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Original article
Heterogeneous contribution of microdeletions in the development of common generalised and focal epilepsies
  1. Eduardo Pérez-Palma1,2,
  2. Ingo Helbig3,4,
  3. Karl Martin Klein5,6,
  4. Verneri Anttila7,8,
  5. Heiko Horn9,
  6. Eva Maria Reinthaler10,
  7. Padhraig Gormley7,11,
  8. Andrea Ganna7,
  9. Andrea Byrnes7,
  10. Katharina Pernhorst12,
  11. Mohammad R Toliat2,
  12. Elmo Saarentaus7,8,
  13. Daniel P Howrigan7,8,
  14. Per Hoffman13,
  15. Juan Francisco Miquel14,
  16. Giancarlo V De Ferrari1,
  17. Peter Nürnberg2,
  18. Holger Lerche15,
  19. Fritz Zimprich10,
  20. Bern A Neubauer16,
  21. Albert J Becker12,
  22. Felix Rosenow5,6,
  23. Emilio Perucca17,18,
  24. Federico Zara19,
  25. Yvonne G Weber14,
  26. Dennis Lal2,7,8
  1. 1 Faculty of Biological Sciences and Medicine, Center for Biomedical Research, Universidad Andres Bello, Santiago, Chile
  2. 2 Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany
  3. 3 Department of Neuropediatrics, University Medical Center Schleswig-Holstein, Kiel, Germany
  4. 4 Division of Neurology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, USA
  5. 5 Department of Neurology, Epilepsy Center Frankfurt Rhine-Main, Center of Neurology and Neurosurgery, University Hospital, Goethe-University Frankfurt, Frankfurt, Germany
  6. 6 Department of Neurology, Epilepsy Center Hessen, University Hospitals Giessen & Marburg, and University of Marburg, Marburg, Germany
  7. 7 Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA
  8. 8 Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  9. 9 Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts, USA
  10. 10 Department of Neurology, Medical University of Vienna, Vienna, Austria
  11. 11 Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA
  12. 12 Department of Neuropathology, University of Bonn, Bonn, Germany
  13. 13 Division of Medical Genetics Department of Biomedicine, University of Basel, Basel, Switzerland
  14. 14 Departamento de Gastroenterología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
  15. 15 Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research,University of Tübingen, Tübingen, Germany
  16. 16 Department of Neuropediatrics, University Medical Center Giessen and Marburg, Giessen, Germany
  17. 17 C. Mondino National Neurological Institute, Pavia, Italy
  18. 18 Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
  19. 19 Laboratory of Neurogenetics, Neuromuscular Disease Unit, Genova, Italy
  1. Correspondence to Dr Dennis Lal, Cologne Center for Genomics (CCG), University of Cologne,Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, 185 Cambridge Street, Massachusetts General Hospital, Boston, MA 02114, USA; dlal{at}


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.

  • microdeletions
  • epilepsy
  • neurodevelopmental
  • hotspot loci

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  • Contributors Design and coordination of the study: EP-P, IH and DL Performed microdeletions statistical analysis: EP-P,PG,AG,KP,ESand DPH.Performed GTex expression analysis: VA, AB .Performed Network analysis: HH.Contributing genetic and/or phenotypic data: MRT, EMR,PN,HL,FZ,AJB,FR,EP,FZ and YGW Writing of the manuscript:EP-P,IH and DL Revision of the manuscript with important intellectual content:JFM,GDF, KMK,BAN,PN and DL. A full list of contributors and associated centers is provided in the online supplementary information file.

  • Funding Funding for the project was provided by the Wellcome Trust.E. P-P. was supported by the Chilean FONDECYT (Fondo Nacional de Desarrollo Científico y Tecnológico) regular grant numbers 1140353 and 1130303 to G.V.D. and J-F.M., respectively. Additionally, the study was funded by the German Ministry of Education and Science and the German Research Council (DFG; Project SI 236/8-1, SI236/9-1, ER 155/6-1).

  • Competing interests None declared.

  • Ethics approval Corresponding institutional review boards of the contributing clinical centers.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement This study makes use of data generated by theDECIPHER community. A full list of centres who contributed to the generation ofthe data is available from and via email

  • Collaborators Membership of the EuroEPINOMICS-RE consortium and Italian League against Epilepsy Consortium is provided in the online supplementary information file.

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