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published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases.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.
- hotspot loci
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Contributors Design and coordination of the study: EP-P, IH and DL Performed microdeletions statistical analysis: EP-P,PG,AG,KP,ESand DPH.Performed GTex expression analysis: VA, AB .Performed Network analysis: HH.Contributing genetic and/or phenotypic data: MRT, EMR,PN,HL,FZ,AJB,FR,EP,FZ and YGW Writing of the manuscript:EP-P,IH and DL Revision of the manuscript with important intellectual content:JFM,GDF, KMK,BAN,PN and DL. A full list of contributors and associated centers is provided in the online supplementary information file.
Funding Funding for the project was provided by the Wellcome Trust.E. P-P. was supported by the Chilean FONDECYT (Fondo Nacional de Desarrollo Científico y Tecnológico) regular grant numbers 1140353 and 1130303 to G.V.D. and J-F.M., respectively. Additionally, the study was funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1).
Competing interests None declared.
Ethics approval Corresponding institutional review boards of the contributing clinical centers.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement This study makes use of data generated by theDECIPHER community. A full list of centres who contributed to the generation ofthe data is available from http://decipher.sanger.ac.uk and via email firstname.lastname@example.org
Collaborators Membership of the EuroEPINOMICS-RE consortium and Italian League against Epilepsy Consortium is provided in the online supplementary information file.
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