Targeted resequencing in epileptic encephalopathies identifies de novo mutations in CHD2 and SYNGAP1

Journal name:
Nature Genetics
Volume:
45,
Pages:
825–830
Year published:
DOI:
doi:10.1038/ng.2646
Received
Accepted
Published online

Epileptic encephalopathies are a devastating group of epilepsies with poor prognosis, of which the majority are of unknown etiology. We perform targeted massively parallel resequencing of 19 known and 46 candidate genes for epileptic encephalopathy in 500 affected individuals (cases) to identify new genes involved and to investigate the phenotypic spectrum associated with mutations in known genes. Overall, we identified pathogenic mutations in 10% of our cohort. Six of the 46 candidate genes had 1 or more pathogenic variants, collectively accounting for 3% of our cohort. We show that de novo CHD2 and SYNGAP1 mutations are new causes of epileptic encephalopathies, accounting for 1.2% and 1% of cases, respectively. We also expand the phenotypic spectra explained by SCN1A, SCN2A and SCN8A mutations. To our knowledge, this is the largest cohort of cases with epileptic encephalopathies to undergo targeted resequencing. Implementation of this rapid and efficient method will change diagnosis and understanding of the molecular etiologies of these disorders.

At a glance

Figures

  1. Pathogenic and likely pathogenic mutations identified in 500 cases of epileptic encephalopathies in new (red) and known (blue) disease-related genes.
    Figure 1: Pathogenic and likely pathogenic mutations identified in 500 cases of epileptic encephalopathies in new (red) and known (blue) disease-related genes.
  2. Protein alterations encoded by de novo mutations in new genes for epileptic encephalopathies.
    Figure 2: Protein alterations encoded by de novo mutations in new genes for epileptic encephalopathies.

    (a,b) Alterations are shown for CHD2 (a) and SYNGAP1 (b). Alterations shown in red were identified in this study; black entries denote previously reported variants of CHD2 in intellectual disability (Thr604Leufs*19)9 and autism (Asp856Gly)10 and of SYNGAP1 in intellectual disability and/or autism9, 14, 15, 16, 17, 18. Bold entries indicate pathogenic variants found in individuals with epilepsy. No evident genotype-phenotype correlations exist for mutations in either CHD2 or SYNGAP1.

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Author information

Affiliations

  1. Department of Pediatrics, Division of Genetic Medicine, University of Washington, Seattle, Washington, USA.

    • Gemma L Carvill,
    • Joseph Cook,
    • Adiba Khan &
    • Heather C Mefford
  2. Department of Medicine, Epilepsy Research Centre, University of Melbourne, Austin Health, Melbourne, Victoria, Australia.

    • Sinéad B Heavin,
    • Simone C Yendle,
    • Jacinta M McMahon,
    • Samuel F Berkovic &
    • Ingrid E Scheffer
  3. Department of Genome Sciences, University of Washington, Seattle, Washington, USA.

    • Brian J O'Roak &
    • Jay Shendure
  4. Department of Psychiatry & Behavioral Sciences, University of Washington, Seattle, Washington, USA.

    • Michael O Dorschner &
    • Molly Weaver
  5. Veteran Affairs Puget Sound Health Care System, Seattle, Washington, USA.

    • Michael O Dorschner &
    • Molly Weaver
  6. Neurosciences Children's Health Queensland, Royal and Mater Children's Hospitals, Brisbane, Queensland, Australia.

    • Sophie Calvert,
    • Stephen Malone &
    • Geoffrey Wallace
  7. Department of Paediatrics, School of Medicine and Health Sciences, University of Otago, Wellington, New Zealand.

    • Thorsten Stanley &
    • Lynette G Sadleir
  8. Department of Paediatric Neurology, University of New South Wales, Sydney Children's Hospital, Sydney, New South Wales, Australia.

    • Ann M E Bye
  9. Department of Neurology, Westmead Hospital, University of Sydney, Sydney, New South Wales, Australia.

    • Andrew Bleasel
  10. Department of Neurology, The Royal Children's Hospital, Parkville, Melbourne, Victoria, Australia.

    • Katherine B Howell,
    • Mark T Mackay,
    • Jeremy L Freeman &
    • Ingrid E Scheffer
  11. Epilepsy Unit, Schneider Children's Medical Center of Israel, Petach Tikvah, Israel.

    • Sara Kivity
  12. Critical Care & Neurosciences Theme, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia.

    • Mark T Mackay &
    • Jeremy L Freeman
  13. Department of Paediatrics, The University of Melbourne, The Royal Children's Hospital, Melbourne, Victoria, Australia.

    • Mark T Mackay &
    • Ingrid E Scheffer
  14. Paediatric Neurology, Monash Medical Centre, Melbourne, Victoria, Australia.

    • Victoria Rodriguez-Casero
  15. TY Nelson Department of Neurology, The Children's Hospital at Westmead, Sydney, New South Wales, Australia.

    • Richard Webster &
    • Deepak Gill
  16. Department of Neurology, Tel-Aviv University, Tel-Aviv, Israel.

    • Amos Korczyn
  17. Tel-Aviv University Medical School, Tel-Aviv, Israel.

    • Zaid Afawi
  18. Department of Pediatrics, Carmel Medical Center, Technion Faculty of Medicine, Haifa, Israel.

    • Nathanel Zelnick
  19. Metabolic-Neurogenetic Service, Wolfson Medical Center, Holon, Israel.

    • Tally Lerman-Sagie &
    • Dorit Lev
  20. Danish Epilepsy Centre, Dianalund, Denmark.

    • Tally Lerman-Sagie &
    • Rikke S Møller
  21. Department of Medicine, Division of Neurology, University of Toronto, Toronto Western Hospital, Krembil Neurosciences Program, Toronto, Ontario, Canada.

    • Danielle M Andrade
  22. Florey Institute, Melbourne, Victoria, Australia.

    • Ingrid E Scheffer

Contributions

G.L.C., H.C.M. and I.E.S. designed the study and wrote the manuscript. H.C.M. and I.E.S. supervised the study. G.L.C. constructed libraries, developed the variant calling pipeline (with assistance from J.C.) and analyzed the sequence data. B.J.O. and J.S. developed the molecular inversion probe (MIP) methodology and analysis pipeline. S.B.H., S.C.Y., J.M.M., S.C., S.M., G.W., T.S., A.M.E.B., A.B., K.B.H., S.K., M.T.M., V.R.-C., R.W., A. Korczyn, Z.A., N.Z., T.L.-S., D.L., R.S.M., D.G., D.M.A., J.L.F., L.G.S., S.F.B. and I.E.S. performed phenotypic analysis. S.B.H., J.M.M., S.F.B. and I.E.S. critically reviewed the manuscript. G.L.C. and A. Khan performed segregation analysis experiments. M.O.D. and M.W. performed Illumina HiSeq sequencing.

Competing financial interests

The authors declare no competing financial interests.

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