotype, the natural history of the disease, and what drugs might work better for a population,” Dr. Myers said.

“I think the field is beginning to appreciate that some forms of epilepsy are genetic and in some cases, that changes medical management,” she continued. “A genetic diagnosis only affects treatment in a small percentage of patients but this will change over time and we really need physicians on board to help drive this understanding.”

For more coverage of AES 2015, go here.


  1. Myers C, McMahon J, Schneider A, et al. Abstract 1.315. Gene discovery in epileptic encephalopathies through targeted resequencing of candidate genes. Presented at: American Epilepsy Society Annual Meeting. Dec 4-8; Philadelphia.