Identification of novel genes for autosomal dominant lateral temporal epilepsy in families without LGI1 mutations

The proposed project aims to identify novel genes causing autosomal dominant lateral temporal epilepsy (ADLTE). Auditory symptoms have been the main clinical indicator of ADLTE, leading to the discovery of mutations in the LGI1 gene. This gene, however, is mutated in less than 50% of ADLTE families and its function is still unclear. We will investigate a collection of Italian and American ADLTE families without LGI1 mutations by whole exome sequencing, a technology that allows for rapid sequencing of nearly all the protein coding genes of an individual. This powerful technique, however, reveals a high number of gene variants in each individual, thus making it difficult to distinguish true pathogenic mutations from apparently benign gene variants. We have already investigated our families by genome-wide linkage analysis using a large number of single nucleotide polymorphisms (SNPs) and have mapped several linkage signals that precisely define genomic regions were ADLTE-causative genes are more likely to reside. These linkage data will guide the search for novel ADLTE genes and lead to their identification. The function of novel ADLTE genes, if known, will clarify the molecular pathway underlying ADLTE. To understand the mechanisms of their action we will study the interactions of their protein products with the Lgi1 protein.