PT  - JOURNAL ARTICLE
AU  - Eduardo Pérez-Palma
AU  - Ingo Helbig
AU  - Karl Martin Klein
AU  - Verneri Anttila
AU  - Heiko Horn
AU  - Eva Maria Reinthaler
AU  - Padhraig Gormley
AU  - Andrea Ganna
AU  - Andrea Byrnes
AU  - Katharina Pernhorst
AU  - Mohammad R. Toliat
AU  - EuroEPINOMICS-RE consortium
AU  - Italian League against Epilepsy Consortium
AU  - Elmo Saarentaus
AU  - Daniel P. Howrigan
AU  - Per Hoffman
AU  - Juan Francisco Miquel
AU  - Giancarlo De Ferrari
AU  - Peter Nürnberg
AU  - Holger Lerche
AU  - Fritz Zimprich
AU  - Bern A. Neubauer
AU  - Albert J. Becker
AU  - Felix Rosenow
AU  - Emilio Perucca
AU  - Federico Zara
AU  - Yvonne G. Weber
AU  - Dennis Lal
TI  - Heterogeneous Contribution of Microdeletions in the Development of Common Generalized and Focal epilepsies
AID  - 10.1101/131359
DP  - 2017 Jan 01
TA  - bioRxiv
PG  - 131359
4099  - http://biorxiv.org/content/early/2017/04/27/131359.short
4100  - http://biorxiv.org/content/early/2017/04/27/131359.full
AB  - Background Microdeletions are known to confer risk to epilepsy, particularly at genomic rearrangement “hotspot” loci. However, deciphering their role outside hotspots and risk assessment by epilepsy sub-type has not been conducted.Methods We assessed the burden, frequency and genomic content of rare, large microdeletions found in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases. These microdeletion sets were assessed in a combined analysis and in sub-type specific approaches against 6,746 ethnically matched controls.Results When hotspots are considered, we detected an enrichment of microdeletions in the combined epilepsy analysis (adjusted-P= 2.00×10-7; OR = 1.89; 95%-CI: 1.51-2.35), where the implicated microdeletions overlapped with rarely deleted genes and those involved in neurodevelopmental processes. Sub-type specific analyses showed that hotspot deletions in the GGE subgroup contribute most of the signal (adjusted-P = 1.22×10-12; OR = 7.45; 95%-CI = 4.20-11.97). Outside hotspot loci, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted-P = 4.78×10-3; OR = 2.30; 95%-CI = 1.42-3.70), whereas no additional signal was observed for RE and AFE. Still, gene content analysis was able to identify known (NRXN1, RBFOX1 and PCDH7) and novel (LOC102723362) candidate genes affected in more than one epilepsy sub-type but not 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 to negligible contribution in the etiology of RE and AFE.