New Childhood Epilepsy Genes
August 12, 2013

International Researchers Find New Epilepsy Genes

Brett Smith for - Your Universe Online

A large, international research consortium has identified 25 new mutations on nine key genes responsible for childhood epilepsy. Because these mutations are not inherited, the scientists used a state-of-the-art genetic technique called exome sequencing to identify them.

"It appears that the time for using this approach to understand complex neurological disorders has arrived," said David Goldstein, study leader and director of the Human Genome Variation Center at Duke University Medical Center. "This moderately-sized study identified an unusually large number of disease-causing mutations and provides a wealth of new information for the epilepsy research community to explore."

The latest study, which was published in the journal Nature, is one result of a $25 million project involving over 40 research institutions on three continents called Epilepsy 4000 (Epi4K). The project is dedicated to sequencing and analyzing DNA from 4000 epilepsy patients and their immediate families. Under a researcher collective known as the Epilepsy Centers without Walls, project scientists share DNA sequences and patient information among the project’s various institutions.

Project scientists suggested that the mysterious nature of epilepsy demands just such a large international undertaking.

“The limitations of what we currently can do for epilepsy patients are completely overwhelming,” said Dr. Daniel Lowenstein, a UCSF neuroscientist who is currently supervising the Epilepsy Phenome/Genome Project (EPGP). “More than a third of our patients are not treatable with any medication, so the idea of finding specific drug targets, instead of a drug that just bathes the brain and may cause problems with normal brain function, is very appealing.”

To identify the novel mutations, scientists collected clinical data and DNA through the EPGP.

"The Epilepsy Phenome/Genome Project, with its massive data set, laid the groundwork for this study, and the key to this success has been the extraordinary level of collaboration among more than 115 investigators, study coordinators and administrative personnel involved in both EPGP and Epi4K," Lowenstein said.

In the study, researchers analyzed exomes culled from the project DNA samples. Exome DNA sequences are used in the production of all the body’s proteins. Using exome comparisons between 264 children with epilepsy and their parents who do not have the condition, the geneticists were able to find disease-causing mutations in six genes – four previously identified mutations and two implicated for the first time.

The team also found that epilepsy-causing mutations are concentrated in highly sensitive genes – genes so sensitive that the smallest change can lead to death or severe forms of disease.

‘The take-home is that a lot of these kids have genetic changes that are unique to them,” said Dr. Elliott Sherr, principal investigator of the Epi4K Epileptic Encephalopathy project. “Most of these genes have been implicated in these or other epilepsies – others were genes that have never been seen before – but many of the kids have one of these smoking guns.”

"One of the most encouraging aspects of this study is that we're beginning to see how best to interpret and make effective use of exome sequence data," Goldstein said. "We anticipate that further studies will identify many new disease-causing genes and we intend to develop a watch list of the genes which summarizes their clinical characteristics in way that will be helpful for doctors, patients, and researchers."