Clinical significance of rare copy number variations in epilepsy: a case-control survey using microarray-based comparative genomic hybridization.

Objective To perform an extensive search for genomic rearrangements by microarray-based comparative genomic hybridization in patients with epilepsy. Design Prospective cohort study. Setting Epilepsy centers in Italy. Patients Two hundred seventy-nine patients with unexplained epilepsy, 265 individuals with nonsyndromic mental retardation but no epilepsy, and 246 healthy control subjects were screened by microarray-based comparative genomic hybridization. Main Outcomes Measures Identification of copy number variations (CNVs) and gene enrichment. Results Rare CNVs occurred in 26 patients (9.3%) and 16 healthy control subjects (6.5%) (P = .26). The CNVs identified in patients were larger (P = .03) and showed higher gene content (P = .02) than those in control subjects. The CNVs larger than 1 megabase (P = .002) and including more than 10 genes (P = .005) occurred more frequently in patients than in control subjects. Nine patients (34.6%) among those harboring rare CNVs showed rearrangements associated with emerging microdeletion or microduplication syndromes. Mental retardation and neuropsychiatric features were associated with rare CNVs (P = .004), whereas epilepsy type was not. The CNV rate in patients with epilepsy and mental retardation or neuropsychiatric features is not different from that observed in patients with mental retardation only. Moreover, significant enrichment of genes involved in ion transport was observed within CNVs identified in patients with epilepsy. Conclusions Patients with epilepsy show a significantly increased burden of large, rare, gene-rich CNVs, particularly when associated with mental retardation and neuropsychiatric features. The limited overlap between CNVs observed in the epilepsy group and those observed in the group with mental retardation only as well as the involvement of specific (ion channel) genes indicate a specific association between the identified CNVs and epilepsy. Screening for CNVs should be performed for diagnostic purposes preferentially in patients with epilepsy and mental retardation or neuropsychiatric features. In approximately 30% to 40% of patients with epilepsy, there is an underlying cause of seizure recurrence, but it is not identifiable in most subjects.1 Although causative mutations have been identified for several epilepsy syndromes, mendelian epilepsies account for only 1% of the cases.2 By contrast, common epilepsies have a complex pattern of inheritance, likely involving combinations of variants in different genes that have proven challenging to discover.2 Linkage and genome-wide association studies have failed to identify robust or unambiguous associations in large series of patients.3 Copy number variations (CNVs) are increasingly recognized as a source of phenotypic variation among humans, and the implementation of genome-wide technologies such as microarray-based comparative genomic hybridization (array-CGH) and single-nucleotide polymorphism genotyping now allows their efficient identification.4,5 A number of studies have recently highlighted the role of CNVs in the etiology of various neuropsychiatric disorders.6,7 Targeted and genome-wide surveys of CNVs have been also performed in individuals with epilepsy, revealing recurrent deletions at 15q11.2, 15q13.3, and 16p13.11 in a small proportion of patients with different epilepsy syndromes.8- 11 However, the role of nonrecurrent CNVs in the etiology of epilepsy has not yet been evaluated in detail.2,5 We performed an array-CGH–based survey of CNVs in subjects with epilepsy of unknown cause.