Abstracts

Rationale: Gene discovery in idiopathic generalized epilepsy has been progressing rapidly in the past decade, but the mutations are often found in single families with very limited application to the sporadic forms of epilepsy. Autosomal recessive epilepsy has traditionally been resistant to gene identification because families are usually small and are not sufficient for linkage analysis. However, gene discovery in autosomal recessive epilepsy may provide insight into a new class of genes that play a role in sporadic idiopathic generalized epilepsy. We have identified a family with a distinct form of autosomal recessive epilepsy that is complicated by ataxia and tremors. This family is consanguineous and large enough for independent linkage analysis, which allows for homozygosity mapping. We were able to map the gene to the pericentromeric region of chromosome 12. Within this region, we identified 10 to 15 candidate genes, but were able to exclude most of them by direct sequencing and other approaches. Methods: Mutation detection in candidate genes is approached by direct sequencing and evaluation of identified variants by calculating population variant allele frequency. We are currently exploring the role of mutational mechanisms other than point mutations in these candidate genes. We also are in the process of identifying other families with similar phenotypes to narrow down the region further.Results: We selected the following outstanding candidate genes for our preliminary pass based on their function or their expression pattern: ASB8, LRRK2, SLC38A2, SLC2A13, NELL2, FLJ20489, GLT8D3, ALG10, ALG10B, and GLT8D3. We used direct sequencing to identify mutations in the exons and intronic splice sites for all of the aforementioned genes. Of the possible 117 exons to sequence, all but 16 were thoroughly completed. We found no etiologic mutations in those exons. We also examined LRRK2 for exonic deletions or duplication.Conclusions: The above mentioned genes were evaluated for point mutations and small deletions or duplications. We are currently expanding our candidate gene list and exploring other mechanisms beyond point mutations and small deletions/ duplications in these and other candidate genes. Since we did not find any mutations in the above mentioned candidate genes, we were able to preliminarily exclude them as the primary source of disease causing mutations in our family. (This research was funded through the gracious support of the American Epilepsy Society.)