Abstracts

Rationale: Autosomal dominant lateral temporal epilepsy (ADLTE) is a focal epileptic syndrome characterized by auditory or aphasic auras. The syndrome is genetically heterogeneous, and less than 50% of ADLTE families have mutations in the LGI1 gene, some of which are structural rearrangements. Copy number variants (CNVs) are known to confer susceptibility to a variety of neurologic and psychiatric disorders, including epilepsy. To identify copy number variants (CNVs) related to ADLTE, we performed a CNV analysis of a collection of ADLTE families without LGI1 mutations. Methods: The epileptic phenotypes of affected members of 21 families, collected at several centers, with at least two patients with lateral temporal epilepsy were carefully re-analyzed and considered eligible for study based on intrafamilial clinical homogeneity. Diagnosis of lateral temporal epilepsy was made based on a history in two or more family members of focal seizures with auditory or receptive aphasic symptoms and absence of brain abnormalities. DNA suitable for single nucleotide polymorphisms (SNP)-array analysis was genotyped using the HumanOmni1-Quad v1.0 beadchip (Illumina), which contains over 1 million SNPs. CNVs were inferred from signal intensity data using the PennCNV algorithm. Rare CNVs were defined as occurring only in a single family and either absent or present with frequency <1% in the database of genome variants (DGV); and common (polymorphic) CNVs as occurring in multiple families and present in DGV with frequency >1%.Results: We analyzed 176 affected and unaffected members of 21 ADLTE families and identified a total of 11,214 CNVs, corresponding to 1890 unique regions with an average size of 67.3 kb. About two-thirds of these CNVs were <50 kb in size, and 38% were absent from public databases. Only a small proportion (1.2%) exceeded 500 kb. We identified 15 rare CNVs that segregated with the disease in single families. Particularly, 2 rare microdeletions were found within or near two genes, RBFOX1 and NRXN1, which have recently been found to be associated with idiopathic generalized epilepsy. We also mapped 96 polymorphic CNVs that occurred in all affected members of at least one family. Some of these polymorphic CNVs disrupted or were close to genes that might confer susceptibility to epilepsy, such as PCDHA9/10, SLC2A3 (GLUT3), and a cluster of ADAM genes. Conclusions: In this study, we did not identify any microdeletion or duplication affecting one or multiple genes with a clear ADLTE-causative effect. However, our results provide clues on novel genes that may confer susceptibility to ADLTE, particularly in those families where the inheritance pattern is less compatible with autosomal dominance.