Domain-dependent clustering and genotype-phenotype analysis of LGI1 mutations in ADPEAF.
OBJECTIVE
In families with autosomal dominant partial epilepsy with auditory features (ADPEAF) with mutations in the LGI1 gene, we evaluated clustering of mutations within the gene and associations of penetrance and phenotypic features with mutation location and predicted effect (truncation or missense).


METHODS
We abstracted clinical and molecular information from the literature for all 36 previously published ADPEAF families with LGI1 mutations. We used a sliding window approach to analyze mutation clustering within the gene. Each mutation was mapped to one of the gene's 2 major functional domains, N-terminal leucine-rich repeats (LRRs) and C-terminal epitempin (EPTP) repeats, and classified according to predicted effect on the encoded protein (truncation vs missense). Analyses of phenotypic features (age at onset and occurrence of auditory symptoms) in relation to mutation site and predicted effect included 160 patients with idiopathic focal unprovoked seizures from the 36 families.


RESULTS
ADPEAF-causing mutations clustered significantly in the LRR domain (exons 3-5) of LGI1 (p = 0.026). Auditory symptoms were less frequent in individuals with truncation mutations in the EPTP domain than in those with other mutation type/domain combinations (58% vs 80%, p = 0.018).


CONCLUSIONS
The LRR region of the LGI1 gene is likely to play a major role in pathogenesis of ADPEAF.
Department of Psychiatry, Columbia University, New York, NY, USA.
Yuan-Yuan
YY
Ho
Iuliana
I
Ionita-Laza
Ruth
R
Ottman
D017668:Age of Onset; D016208:Databases, Factual; D017034:Epilepsy, Frontal Lobe / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D011506:Proteins / Q000235:genetics*; D012893:Sleep Wake Disorders / Q000235:genetics*
D047908:Intracellular Signaling Peptides and Proteins; C116499:LGI1 protein, human; D011506:Proteins