TY  - JOUR
A1  - Pérez-Palma, Eduardo
A1  - Helbig, Ingo
A1  - Klein, Karl Martin
A1  - Anttila, Verneri
A1  - Horn, Heiko
A1  - Reinthaler, Eva Maria
A1  - Gormley, Padhraig
A1  - Ganna, Andrea
A1  - Byrnes, Andrea
A1  - Pernhorst, Katharina
A1  - Toliat, Mohammad Reza
A1  - Saarentaus, Elmo
A1  - Howrigan, Daniel P.
A1  - Hoffman, Per
A1  - Miquel, Juan Francisco
A1  - De Ferrari, Giancarlo V.
A1  - Nürnberg, Peter
A1  - Lerche, Holger
A1  - Zimprich, Fritz
A1  - Neubauer, Bern A.
A1  - Becker, Albert John
A1  - Rosenow, Felix
A1  - Perucca, Emilio
A1  - Zara, Federico
A1  - Weber, Yvonne G.
A1  - Lal, Dennis
T1  - Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies
T2  - Journal of medical genetics
N2  - 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published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases.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.
KW  - epilepsy
KW  - hotspot loci
KW  - microdeletions
KW  - neurodevelopmental
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45768
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-457682
SN  - 1468-6244
SN  - 0022-2593
N1  - © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.
This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
VL  - 54
IS  - 9
SP  - 598
EP  - 606
ER  -