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

Eduardo Pérez-Palma, Ingo Helbig, Karl Martin Klein, Verneri Anttila, Heiko Horn, Eva Maria Reinthaler, Padhraig Gormley, Andrea Ganna, Andrea Byrnes, Katharina Pernhorst, Mohammad R Toliat, Elmo Saarentaus, Daniel P Howrigan, Per Hoffman, Juan Francisco Miquel, Giancarlo V De Ferrari, Peter Nürnberg, Holger Lerche, Fritz Zimprich, Bern A NeubauerAlbert J Becker, Felix Rosenow, Emilio Perucca, Federico Zara, Yvonne G Weber, Dennis Lal

Research output: Contribution to journalArticlepeer-review


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published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases.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,RBFOX1andPCDH7) 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.

Original languageEnglish
Pages (from-to)598-606
Number of pages9
JournalJournal of Medical Genetics
Issue number9
Publication statusPublished - Sep 2017

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