Abstracts

Rationale: The leucine-rich, glioma inactivated 1 gene (LGI1) encodes a secretory protein with two major functional domains: the N-terminal leucine-rich repeats (LRR) and the C-terminal epitempin repeats (EPTP). Mutations in LGI1 cause autosomal dominant partial epilepsy with auditory symptoms (ADPEAF) (OMIM600512), a focal epilepsy syndrome with auditory symptoms as prominent ictal manifestations, with an estimated penetrance of 67%. We conducted a systematic study to investigate genotype-phenotype correlation in ADPEAF with two hypotheses: 1) the distribution of ADPEAF-causing mutations is not uniform within the LGI1 gene, and 2) phenotypic features in affected individuals differ depending on the coding domain in which mutations are found. Methods: Clustering of mutations within the gene was analyzed for all 30 previously reported ADPEAF-causing mutations using a sliding window approach. Phenotypic and genetic information were analyzed on 52 patients with idiopathic focal unprovoked seizures from 11 ADPEAF families with LGI1 mutations. Bivariate analysis was performed using general estimating equations to test for association between mutation site and auditory symptoms. 95% confidence intervals (CI) for the odds ratios (OR) were calculated by the logit method. Results: ADPEAF-causing mutations clustered significantly in the LRR domain (exons 3-5) of LGI1 (p =0.001). The coding domain in which mutations were located was not associated with disease penetrance. Auditory symptoms were present in 91% of patients with mutations in the LRR domain and 73% of patients with mutations in the EPTP domain (OR=3.7; 95% CI=1.1-12.5, p =0.038). Conclusions: ADPEAF-causing mutations cluster significantly within the LRR region of the LGI1 gene, and mutations in this region are also associated with an increased likelihood of manifesting auditory symptoms in ADPEAF.