Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies

Abstract

Background: Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement 'hotspot' loci. However, microdeletion burden not overlapping these regions or within different epilepsy subtypes has not been ascertained.

Objective: To decipher the role of microdeletions outside hotspots loci and risk assessment by epilepsy subtype.

Methods: We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases. Microdeletions were assessed in a combined and subtype-specific approaches against 6746 controls.

Results: When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted p=1.06×10^-6,OR 1.89, 95% CI 1.51 to 2.35). Epilepsy subtype-specific analyses showed that hotspot microdeletions in the GGE subgroup contribute most of the overall signal (adjusted p=9.79×10^-12, OR 7.45, 95% CI 4.20-13.5). Outside hotspots , microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13×10^-3,OR 2.85, 95% CI 1.62-4.94). No additional signal was observed for RE and AFE. Still, gene-content analysis identified known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes across epilepsy subtypes that were not deleted in controls.

Conclusions: Our results show a heterogeneous effect of recurrent and non-recurrent microdeletions as part of the genetic architecture of GGE and a minor contribution in the aetiology of RE and AFE.

Keywords: epilepsy; hotspot loci; microdeletions; neurodevelopmental.

Figure 1

Microdeletion burden analysis in common epilepsy types. For adult focal epilepsies (AFEs, cyan), rolandic epilepsies (RE, green) and genetic generalised epilepsies (GGEs, red) data sets, the burden analysis without genomic rearrangement hotspots loci consideration is shown using the following microdeletion sets: all microdeletions; overlapping at least one: CNV constrained gene, neurodevelopmental gene, autism spectrum disorder (ASD)-related gene, developmental disorders genes and loss-of-function intolerant genes. The effect size observed (OR), CI (horizontal lines) and multiple testing corrected p value obtained is shown for each data set. Triangles denote if the signal is nominally significant. CI values above 9 are shown in numbers.

Figure 2

Protein–protein interaction network of brain-expressed genes exclusively deleted in cases. Top panel: direct connection network obtained with for the combined epilepsy analysis. Bottom panel: direct connection network obtained with for the GGE subtype analysis. Each gene (node) in the network is coloured based on the significance of having more-than-expected edges (interactions) following the q value legend provided at the bottom-right corner.