Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses

Abstract

Background: Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.

Objective: To identify rare, causal CNV in patients with RE.

Methods: We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.

Results: We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.

Conclusion: Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

Keywords: copy-number; developmental; epilepsy and seizures; genome-wide.

Figure 1

Breakpoints of 5 cases with Xp22.31 hotspot CNVs in our rolandic epilepsy (RE) case series, 2 cases with RE and Xp22.31 CNVs from the literature and 19 further cases with epilepsy or seizures form the literature. Individual IDs or publication references are shown to the left and references are in online supplementary table 3. Blue lines indicate duplications and red lines deletions. Gene positions are shown above the CNVs. Positions of segmental duplication sequence (locus control regions) are shown in the middle of the figure with grey bars. From http://genome.ucsc.edu/, hg19 assembly. UCSC, University of California, Santa Cruz.

Figure 2

Network created by Ingenuity Pathway Analysis using the top 36 most highly connected genes disrupted by rolandic epilepsy (RE) CNVs as assessed by the Disease Association Protein-Protein Link Evaluator. Orange indicates a gene within a CNV, pink a hub gene, green an epilepsy-associated gene not found within a CNV and white are genes added by Ingenuity Pathway Analysis during network generation due to direct physical or indirect (eg, via activation) interactions with the input list.