Abstracts

Rationale: Epilepsy affects 1% of the world population with one-third of patients being refractory to anti-epilepsy drugs. Most patients (60%) have no known symptomatic cause and are considered to have idiopathic or presumed genetic epilepsy. Temporal lobe epilepsy (TLE) is the most common form of focal or generalized epilepsy. Genome-wide association studies of patients with TLE have yielded little insight into the pathophysiology of this disorder, suggesting that rare heritable variants or de novo somatic mutations might be causative. We investigated whether somatic mutation involving long interspersed element-1 (LINE-1) retrotransposons might explain some idiopathic TLE cases. Methods: Patients with medication-resistant TLE underwent electroencephalograph-directed craniotomy in which the temporal lobe was resected.  Samples of temporal cortex (BA38) from control subjects or TLE patients (N=33 each) were analyzed for LINE-1 content by PCR-based LINE-1 amplification and next-generation sequencing.  Results: Bioinformatics analysis identified genomic positions of novel LINE-1 sequences.  LINE-1 elements specific to cases and controls were identified. Two gene lists from intra-genic LINE-1 sequences, one for cases and another for controls, were used as input for PANTHER gene ontology and pathway analyses.  PANTHER analyses showed Bonferroni-corrected statistically significant enrichments for pathways and ontologies in TLE cases only.  A number of LINE-1 sequences were detected within genes having known associations with seizures/epilepsies among TLE cases and controls; however, the seizure/epilepsy-associated intra-genic LINE-1 sequences had distinct locations between the groups.  Each novel LINE-1 is currently being validated and assessed for functional significance.  Conclusions: Preliminary results of this study suggest that LINE-1 retrotransposons may contribute to the etiology of some cases of idiopathic TLE. Funding: NIH Grant: 1R21NS095756-01