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Steward CA, Roovers J, Suner MM, et al. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in . NPJ Genom Med. 2019;4:31doi: 10.1038/s41525-019-0106-7.
Steward, C. A., Roovers, J., Suner, M. M., Gonzalez, J. M., Uszczynska-Ratajczak, B., Pervouchine, D., Fitzgerald, S., Viola, M., Stamberger, H., Hamdan, F. F., Ceulemans, B., Leroy, P., Nava, C., Lepine, A., Tapanari, E., Keiller, D., Abbs, S., Sanchis-Juan, A., Grozeva, D., Rogers, A. S., Diekhans, M., Guigó, R., Petryszak, R., Minassian, B. A., Cavalleri, G., Vitsios, D., Petrovski, S., Harrow, J., Flicek, P., Lucy Raymond, F., Lench, N. J., Jonghe, P., Mudge, J. M., Weckhuysen, S., Sisodiya, S. M., & Frankish, A. (2019). Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in . NPJ genomic medicine, 431. https://doi.org/10.1038/s41525-019-0106-7
Steward, Charles A, et al. "Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in ." NPJ genomic medicine vol. 4 (2019): 31. doi: https://doi.org/10.1038/s41525-019-0106-7
Steward CA, Roovers J, Suner MM, Gonzalez JM, Uszczynska-Ratajczak B, Pervouchine D, Fitzgerald S, Viola M, Stamberger H, Hamdan FF, Ceulemans B, Leroy P, Nava C, Lepine A, Tapanari E, Keiller D, Abbs S, Sanchis-Juan A, Grozeva D, Rogers AS, Diekhans M, Guigó R, Petryszak R, Minassian BA, Cavalleri G, Vitsios D, Petrovski S, Harrow J, Flicek P, Lucy Raymond F, Lench NJ, Jonghe P, Mudge JM, Weckhuysen S, Sisodiya SM, Frankish A. Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in . NPJ Genom Med. 2019 Dec 02;4:31. doi: 10.1038/s41525-019-0106-7. eCollection 2019. PMID: 31814998; PMCID: PMC6889285.
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NPJ Genom Med. 2019 Dec 02;4:31. doi: 10.1038/s41525-019-0106-7. eCollection 2019.

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in .

NPJ genomic medicine

Charles A Steward, Jolien Roovers, Marie-Marthe Suner, Jose M Gonzalez, Barbara Uszczynska-Ratajczak, Dmitri Pervouchine, Stephen Fitzgerald, Margarida Viola, Hannah Stamberger, Fadi F Hamdan, Berten Ceulemans, Patricia Leroy, Caroline Nava, Anne Lepine, Electra Tapanari, Don Keiller, Stephen Abbs, Alba Sanchis-Juan, Detelina Grozeva, Anthony S Rogers, Mark Diekhans, Roderic Guigó, Robert Petryszak, Berge A Minassian, Gianpiero Cavalleri, Dimitrios Vitsios, Slavé Petrovski, Jennifer Harrow, Paul Flicek, F Lucy Raymond, Nicholas J Lench, Peter De Jonghe, Jonathan M Mudge, Sarah Weckhuysen, Sanjay M Sisodiya, Adam Frankish

Affiliations

  1. Congenica Ltd, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1DR UK.
  2. 2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
  3. 3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
  4. 4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
  5. 5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
  6. 6Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
  7. 7Universitat Pompeu Fabra (UPF), Barcelona, Spain.
  8. 8Centre of New Technologies, University of Warsaw, Warsaw, Poland.
  9. Skolkovo Institute for Science and Technology 3 Nobel St., Skolkovo Innovation Centre, Moscow, Russia.
  10. 10Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.
  11. 11Molecular Diagnostic Laboratory and Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, H3T 1C5 Canada.
  12. 12Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.
  13. Department of Neuropediatrics, CHR Citadelle, CHU Sart-Tilman, Liège, Belgium.
  14. 14Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
  15. 15Sorbonne Universities, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.
  16. 16Pediatric Neurology Department, Timone Hospital, APHM, Marseille, France.
  17. 17Anglia Ruskin University, Cambridge, CB1 1PT UK.
  18. 18Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ UK.
  19. 19Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, CB2 0PT UK.
  20. 20Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY UK.
  21. 21Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA USA.
  22. 22The Hospital for Sick Children, Toronto, Canada.
  23. 23Department of Pediatrics (Neurology), University of Texas Southwestern, Dallas, Texas USA.
  24. 24The FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.
  25. 25Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 0AA UK.
  26. 26Illumina Inc, Great Chesterford, Essex, CB10 1XL UK.
  27. 27North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.
  28. 28Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG UK.
  29. Chalfont Centre for Epilepsy, Bucks, SL9 0RJ UK.

PMID: 31814998 PMCID: PMC6889285 DOI: 10.1038/s41525-019-0106-7

Abstract

The developmental and epileptic encephalopathies (DEE) are a group of rare, severe neurodevelopmental disorders, where even the most thorough sequencing studies leave 60-65% of patients without a molecular diagnosis. Here, we explore the incompleteness of transcript models used for exome and genome analysis as one potential explanation for a lack of current diagnoses. Therefore, we have updated the GENCODE gene annotation for 191 epilepsy-associated genes, using human brain-derived transcriptomic libraries and other data to build 3,550 putative transcript models. Our annotations increase the transcriptional 'footprint' of these genes by over 674 kb. Using

© The Author(s) 2019.

Keywords: Medical genomics; Molecular medicine

Conflict of interest statement

Competing interestsC.A.S., A.S.R. and N.J.L. are employed by Congenica Ltd. P.F. is a member of the scientific advisory boards for Fabric Genomics, Inc., and Eagle Genomics, Ltd. S.P. is an employee a

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