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Identification of new risk factors for rolandic epilepsy: CNV at Xp22.31 and alterations at cholinergic synapses
  1. Laura Addis1,2,
  2. William Sproviero1,
  3. Sanjeev V Thomas3,
  4. Roberto H Caraballo4,
  5. Stephen J Newhouse5,6,7,
  6. Kumudini Gomez8,
  7. Elaine Hughes9,
  8. Maria Kinali10,
  9. David McCormick9,
  10. Siobhan Hannan10,
  11. Silvia Cossu11,12,
  12. Jacqueline Taylor13,
  13. Cigdem I Akman14,
  14. Steven M Wolf15,
  15. David E Mandelbaum16,
  16. Rajesh Gupta17,
  17. Rick A van der Spek18,
  18. Dario Pruna12,
  19. Deb K Pal1
  1. 1 Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London, UK
  2. 2 Neuroscience Discovery Research, Eli Lilly and Company, Surrey, UK
  3. 3 Department of Neurology, Sree Chitra Tirunal Institute for Medical Sciences and Technology, Trivandrum, Kerala, India
  4. 4 Department of Neurology, Hospital de Pediatría Prof. Dr. J.P. Garrahan, Combate de los Pozos 1881, Buenos Aires, Argentina
  5. 5 Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK
  6. 6 NIHR Biomedical Research Centre at South London and Maudsley NHS Foundation Trust, Bethlem Royal Hospital, Beckenham, UK
  7. 7 Farr Institute of Health Informatics Research, UCL Institute of Health Informatics, University College London, London, UK
  8. 8 Department of Paediatrics, University Hospital Lewisham, Lewisham and Greenwich NHS Trust, London, UK
  9. 9 Department of Paediatric Neurosciences, Evelina London Children’s Hospital, St Thomas’ Hospital, London, UK
  10. 10 Department of Paediatric Neurology, Chelsea and Westminster Hospital, London, UK
  11. 11 Neurosurgery Unit, Neuroscience and Neurorehabilitation Department, Bambino Gesù Children Hospital, Rome, Italy
  12. 12 Neurology Unit, Pediatric Hospital A. Cao, Brotzu Hospital Trust, Cagliari, Italy
  13. 13 Barnet and Chase Farm Hospitals, London, UK
  14. 14 Division of Pediatric Neurology, College of Physicians and Surgeons of Columbia University, New York City, New York, USA
  15. 15 Department of Neurology, Mount Sinai Health System, New York City, New York, USA
  16. 16 Departments of Pediatrics, Alpert Medical School of Brown University, Providence, Rhode Island, USA
  17. 17 Department of Paediatrics, Tunbridge Wells Hospital, Pembury, UK
  18. 18 Department of Neurology, Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands
  1. Correspondence to Dr Laura Addis, Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, Maurice Wohl Clinical Neuroscience Institute, King’s College London, London SE5 9RX, UK; laura.addis{at}


Background Rolandic epilepsy (RE) is the most common genetic childhood epilepsy, consisting of focal, nocturnal seizures and frequent neurodevelopmental impairments in speech, language, literacy and attention. A complex genetic aetiology is presumed in most, with monogenic mutations in GRIN2A accounting for >5% of cases.

Objective To identify rare, causal CNV in patients with RE.

Methods We used high-density SNP arrays to analyse the presence of rare CNVs in 186 patients with RE from the UK, the USA, Sardinia, Argentina and Kerala, India.

Results We identified 84 patients with one or more rare CNVs, and, within this group, 14 (7.5%) with recurrent risk factor CNVs and 15 (8.0%) with likely pathogenic CNVs. Nine patients carried recurrent hotspot CNVs including at 16p13.11 and 1p36, with the most striking finding that four individuals (three from Sardinia) carried a duplication, and one a deletion, at Xp22.31. Five patients with RE carried a rare CNV that disrupted genes associated with other epilepsies (KCTD7, ARHGEF15, CACNA2D1, GRIN2A and ARHGEF4), and 17 cases carried CNVs that disrupted genes associated with other neurological conditions or that are involved in neuronal signalling/development. Network analysis of disrupted genes with high brain expression identified significant enrichment in pathways of the cholinergic synapse, guanine-exchange factor activation and the mammalian target of rapamycin.

Conclusion Our results provide a CNV profile of an ethnically diverse cohort of patients with RE, uncovering new areas of research focus, and emphasise the importance of studying non-western European populations in oligogenic disorders to uncover a full picture of risk variation.

  • copy-number
  • developmental
  • genome-wide
  • epilepsy and seizures

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  • Contributors All authors contributed to revising critically the final version of the manuscript. LA carried out DNA extraction, called and validated the CNVs, carried out the network analysis and wrote the manuscript. WS carried out the QC and ethnicity matching for the case-control analysis. SJN extracted and carried out QC on the genotypes. RAvdS provided the NL control data. SVT, RHC, KG, EH, MK, DM, SH, SC, JT, CIA, SMW, DEM, RG, DP and DKP provided patient samples and deeply phenotyped the individuals and their family members.

  • Funding This paper represents independent research part funded by the National Institute for Health Research (NIHR) Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King’s College London. This work was supported by a Lilly Innovation Fellowship award (LA); Waterloo Foundation (LA, DKP); European Union Marie Curie International Reintegration Award of the Seventh Framework Programme (DKP); Charles Sykes Epilepsy Research Trust (DKP); Ali Paris Fund for Epilepsy Research (DKP); European Union Grant agreement 602531: “Strategies for Innovative Research to Improve Diagnosis, Prevention and Treatment in Children with Difficult to Treat Epilepsy (DESIRE)” of the Seventh Framework Programme (DKP); Canadian Institutes for Health Research (DKP); NIHR Specialist Biomedical Research Centre for Mental Health of South London and Maudsley NHS Foundation Trust (DKP). SJN is supported by the National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, and by awards establishing the Farr Institute of Health Informatics Research at UCLPartners, from the Medical Research Council, Arthritis Research UK, British Heart Foundation, Cancer Research UK, Chief Scientist Office, Economic and Social Research Council, Engineering and Physical Sciences Research Council, National Institute for Health Research, National Institute for Social Care and Health Research, and Wellcome Trust (grant MR/K006584/1).

  • Disclaimer The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health.

  • Competing interests LA is a contractor for Eli Lilly and Company. SVT has received research grants from the Scientific bodies under the Government of India. DM consults for Cyberonics.

  • Patient consent Not required.

  • Ethics approval All respective local institutional review boards approved the study.

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

  • Data sharing statement Gene lists from the IPA analysis are available from the corresponding author.

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