Eduardo Pérez-Palma, Ingo Helbig, Karl Martin Klein, Verneri Anttila, Heiko Horn, Eva Maria Reinthaler, Padhraig Gormley, Andrea Ganna, Andrea Byrnes, Katharina Pernhorst, Mohammad Reza Toliat, Elmo Saarentaus, Daniel P. Howrigan, Per Hoffman, Juan Francisco Miquel, Giancarlo V. De Ferrari, Peter Nürnberg, Holger Lerche, Fritz Zimprich, Bern A. Neubauer, Albert John Becker, Felix Rosenow, Emilio Perucca, Federico Zara, Yvonne G. Weber, Dennis Lal
- 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published cohort of 1366 patients with genetic generalised epilepsy (GGE) in addition to two sets of additional unpublished genome-wide microdeletions found in 281 patients with rolandic epilepsy (RE) and 807 patients with adult focal epilepsy (AFE), totalling 2454 cases.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.
MetadatenAuthor: | Eduardo Pérez-PalmaORCiD, Ingo HelbigORCiDGND, Karl Martin KleinORCiD, Verneri AnttilaORCiDGND, Heiko HornORCiD, Eva Maria Reinthaler, Padhraig GormleyORCiD, Andrea GannaORCiD, Andrea Byrnes, Katharina Pernhorst, Mohammad Reza ToliatORCiD, Elmo SaarentausORCiD, Daniel P. HowriganORCiD, Per Hoffman, Juan Francisco MiquelORCiD, Giancarlo V. De FerrariORCiD, Peter NürnbergORCiD, Holger LercheORCiDGND, Fritz ZimprichORCiDGND, Bern A. Neubauer, Albert John Becker, Felix RosenowORCiDGND, Emilio PeruccaGND, Federico ZaraORCiD, Yvonne G. Weber, Dennis LalGND |
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URN: | urn:nbn:de:hebis:30:3-457682 |
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DOI: | https://doi.org/10.1136/jmedgenet-2016-104495 |
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ISSN: | 1468-6244 |
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ISSN: | 0022-2593 |
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Pubmed Id: | https://pubmed.ncbi.nlm.nih.gov/28756411 |
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Parent Title (English): | Journal of medical genetics |
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Document Type: | Article |
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Language: | English |
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Year of Completion: | 2017 |
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Date of first Publication: | 2017/08/22 |
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Publishing Institution: | Universitätsbibliothek Johann Christian Senckenberg |
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Release Date: | 2018/02/27 |
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Tag: | epilepsy; hotspot loci; microdeletions; neurodevelopmental |
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Volume: | 54 |
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Issue: | 9 |
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Page Number: | 10 |
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First Page: | 598 |
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Last Page: | 606 |
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Note: | © 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/ |
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HeBIS-PPN: | 431958181 |
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Institutes: | Medizin / Medizin |
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Dewey Decimal Classification: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
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Sammlungen: | Universitätspublikationen |
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Licence (German): | Creative Commons - Namensnennung-Nicht kommerziell - Keine Bearbeitung 4.0 |
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