Genome-Wide Copy Number Variation in Epilepsy: Novel Susceptibility Loci in Idiopathic Generalized and Focal Epilepsies

Abstract

Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy. Epilepsy, a common neurological disorder characterized by recurrent seizures, affects up to 3% of the population. In some cases, the epilepsy has a clear cause such as an abnormality in the brain or a head injury. However, in many cases there is no obvious cause. Numerous studies have shown that genetic factors are important in these types of epilepsy, but although several epilepsy genes are known, we can still only identify the genetic cause in a very small fraction of cases. In order to identify new genes that contribute to the genetic causes of epilepsy, we searched the human genome for deletions (missing copies) and duplications (extra copies) of genes in ∼500 patients with epilepsy that are not found in control individuals. Using this approach, we identified several large deletions that are important in at least 3% of epilepsy cases. Furthermore, we found new candidate genes, some of which are also thought to play a role in other related disorders such as autism and intellectual disability. These genes are candidates for further studies in patients with epilepsy.