Abstracts

Rationale: The early-onset absence epilepsies (EOAE) are a rare subtype of the genetic generalized epilepsies (GGE). Absence epilepsies account for approximately 30-40% of GGE and three subgroups can be distinguished according to their age-of-onset: EOAE (<4y), childhood absence epilepsy (CAE, 4-10y) and juvenile absence epilepsy (JAE, >10y). Genetic predisposition for EOAE has been suggested and mutations in GLUT1 have been identified in 10% of patients. Other causative genetic factors still remain to be identified. Copy Number Variants (CNVs) have been shown to play a role in epilepsies, especially in early onset epilepsies and encephalopathies. This study aimed to explore the role of CNVs in EOAE. Methods: 100 patients with EOAE were screened for structural genomic imbalances using the Affymetrix Genome-Wide Human SNP Array 6.0 and the Affymetrix Genotyping Console 3.0 algorithm. Quality Control (QC) criteria included a SNP call rate >97%, contrast QC >= 0.40 and MAPD < 0.4. Regions, which were determined as significantly deviated by the software, and which included more than 25 single oligonucleotides or spanning more than 200 kb, were regarded as aberrant. Identified structural genomic variants were compared to variants described in the Toronto Database (2009) of Genomic Variants and to 1075 population controls of Northern European descent. Variations were validated by qPCR. Results: 90 patients fulfilled the QC criteria. After qPCR-validation 26 CNVs were detected in 23 of 90 patients (26%). Five variations were classified as pathogenic (4 dels, 1 dup), 3 as likely pathogenic (2 dels, 1 dup) and 18 as variants of unknown significance (1 del, 17 dup). In 3 patients 2 different variations were detected. Duplications encompassing the SHANK3 gene were found in two unrelated patients. Conclusions: Approximately 25% of EOAE patients carry CNVs. In 9% of patients CNVs could be classified as pathogenic or likely pathogenic. The variations encompass several new genes. SHANK3 variants were previously described is the context of autism and this gene codes for a protein of the postsynaptic density. In our current study, we expand the spectrum of SHANK3-related disorders to the early onset absence epilepsies.