TY  - INPR
A1  - Pérez-Palma, Eduardo
A1  - Helbig, Ingo
A1  - Klein, Karl Martin
A1  - Anttila, Verneri
A1  - Horn, Heiko
A1  - Maria Reinthaler, Eva
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
A1  - Nürnberg, Peter
A1  - Lerche, Holger
A1  - Zimprich, Fritz
A1  - Neubauer, Bern A.
A1  - Becker, Albert J.
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  - bioRxiv
N2  - 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in a previously published cohort of 1,366 patients with Genetic Generalized Epilepsy (GGE) plus two sets of additional unpublished genome-wide microdeletions found in 281 Rolandic Epilepsy (RE) and 807 Adult Focal Epilepsy (AFE) patients, totaling 2,454 cases.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.
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/83624
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-836248
UR  - https://www.biorxiv.org/content/10.1101/131359v1
IS  - 131359 Version 1
PB  - bioRxiv
ER  -