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Exome Sequencing Study Uncovers Mutations in Nine Genes Linked to Childhood Epilepsy

NEW YORK (GenomeWeb News) – Researchers from the Epi4K consortium and the Epilepsy Phenome/Genome Project have identified mutations in nine genes linked to two childhood forms of epilepsy, they reported in an online, early Nature paper yesterday.

Epilepsy is caused by the misfiring of nerve cells in the brain that bring about seizures as well as other symptoms, and these childhood epileptic encephalopathies are severe forms of the disorder that affect about one in 2,000 children, according to the researchers. In this study, the consortium narrowed in on two classic types of the disease, infantile spasms and Lennox-Gastaut Syndrome. Infantile spasms often lead to Lennox-Gastaut Syndrome, the researchers noted.

"Unlike some diseases, many of the genetic mutations associated with severe childhood epilepsies appear to be new mutations that are not inherited," Randall Stewart, a program director at the National Institute of Neurological Disorders and Stroke, which was one of the funders of the project, said in a statement.

The Epi4K study and the Epilepsy Phenome/Genome Project began in 2012 and 2007, respectively, to search for genetic mutations underlying epilepsy. In particular, the Epi4K group, led by David Goldstein at Duke University, is tasked with sequencing and analyzing the DNA of 4,000 epilepsy patients and their relatives to search for mutations.

Using exome sequencing of 264 trios of epilepsy patients and their parents — a subset of the main group comprised of patients who are the only ones in their family with epilepsy — Goldstein and his colleagues searched for de novo mutations that could be at the root of the patients' disease. From this, they found 439 putative de novo mutations, 329 of which were confirmed by Sanger sequencing.

Nine genes containing such de novo SNVs showed up in two or more of the probands, and five of those had been linked previously to epileptic encephalopathy. Two of the remaining genes, GABRB3 and ALG13, contained a number of mutations each and had never been linked before to epileptic encephalopathy. Goldstein and his team calculated that the final two genes actually appear in their dataset by chance alone.

"The take-home is that a lot of these kids have genetic changes that are unique to them," said UCSF's Elliott Sherr, a principal investigator of the Epi4K Epileptic Encephalopathy project. "Most of these genes have been implicated in these or other epilepsies [but] others were genes that have never been seen before."

The investigators also determined that the epileptic encephalopathy-related genes they uncovered were located in regions of the genome that don't tolerate change well. Through a scoring system they developed that drew on human population polymorphic data, they found that putatively damaging epileptic encephalopathy-linked genes were among the most intolerant to mutations. Some 90 genes, they added, are including among those intolerant ones and may confer risk of disease, with each mutation conferring a high risk.

Further, the genes linked to the disease were overrepresented by genes also affecting ion channels as well as ones linked to autism spectrum disorder, intellectual disability, and Fragile X Syndrome.

Through a protein-protein interaction analysis of the genes associated with infantile spasms and Lennox-Gastaut Syndrome, the researchers closed in on a network comprised of 71 proteins. Six of the genes the researchers uncovered with de novo mutations are known genes linked to epileptic encephalopathy, according to the Online Mendelian Inheritance in Man database. The network contains other epileptic encephalopathy-related genes that had not been picked up by the exome study, the researchers noted.

The researchers further pointed out six mutations that all affect subunits of the GABA ionotropic receptor, saying that this — and other interactions they observed — offers support for the hypothesis that rare variants linked to disease may converge on related pathways.

"One of the most fascinating and promising findings in this study is that many of the gene mutations affect molecules that are involved in a relatively limited number of cellular pathways," said UCSF's Daniel Lowenstein, who is one of the leaders of the Epilepsy Phenome/Genome Project. "This suggests that it may be sufficient to target therapies at a limited set of pathways rather than every mutated protein in every patient."