Journal article
Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A
CA Steward, J Roovers, MM Suner, JM Gonzalez, B Uszczynska-Ratajczak, D Pervouchine, S Fitzgerald, M Viola, H Stamberger, FF Hamdan, B Ceulemans, P Leroy, C Nava, A Lepine, E Tapanari, D Keiller, S Abbs, A Sanchis-Juan, D Grozeva, AS Rogers Show all
Npj Genomic Medicine | NATURE PORTFOLIO | Published : 2019
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 SCN1A as a case study, due to its cl..
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Awarded by Federal Agency for Science and Innovation
Funding Acknowledgements
We thank the following: all patients, their families and carers 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; Dr. Gautam Ambegaonkar, Dr. Rajiv Chaudhary, Ms Helen Dolling, Ms Margo Elsworth, Dr. Jill Gordon, Dr. Alasdair Parker, Dr. Elizabeth Radford, Ms Kuldeep Stohr (NHS England) for clinical support and advice; Dr. Andrew Jaffe (Lieber Institute for Brain Development, USA) for advice with utilising the 6 different life-stage transcriptomic datasets used in this study; Dr. Matthew Hurles (Wellcome Sanger Institute, UK) for initial discussions regarding this study. We also thank Imogen and Jasper Steward, both of whom have rare neurological disorders and have been instrumental in driving this study. This work was supported in part by the National Human Genome Research Institute (NHGRI) (2U41HG007234), Wellcome Trust (WT108749/Z/15/Z) and the European Molecular Biology Laboratory. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The work was partly undertaken at UCLH/UCL, which received a proportion of funding from the Department of Health's NIHR Biomedical Research Centres funding scheme. S.M.S. is partly supported by the Epilepsy Society. J.R. is funded by the Agency for Innovation by Science and Technology, IWT. H.S. is a PhD fellow of the Fund for Scientific Research Flanders (FWO, 1125416N). G.C. was funded by Science Foundation Ireland (SFI) and the European Regional Development Fund, grant number 16/RC/3948. S.W. is partly supported by the BOF-University of Antwerp (FFB180053) and FWO (1861419N).