Copy number variants in absence epilepsy

Further complications of the picture After years of largely unsuccessful association studies attempting to detect genetic variants underlying common epilepsies, the recent identification of copy number variants (CNVs) in epilepsy has generated a lot of excitement. CNVs are defined as genomic deletions or duplications larger than 1 kb and up to several Mb in size. A proportion occur at genomic hotspots (recurrent CNVs), whereas others can occur anywhere in the genome. Although individually rare, these CNVs collectively constitute the single largest risk factor for sporadic epilepsies known to date. Depending on the exact phenotype, CNVs have been reported in up to 28% of patients with epilepsy. 1 Subsequently, exon-disrupting deletions in a range of genes previously implicated in a variety of neuro-developmental disorders were also identified in patients with epilepsy. 2–4 Genetic generalized epilepsy (GGE), either associated or not associated with intellectual disability, is the most commonly reported phenotype in patients carrying these CNVs. The GGEs comprise a large group of phenotypically heterogeneous disorders with a known or presumed genetic cause, which may vary from rare monogenic cases to complex polygenic inheritance. In the current issue of Neurology ® Genetics, Addis et al. 5 used single-nucleotide polymorphism arrays to detect CNVs in a cohort of 144 previously collected patients with absence epilepsy, including 95 with childhood absence epilepsy, 23 with juvenile absence epilepsy, and 26 with unclassified absence epilepsy. They identified recurrent CNVs previously reported in patients with GGE in 4 individuals, recurrent CNVs previously associated with a range of neurodevelopmental disorders in 4 individuals, and novel CNVs disrupting a range of genes involved in neuronal development and function in 15 individuals. They observed the different categories of CNVs across the 3 types of absence epilepsy, lending support to the hypothesis that these different subtypes of epilepsy share common genetic mechanisms. The present study is the first to systematically address the identification of CNVs in patients with absence epilepsy specifically. Many previous studies have reported the presence of recurrent and novel CNVs in a variety of GGE syndromes, including absence epilepsies, but because of the heterogeneity of phenotypes included in these studies, the distribution of CNVs in this specific subtype of GGE is presently unclear. GGE, and epilepsy in general, is not a single disease, and the large variety of syndromes and inherent difficulties in classifying the epilepsies constitute a unique challenge to the elucidation of the underlying genetic and …