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Researchers Link De Novo Mutations to Epileptic Encephalopathies

NEW YORK (GenomeWeb) – In the American Journal of Human Genetics, researchers from three consortia report a prominent role for de novo mutations in epileptic encephalopathies.

By combining exome sequencing data from more than 350 parent-child trios, the researchers uncovered some 430 de novo mutations in the patients, more than expected based on the number of de novo mutations found in controls. Additionally, for 12 percent of the patients, the researchers traced the cause of their disease to such a de novo mutation.

"[I]t is the first time a significant proportion of genetic epilepsies can be explained through molecular findings," said University Medical Center Schleswig-Holstein's Ulrich Stephani, a member of the EuroEPINOMICS-RES consortium, in a statement.

In previous work, the Epi4K/Epilepsy Phenome/Genome Project had homed in on a handful of de novo mutations linked to epileptic encephalopathies, and now by folding in additional samples from EPGP and EuroEPINOMICS-RES consortia, they aimed to uncover additional de novo mutations and examine their pathogenicity.

Through their analysis of the exome sequencing data generated from the trios, Stephani and his colleagues identified 429 de novo mutations in the cases, or a mean 1.2 de novo mutations per person. About 14 percent of those were predicted to be loss-of-function mutations.

Through a likelihood analysis, Stephani and his colleagues calculated that individuals with epileptic encephalopathies had more exonic de novo mutations, as compared to controls. They also had an excess of de novo mutations that fell into so-called hot zones. And some 12 percent of the individuals with epileptic encephalopathies, the researchers estimated, have disease-causing de novo mutations in protein-coding regions.

"These findings underscore the prominent role of de novo mutations in the etiology of epileptic encephalopathies," the researchers said in their paper.

Some 19 genes, the researchers found, had a de novo mutation in two or more probands.

Five probands, though, harbored de novo mutations in DNM1, which had not previously been linked to disease. The DNM1 gene, the researchers noted, encodes dynamin-1, a GTPase that is expressed in the brain and involved in synaptic vesicle endocytosis and membrane recycling.

All five mutations in DNM1 the researchers uncovered were substitutions that affected highly conserved residues.

This led Stephani and his colleagues to hypothesize that a DNM1 mutation could affect synaptic vesicle recycling, which then could impair the firing of inhibitory synapses and lead to seizures. They cautioned, though, that closer study of the five mutations they found is needed.

A number of the genes the researchers found with de novo mutation, including DNM1 and others, form an interacting network of genes encoding proteins involved in synaptic junction transmission.

Mutations in two other genes — GABBR2 and RYR3 — were present in multiple probands, and they, too, form part of this protein network. These two, along with FASN, are also strong candidate genes for epileptic encephalopathies, the researchers noted.

Such genetic heterogeneity in epileptic encephalopathies underscores the need for a centralized data repository to speed the discovery of genes involved in the conditions, the researchers argued.

"These genes will hopefully tell us a bit more about the underlying disease mechanisms and how we can address them with new treatments," added Ingo Helbig from Kiel University and the Children's Hospital of Philadelphia.

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