A polygenic heterogeneity model for common epilepsies with complex genetics.

Approximately 40% of epilepsy has a complex genetic basis with an unknown number of susceptibility genes. The effect of each susceptibility gene acting alone is insufficient to account for seizure phenotypes, but certain numbers or combinations of variations in susceptibility genes are predicted to raise the level of neuronal hyperexcitability above a seizure threshold for a given individual in a given environment. Identities of susceptibility genes are beginning to be determined, initially by translation of knowledge gained from gene discovery in the monogenic epilepsies. This entrée into idiopathic epilepsies with complex genetics has led to the experimental validation of susceptibility variants in the first few susceptibility genes. The genetic architecture so far emerging from these results is consistent with what we have designated as a polygenic heterogeneity model for the epilepsies with complex genetics.