Abstract

Epilepsy is a frequent feature of neurodevelopmental disorders (NDDs), but little is known about genetic differences between NDDs with and without epilepsy. We analyzed de novo variants (DNVs) in 6,753 parent–offspring trios ascertained to have different NDDs. In the subset of 1,942 individuals with NDDs with epilepsy, we identified 33 genes with a significant excess of DNVs, of which SNAP25 and GABRB2 had previously only limited evidence of disease association. Joint analysis of all individuals with NDDs also implicated CACNA1E as a novel disease-associated gene. Comparing NDDs with and without epilepsy, we found missense DNVs, DNVs in specific genes, age of recruitment, and severity of intellectual disability to be associated with epilepsy. We further demonstrate the extent to which our results affect current genetic testing as well as treatment, emphasizing the benefit of accurate genetic diagnosis in NDDs with epilepsy.

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Acknowledgements

We thank all patients and their families who participated in this study, as well as the teams who were involved in recruiting patients and gathering samples and data at the respective study sites. We thank L. Vissers and C. Gilissen for epilepsy and age phenotypes from the cohort of Lelieveld et al.23 and J. McRae for useful discussions on the DDD cohort7. We are grateful to members of the ATGU and the Institute for Human Genetics in Leipzig for insightful discussions. We thank J. Krause for support in figure design and helpful conversations. This work was supported by the Eurocores program EuroEPINOMICS, the Fund for Scientific Research Flanders (FWO), International Coordination Action (ICA) grant G0E8614N, and the University of Antwerp (research fund). H.O.H. was supported by stipends from the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 and the German Research Foundation (DFG): HE7987/1-1. H.S. was supported as a PhD fellow of the Fund for Scientific Research Flanders (1125416 N). I.H. and Y.G.W. were supported by DFG grants WE4896/3-1 and HE5415/6-1. R.G. received funding through the EU Seventh Framework Programme (FP7) under the project DESIRE grant N602531. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant HICF-1009-003), a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute (grant WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or the Department of Health. The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.

Author information

Author notes

  1. A list of members and affiliations appears at the end of the paper

Affiliations

  1. University of Leipzig Hospitals and Clinics, Leipzig, Germany

    • Henrike O. Heyne
    • , Rami Abou Jamra
    •  & Johannes R. Lemke
  2. Program in Medical and Population Genetics, and Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, USA

    • Henrike O. Heyne
    • , Tarjinder Singh
    • , Jack A. Kosmicki
    • , Aarno Palotie
    • , Mark J. Daly
    •  & Dennis Lal
  3. Integrated Research and Treatment Center (IFB) Adiposity Diseases, University of Leipzig Hospitals and Clinics, Leipzig, Germany

    • Henrike O. Heyne
  4. Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    • Henrike O. Heyne
    • , Tarjinder Singh
    • , Jack A. Kosmicki
    • , Mark J. Daly
    •  & Dennis Lal
  5. Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp, Belgium

    • Hannah Stamberger
    • , Peter De Jonghe
    • , Tania Djémié
    • , Arvid Suls
    •  & Sarah Weckhuysen
  6. Laboratory of Neurogenetics, Institute Born–Bunge, University of Antwerp, Antwerp, Belgium

    • Hannah Stamberger
    • , Peter De Jonghe
    • , Tania Djémié
    • , Arvid Suls
    •  & Sarah Weckhuysen
  7. Division of Neurology, University Hospital Antwerp, Antwerp, Belgium

    • Hannah Stamberger
    • , Peter De Jonghe
    • , Tania Djémié
    • , Arvid Suls
    •  & Sarah Weckhuysen
  8. Department of Molecular Biology and Genetics, Bogaziçi University, Istanbul, Turkey

    • Hande Caglayan
  9. ‘Carol Davila’ University of Medicine Bucharest, Department of Clinical Neurosciences (No. 6), Pediatric Neurology Clinic, Alexandru Obregia Hospital, Bucharest, Romania

    • Dana Craiu
  10. Pediatric Neurology and Neurogenetics Unit and Laboratories, A. Meyer Children’s Hospital–University of Florence, Florence, Italy

    • Renzo Guerrini
    •  & Carla Marini
  11. Division of Neurology, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    • Katherine L. Helbig
    •  & Ingo Helbig
  12. Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands

    • Bobby P. C. Koeleman
    •  & Carolien de Kovel
  13. Department of Pediatric Neurology, Children’s Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

    • Tarja Linnankivi
  14. Luxembourg Centre for Systems Biomedicine, University of Luxembourg, Esch-sur-Alzette, Luxembourg

    • Patrick May
  15. Department of Neuropediatrics, University Medical Center Schleswig–Holstein, Christian–Albrechts University, Kiel, Germany

    • Hiltrud Muhle
    • , Manuela Pendziwiat
    • , Johanna Jähn
    • , Stefanie H. Müller
    • , Ulrich Stephani
    •  & Ingo Helbig
  16. Danish Epilepsy Centre, Dianalund, Denmark

    • Rikke S. Møller
  17. Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark

    • Rikke S. Møller
  18. Department of Pediatric Neurology, University Hospital Giessen, Giessen, Germany

    • Bernd A. Neubauer
  19. Pediatric Neurology and Muscular Diseases Unit, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics, and Maternal and Child Health, University of Genoa ‘G. Gaslini’ Institute, Genoa, Italy

    • Pasquale Striano
  20. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA

    • Sha Tang
    •  & Sitao Wu
  21. Epilepsy Genetics Program, Department of Neurology, Division of Epilepsy and Clinical Neurophysiology, Boston Children’s Hospital, Boston, MA, USA

    • Annapurna Poduri
  22. Department of Neurology and Epileptology, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

    • Niklas Schwarz
    •  & Yvonne G. Weber
  23. Department of Clinical and Experimental Epilepsy, NIHR, University College London Hospitals Biomedical Research Centre, UCL Institute of Neurology, London, UK

    • Sanjay M. Sisodiya
  24. The Epilepsy Society, Chalfont-St-Peter Bucks, UK

    • Sanjay M. Sisodiya
  25. Cologne Center for Genomics (CCG), Cologne, Germany

    • Dennis Lal
  26. Division of Clinical Genomics, Ambry Genetics, Aliso Viejo, CA, USA

    • Department of Physiology and Pharmacology, Tel Aviv University Medical School, Ramat Aviv, Israel

      • Zaid Afawi
    • Department of Language and Genetics, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands

      • Carolien de Kovel
    • Epilepsy Center, Department of Neurosurgery, University Hospital ‘St. Ivan Rilski’, Sofia, Bulgaria

      • Petia Dimova
    • Neurology Department, Medical Academy, Lithuanian University of Health Services, Kaunas, Lithuania

      • Milda Endziniene
    • Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland

      • Dorota Hoffman-Zacharska
    • Neuropediatrics Unit, University of Geneva, Geneva, Switzerland

      • Christian Korff
    • Folkhälsan Institute of Genetics, Helsinki, Finland

      • Anna-Elina Lehesjoki
    • Neuroscience Center, University of Helsinki, Helsinki, Finland

      • Anna-Elina Lehesjoki
    • Research Programs Unit, Molecular Neurology, University of Helsinki, Helsinki, Finland

      • Anna-Elina Lehesjoki
    • Department of Basic and Clinical Neurosciences, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, UK

      • Deb Pal
      •  & Shan Tang
    • Department of Medical Genetics, Oslo University Hospital, Oslo, Norway

      • Kaja Selmer
    • Neurology Laboratory and Epilepsy Unit, Department of Neurology, IIS–Fundacion Jimenez Diaz, UAM, Madrid, Spain

      • Jose Serratosa
    • Centro Investigacion Biomedica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

      • Jose Serratosa
    • Department of Pediatric Neurology, Second Faculty of Medicine, Charles University in Prague and University Hospital Motol, Prague, Czech Republic

      • Katalin Štěrbová
    • Department of General Paediatrics, Division of Child Neurology and Inherited Metabolic Diseases, Centre for Paediatrics and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany

      • Steffen Syrbe
    • Tallinn Children’s Hospital, Tallinn, Estonia

      • Inga Talvik
    • Department of Neuropediatrics, Christian-Albrechts-University, Kiel, Germany

      • Sarah von Spiczak
    • Northern German Epilepsy Center for Children & Adolescents, Schwentinental/OT, Raisdorf, Germany

      • Sarah von Spiczak
    • Laboratory of Genetics and Neuroscience, Institute of G. Gaslini, Genoa, Italy

      • Federico Zara

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    Consortia

    1. EuroEPINOMICS RES Consortium

    Contributions

    H.O.H. performed the analyses and drafted the manuscript. H.O.H. and J.R.L. conceived the study. H.O.H., J.R.L., M.J.D., T.S., D.L. and H.S. contributed to analysis concepts and methods. H.O.H., J.R.L., D.L., I.H., T.S., M.J.D., S.M.S., and S. Weckhuysen interpreted the results. T.S., H.S., R.A.J., H.C., D.C., P.D.J., R.G., K.L.H., B.P.C.K., J.A.K., D.L., T.L., P.M., H.M., R.S.M., B.A.N., A. Palotie, M.P., P.S., S.T., S. Wu, the EuroEPINOMICS RES Consortium, S.T., A. Poduri, Y.G.W., S. Weckhuysen, and I.H. provided patient data or analysis tools. All authors revised and approved the final manuscript.

    Competing interests

    The authors declare no competing interests.

    Corresponding authors

    Correspondence to Henrike O. Heyne or Johannes R. Lemke.

    Supplementary information

    1. Supplementary Figures

      Supplementary Figures 1–10 and Supplementary Note

    2. Reporting Summary

    3. Supplementary Table 1

      Description of cohorts analyzed in this study

    4. Supplementary Table 2

      List of all DNVmis, DNVtrunc, and DNVsynonymous of all NDD cohorts (n = 6,753) and controls (n = 1,911) analyzed in this study

    5. Supplementary Table 3

      List of 50 dominant and X-linked known EE genes

    6. Supplementary Table 4

      Genes with at least two DNVmis+trunc in NDDEE+uE (n = 1,942)

    7. Supplementary Table 5

      Genes with at least two DNVmis+trunc in all NDD (NDD EE+uE +woE, n = 6,753)

    8. Supplementary Table 6

      Significantly enriched HPO terms in 33 genes with DNV burden in NDD with epilepsy

    9. Supplementary Table 7

      Evaluating genes with at least two DNVmis+trunc in NDD with epilepsy for therapeutic consequences

    10. Supplementary Table 8

      Gene sets significantly enriched (odds raio > 1) or depleted (odds ratio < 1) for DNV in epilepsy compared to no epilepsy

    11. Supplementary Table 9

      DNV in epilepsy vs. no epilepsy

    12. Supplementary Table 10

      DNV in NDDuE vs. NDDEE

    13. Supplementary Table 11

      Diagnostic sequencing panels from 24 different academic and commercial providers

    14. Supplementary Table 12

      191 dominant/X-linked genes in sequencing panels from 24 different academic/commercial providers with three criteria for disease association in NDD with epilepsy (DNV burden, constraint, brain expression)

    15. Supplementary Table 13

      Evaluating 50 genes lacking features of DNV-enriched genes (DNV enrichment, constraint, brain expression) for published evidence for disease association using guidelines from the ClinGen Gene Curation Workgroup

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    DOI

    https://doi.org/10.1038/s41588-018-0143-7