Newly identified genetic factors drive severe childhood epilepsies

The findings by an international research collaboration, which includes investigators from Duke Medicine, appear Aug. 11 in the journal Nature.

Epileptic encephalopathies are a devastating group of severe brain disorders characterized by the onset of seizures at an early age. The seizures are often accompanied by cognitive and behavioral issues, which can hinder the quality of life of affected children and their families.

The cause of epileptic encephalopathies is largely unknown; while genes are believed to play an important role, specific genes have only been identified in a small number of cases.

"One important aspect of the study is that we identified an unusually large number of distinct disease-causing mutations -- 25 in total, all of which were de novo mutations. These mutations will be an invaluable resource to scientists working to elucidate the underlying causes of the epilepsies," said study author David Goldstein, PhD, director of the Duke Center for Human Genome Variation.

A de novo mutation is a new alteration in a gene that appears for the first time in a family, and results from a genetic mutation in a parent's germ cell (egg or sperm).

Learning more about the disorders' origin will guide development of effective therapies, which is the goal of Epi4K, an international research consortium funded by the National Institute of Neurological Diseases and Stroke (NINDS).

"This research focusing on epileptic encephalopathies is the first large-scale project of Epi4K," said study author Erin Heinzen, PhD, assistant professor of medicine in the Division of Medical Genetics at Duke. "The study was designed to identify de novo mutations and search for ones that contribute to risk."

The Epi4K researchers partnered with the Epilepsy Phenome/Genome Project, another NINDS-funded group working to unlock the mysteries of epilepsy. Led by Daniel Lowenstein, M.D., professor of neurology at the University of California, San Francisco, the researchers in the Epilepsy Phenome/Genome Project gathered genetic information on 264 children with epileptic encephalopathies and their parents.

The Epi4K researchers then focused on identifying all new mutations in the children using next-generation sequenced data, which looks at the part of genome that encodes protein. The Center for Human Genome Variation at Duke conducted this analysis, and confirmed 329 de novo mutations. Most of these mutations had no connection to the risk of disease, but the researchers showed that a fraction of them strongly influence risk.

The researchers saw that the genes already known to cause epileptic encephalopathies carried multiple de novo mutations. However, they found multiple de novo mutations in two additional genes- GABRB3 and ALG13 -- not previously connected to epileptic encephalopathies. Developing and applying new statistical approaches to determine risk factors, the researchers identified a statistical excess of mutations of those genes, and concluded that the two new genes were influencing epileptic encephalopathies.

Combining the known genetic mutations with the newly identified genetic mutations, the researchers have now pinpointed the genetic cause of more than 10 percent of epileptic encephalopathies.

"It won't be long before a reasonable fraction of epileptic encephalopathy patients come into the clinic genetically explained," said Goldstein. "Right now, the vast majority of patients are genetically unexplained, and in consequence, genetics plays little role in patient care. What we see here is a clear direction for the systematic identification of the genes responsible for severe epilepsies, and the beginnings of a program to use that information to improve the care of patients with epilepsy. It's about as encouraging as we could have hoped for when we started this work."

Genetics can be applied to clinical care in a variety of ways. Most fundamentally, genetics can provide new information about the underlying biology of the disease, suggesting new directions for treatment. Genetics can also help stratify patients in ways that are meaningful both for prognosis and for optimizing treatment.

In the case of epileptic encephalopathies, tailoring treatment to each mutation would be challenging, given the rarity of the mutations. However, the researchers observed that the mutations identified organize into a small number of biologic pathways. Focusing drug development efforts on the pathways involved would allow physicians to treat patients based on the affected pathways.

"These promising results highlight the strength of supporting large international research teams devoted to studying the genetics behind highly complex neurological disorders," said Story Landis, PhD, director of the NINDS.

The study resulted from a collaboration between researchers at more than 40 institutions across three continents. A full list of authors can be found in the manuscript.

The research was supported by the NINDS (NS053998, NS077364, NS077274, NS077303, and NS077276), Finding a Cure for Epilepsy and Seizures, and the Richard Thalheimer Philanthropic Fund.