Major Susceptibility Genes for Common Idiopathic Epilepsies: ELP4 in Rolandic Epilepsy and BRD2 in Juvenile Myoclonic Epilepsy

Clinical observations confirm that the idiopathic epilepsies are neurodevelopmental disorders strongly influenced by genetic factors. Genetic epidemiological studies prove major genetic influences on two common forms of idiopathic epilepsy to be discussed here: rolandic epilepsy (RE) and juvenile myoclonic epilepsy (JME). The common forms of these idiopathic syndromes have a complex genetic inheritance and this fact complicates finding and elucidating the susceptibility genes as well as proving their pathogenic role. Genetic heterogeneity and phenotype definition are much more serious factors in studying common complex epilepsies than they are in the study of densely affected epilepsy pedigrees showing Mendelian inheritance. In complex disorders, several genes and sometimes environmental factors are believed to contribute to disease etiology; as a result, proving a causative role for any one gene, in a genetic model involving multiple genes, can present a challenge.

In this chapter, we first review the methodological issues associated with analyzing complex genetic disorders, then explain the strategy that we have used in investigating these two particular syndromes. Genomewide linkage analyses and fine-mapping have resulted in the identification of susceptibility genes ELP4 in Rolandic epilepsy and BRD2 in juvenile myoclonic epilepsy. We discuss the evidence in favor of a pathogenic role for each gene and the further steps that are required to establish causality.