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

Medical genomics Molecular medicine

Journal

NPJ genomic medicine
ISSN: 2056-7944
Titre abrégé: NPJ Genom Med
Pays: England
ID NLM: 101685193

Informations de publication

Date de publication:
2019
Historique:
received: 31 05 2019
accepted: 01 11 2019
entrez: 10 12 2019
pubmed: 10 12 2019
medline: 10 12 2019
Statut: epublish

Résumé

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

Identifiants

pubmed: 31814998
doi: 10.1038/s41525-019-0106-7
pii: 106
pmc: PMC6889285
doi:

Types de publication

Journal Article

Langues

eng

Pagination

31

Subventions

Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NHGRI NIH HHS
ID : U41 HG007234
Pays : United States

Informations de copyright

© The Author(s) 2019.

Déclaration de conflit d'intérêts

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 and D.V. is a postdoc of AstraZeneca. The remaining authors declare they have no competing interests.

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Auteurs

Charles A Steward (CA)

Congenica Ltd, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1DR UK.
2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.

Jolien Roovers (J)

3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Marie-Marthe Suner (MM)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Jose M Gonzalez (JM)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Barbara Uszczynska-Ratajczak (B)

6Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
7Universitat Pompeu Fabra (UPF), Barcelona, Spain.
8Centre of New Technologies, University of Warsaw, Warsaw, Poland.

Dmitri Pervouchine (D)

Skolkovo Institute for Science and Technology 3 Nobel St., Skolkovo Innovation Centre, Moscow, Russia.

Stephen Fitzgerald (S)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.

Margarida Viola (M)

3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.

Hannah Stamberger (H)

3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
10Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.

Fadi F Hamdan (FF)

11Molecular Diagnostic Laboratory and Division of Medical Genetics, Department of Pediatrics, CHU Sainte-Justine, Montreal, H3T 1C5 Canada.

Berten Ceulemans (B)

12Department of Pediatric Neurology, University Hospital Antwerp, Antwerp, Belgium.

Patricia Leroy (P)

Department of Neuropediatrics, CHR Citadelle, CHU Sart-Tilman, Liège, Belgium.

Caroline Nava (C)

14Department of Genetics, La Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris, Paris, France.
15Sorbonne Universities, UPMC Univ Paris 06, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France.

Anne Lepine (A)

16Pediatric Neurology Department, Timone Hospital, APHM, Marseille, France.

Electra Tapanari (E)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Don Keiller (D)

17Anglia Ruskin University, Cambridge, CB1 1PT UK.

Stephen Abbs (S)

18Department of Clinical Genetics, Cambridge University Hospitals NHS Foundation Trust, Cambridge, CB2 0QQ UK.

Alba Sanchis-Juan (A)

19Department of Haematology, University of Cambridge, NHS Blood and Transplant Centre, Cambridge, CB2 0PT UK.

Detelina Grozeva (D)

20Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY UK.

Anthony S Rogers (AS)

Congenica Ltd, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1DR UK.

Mark Diekhans (M)

21Center for Biomolecular Science and Engineering, University of California, Santa Cruz, CA USA.

Roderic Guigó (R)

6Centre for Genomic Regulation (CRG), Barcelona Institute of Science and Technology, Dr. Aiguader 88, 08003 Barcelona, Spain.
7Universitat Pompeu Fabra (UPF), Barcelona, Spain.

Robert Petryszak (R)

5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Berge A Minassian (BA)

22The Hospital for Sick Children, Toronto, Canada.
23Department of Pediatrics (Neurology), University of Texas Southwestern, Dallas, Texas USA.

Gianpiero Cavalleri (G)

24The FutureNeuro Research Centre, Royal College of Surgeons in Ireland, Dublin, Ireland.

Dimitrios Vitsios (D)

25Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 0AA UK.

Slavé Petrovski (S)

25Centre for Genomics Research, Precision Medicine and Genomics, IMED Biotech Unit, AstraZeneca, Cambridge, CB2 0AA UK.

Jennifer Harrow (J)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.
26Illumina Inc, Great Chesterford, Essex, CB10 1XL UK.

Paul Flicek (P)

5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

F Lucy Raymond (F)

20Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY UK.

Nicholas J Lench (NJ)

Congenica Ltd, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1DR UK.
27North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK.

Peter De Jonghe (P)

3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
10Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.

Jonathan M Mudge (JM)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Sarah Weckhuysen (S)

3Neurogenetics Group, Center for Molecular Neurology, University of Antwerp, Antwerp, Belgium.
4Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp, Belgium.
10Department of Neurology, University Hospital Antwerp, Antwerp, Belgium.

Sanjay M Sisodiya (SM)

28Department of Clinical and Experimental Epilepsy, UCL Queen Square Institute of Neurology, London, WC1N 3BG UK.
Chalfont Centre for Epilepsy, Bucks, SL9 0RJ UK.

Adam Frankish (A)

2Wellcome Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SA UK.
5European Molecular Biology Laboratory, European Bioinformatics Institute, EMBL-EBI, Wellcome Genome Campus, Hinxton, Cambridge, CB10 1SD UK.

Classifications MeSH