The epilepsies are a common, clinically heterogeneous group of disorders defined by recurrent unprovoked seizures 1 . Here we describe identification of the causative gene in autosomal-dominant partial epilepsy with auditory features (ADPEAF, MIM 600512), a rare form of idiopathic lateral temporal lobe epilepsy characterized by partial seizures with auditory disturbances 2,3 . We constructed a complete, 4.2-Mb physical map across the genetically implicated disease-gene region, identified 28 putative genes ( Fig. 1) and resequenced all or part of 21 genes before identifying presumptive mutations in one copy of the leucine-rich, glioma-inactivated 1 gene (LGI1) in each of five families with ADPEAF. Previous studies have indicated that loss of both copies of LGI1 promotes glial tumor progression. We show that the expression pattern of mouse Lgi1 is predominantly neuronal and is consistent with the anatomic regions involved in temporal lobe epilepsy. Discovery of LGI1 as a cause of ADPEAF suggests new avenues for research on pathogenic mechanisms of idiopathic epilepsies.Correspondence should be addressed to R.O. (e-mail: ro6@columbia.edu). NIH Public Access Author ManuscriptNat Genet. Author manuscript; available in PMC 2008 December 22. Published in final edited form as:Nat Genet. 2002 March ; 30(3): 335-341. doi:10.1038/ng832. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptIn 1995 we mapped the ADPEAF locus to a 10-cM region on chromosome 10q24 in a single extended pedigree 2 . Linkage was subsequently reported to an overlapping interval in another large family, narrowing the minimal genetic region to approximately 3 cM, assuming the causative gene was the same 4 . Analysis of additional pedigrees confirmed the linkage but failed to narrow the region further 5-7 . To screen for disease-related mutations, we resequenced all coding-exon and bordering-intron sequences from positional candidate genes in the overlap interval in one affected individual from each of three ADPEAF pedigrees showing linkage to chromosome 10q24 (families 6610, A and B; Fig. 2) 2,7 . We then genotyped putative diseaserelated mutations in all available family members from the three linked pedigrees, all family members from two smaller families with ADPEAF (families C and D; Fig. 2) and 123 unrelated control individuals.Resequencing of LGI1 identified presumptive mutations in each of the five families with ADPEAF (Table 1 and Fig. 2). All tested affected individuals from the five families harbored a single copy of a putative disease mutation, as did all obligate carriers and individuals classified as 'unknown' who were found to carry the disease-linked haplotype (Fig. 2). Several unaffected individuals also carried the disease haplotype and presumptive mutation. Whether these individuals manifest subclinical signs of disease or have undergone recent changes in affection status is not yet known, but the results are consistent with our previous estimate of 71% disease-gene penetrance in family 6610 (ref.2).To di...

LGI1 mutations are a common cause of autosomal dominant partial epilepsy with auditory features. Current data do not reveal a clinical feature that clearly predicts which families with autosomal dominant partial epilepsy with auditory features have a mutation. Some families with LGI1 mutations contain individuals with idiopathic generalized epilepsies. This could result from either an effect of LGI1 on risk for generalized epilepsy or an effect of co-occurring idiopathic generalized epilepsy-specific genes in these families.

Citation for final published version:Thomas, Rhys 2017. Ultra-rare genetic variation in common epilepsies: a case-control sequencing study. Please note: Changes made as a result of publishing processes such as copy-editing, formatting and page numbers may not be reflected in this version. For the definitive version of this publication, please refer to the published source. You are advised to consult the publisher's version if you wish to cite this paper.This version is being made available in accordance with publisher policies. See http://orca.cf.ac.uk/policies.html for usage policies. Copyright and moral rights for publications made available in ORCA are retained by the copyright holders.