New Childhood Epilepsy Genes Discovered

Pauline Anderson

August 15, 2013

Using a cutting-edge strategy called exome sequencing to search for de novo mutations, researchers have found genetic defects that might cause infantile spasm and Lennox-Gastaut syndrome (LGS), 2 devastating childhood epileptic encephalopathies.

Exome sequencing selectively targets critical protein-coding regions of the genome. The technique allows for analysis of larger samples than is practical with the alternative whole-genome sequencing.

Results of a new study suggest that exome sequencing may be highly effective in finding and confirming gene mutations linked to epilepsies and related disorders. Understanding the genetics of diseases should improve diagnosis, reveal pathogenic mechanisms, and lead to better future treatments.

"It appears that the time for using this approach to understand complex neurological disorders has arrived," said the study's lead author, David Goldstein, PhD, director of the Center for Human Genome Variation at Duke University Medical Center, Durham, North Carolina, in a press release from the National Institutes of Health (NIH). "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 study was published online August 11 in Nature.

Epilepsy Initiatives

Although the genetics of epilepsy has been vigorously pursued since the mid-1990s, with dozens of gene mutations for various forms of epilepsy now identified, almost all of them have been from patients with other affected family members.

But with initiatives such as the NIH-funded Epilepsy Phenome/Genome Project (EPGP), an international consortium of clinical centers in the United States and elsewhere, and Epilepsy 4000 (Epi4K), a series of worldwide dedicated research projects, scientists are now exploring whether de novo mutations affect critical genes for neuronal function.

The aim of Epi4K, a $25 million initiative largely funded by the NIH, is to screen patient genomes for relevant mutations, providing important information on the genetic basis of epileptic encephalopathies that generally don't run in families. Researchers are using cutting-edge technologies to sequence and analyze DNA, collected through the EPGP, from 4000 patients with epilepsy and their relatives.

For this new study, scientists used several statistical tools to analyze exome sequences of 264 children (149 with infantile spasms and 115 with LGS) and compared them to those of their parents, who do not have epilepsy. They confirmed 329 de novo mutations that are the most intolerant to functional genetic variation in the human population (P = 2.9 × 10-3). Among these are GABRB3, with de novo mutations in 4 patients, and ALG13, with the same de novo mutation in 2 patients. Both genes show clear statistical evidence of association with epileptic encephalopathy, said the study authors.

The researchers also demonstrated that epilepsy-causing mutations are concentrated in genes that are so sensitive to changes in the DNA sequence that even the slightest alteration can cause the gene not to work, leading to death or severe forms of diseases.

"These promising results highlight the strength of supporting large international research teams devoted to studying the genetics behind highly complex neurological disorders," commented Story Landis, PhD, director of NIH's National Institute of Neurological Disorders and Stroke (NINDS) in the statement.

Sensitive to Mutations

In their hunt for more genes with epilepsy-causing mutations, the researchers searched thousands of exome sequences from healthy volunteers who participated in the National Heart, Lung, and Blood Institute Exome Sequencing Project, according to the press release.

They looked for gene sequences that had only slight differences among patients because previous studies showed that these sequences are highly sensitive to mutations. The researchers estimated that up to 90 genes could carry epilepsy-causing mutations and that many of the mutations implicated in the risk of epilepsy have been previously associated with autism and other neurodevelopmental diseases.

"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," said Dr. Goldstein. "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."

More than 2 million people in the United States suffer from epilepsies. Infants and children have a greater chance of having the disorders than adults.

In addition to grants from NINDS, the study was funded by Finding a Cure for Epilepsy and Seizures and the Richard Thalheimer Philanthropic Fund.

Nature. Published online August 11, 2013. Abstract

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