Perez-Palma, Eduardo ORCID: 0000-0003-0546-5141, Helbig, Ingo ORCID: 0000-0001-8486-0558, Klein, Karl Martin ORCID: 0000-0002-6654-1665, Anttila, Verneri, Horn, Heiko, Reinthaler, Eva Maria, Gormley, Padhraig ORCID: 0000-0002-8908-6968, Ganna, Andrea ORCID: 0000-0002-8147-240X, Byrnes, Andrea, Pernhorst, Katharina, Toliat, Mohammad R., Saarentaus, Elmo ORCID: 0000-0002-8475-7187, Howrigan, Daniel P., Hoffman, Per, Miquel, Juan Francisco, De Ferrari, Giancarlo V., Nuernberg, Peter, Lerche, Holger, Zimprich, Fritz ORCID: 0000-0002-6998-5480, Neubauer, Bern A., Becker, Albert J., Rosenow, Felix, Perucca, Emilio, Zara, Federico ORCID: 0000-0001-9744-5222, Weber, Yvonne G. and Lal, Dennis (2017). Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies. J. Med. Genet., 54 (9). S. 598 - 607. LONDON: BMJ PUBLISHING GROUP. ISSN 1468-6244

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Abstract

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published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases.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=1.06x10(-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=9.79x10(-12), OR 7.45, 95% CI 4.20-13.5). Outside hotspots, microdeletions were enriched in the GGE cohort for neurodevelopmental genes (adjusted p=9.13x10(-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.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Perez-Palma, EduardoUNSPECIFIEDorcid.org/0000-0003-0546-5141UNSPECIFIED
Helbig, IngoUNSPECIFIEDorcid.org/0000-0001-8486-0558UNSPECIFIED
Klein, Karl MartinUNSPECIFIEDorcid.org/0000-0002-6654-1665UNSPECIFIED
Anttila, VerneriUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Horn, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Reinthaler, Eva MariaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Gormley, PadhraigUNSPECIFIEDorcid.org/0000-0002-8908-6968UNSPECIFIED
Ganna, AndreaUNSPECIFIEDorcid.org/0000-0002-8147-240XUNSPECIFIED
Byrnes, AndreaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Pernhorst, KatharinaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Toliat, Mohammad R.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Saarentaus, ElmoUNSPECIFIEDorcid.org/0000-0002-8475-7187UNSPECIFIED
Howrigan, Daniel P.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoffman, PerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Miquel, Juan FranciscoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
De Ferrari, Giancarlo V.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Nuernberg, PeterUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lerche, HolgerUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zimprich, FritzUNSPECIFIEDorcid.org/0000-0002-6998-5480UNSPECIFIED
Neubauer, Bern A.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Becker, Albert J.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Rosenow, FelixUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Perucca, EmilioUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zara, FedericoUNSPECIFIEDorcid.org/0000-0001-9744-5222UNSPECIFIED
Weber, Yvonne G.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Lal, DennisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-220915
DOI: 10.1136/jmedgenet-2016-104495
Journal or Publication Title: J. Med. Genet.
Volume: 54
Number: 9
Page Range: S. 598 - 607
Date: 2017
Publisher: BMJ PUBLISHING GROUP
Place of Publication: LONDON
ISSN: 1468-6244
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
COPY NUMBER VARIATION; AUTISM SPECTRUM DISORDERS; ROLANDIC EPILEPSY; GRIN2A MUTATIONS; INCREASE RISK; VARIANTS; GENOME; DELETIONS; GENETICS; APHASIAMultiple languages
Genetics & HeredityMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/22091

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