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Two Genes Appear to Be Associated with Epilepsy

SAN FRANCISCO—Two different genes seem to play a role in epilepsy, investigators in Philadelphia and Germany found based on studies of genome-wide associations and copy number variations in hundreds of epilepsy patients, as compared to thousands of healthy people.

Their comparisons point to two genes, MHY11 and CNTN4, which the investigators say may play a role in producing epilepsy. CNTN4 is already implicated in psychiatric disorders, whereas the MHY11 gene has not previously been identified as a disease suspect.

The genes are not involved in ion channels but instead appear to be active in forming the network of the brain during development, said Russ Buono, PhD, associate chief of staff-research at the Coatesville Veterans Affairs Medical Center, who presented the results here at the annual meeting of the Society for Neuroscience in November.

Dr. Buono, a research associate professor of neurology at Thomas Jefferson University Hospital and research scientist at the Children's Hospital of Philadelphia — and colleagues who are collecting and analyzing the blood samples — said that epilepsy is probably caused by thousands of alleles, and that these two are just part of the picture.

The genome-wide association study sought small variations in genes among people with common forms of generalized epilepsy, as well as focal epilepsies.

The different forms of the disease likely have different genetic players, Dr. Buono noted.

The investigators found gene deletions at two locations in chromosome 15 (five patients total) and one location at chromosome 16 (two patients) for a total of 2.4 percent of the patients with idiopathic generalized epilepsy (IGE). These changed chromosomes appear in 0.5 percent of controls (p = 1.5 × 10-4).

With copy number variation, the researchers also identified duplications at the CNTN4 locus found in two patients with IGE (p=0.03). By contrast, there were no copy number variations with focal epilepsy, as another group published earlier this year in July in the journal Brain.

SNPs in the gene MYH11 —the location of a CNV deletion on chromosome 16 — and the gene CNTN4 — the location of a duplication on chromosome 3 — reached significance (p = 1.3 × 10 −9 and 3.8 × 10 −8 respectively) in IGE.

The MHY11 gene is on a part of chromosome 16 that was previously implicated in copy number variation in autism and schizoaffective disorder. This gene codes myosin heavy chain, mostly involved in contractile functions, but a gene near one end of this protein is involved in neuronal migration as well.

The other marker that reached significance, CNTN4, the contactin 4 protein, a cell adhesion factor, also is linked to schizoaffective disorders and autism, Dr. Buono said.

“Genetics is believed to be a factor in approximately 50 percent of epilepsy cases,” said Martin Gallagher, MD, PhD, assistant professor of neurology at Vanderbilt University in Nashville, and a researcher in its Kennedy Center for developmental studies, who chaired the session. Most genetic epilepsy cases result from the complex inheritance of multiple interacting genes rather than the simple inheritance of a single gene. .

“The investigators found an association only within one subset, but it was greater than in controls. It's one approach to find possible genomic and genetic effects that can contribute to epilepsy.”


Kasperaviciute D, Catarino CB, Heinzen EL, et al, Common genetic variation and susceptibility to partial epilepsies: a genome-wide association study. Brain 2010; 133(Pt 7):2136-47. E-pub 2010 Jun 3.