Royal College of Surgeons in Ireland
Re annotation of 191 developmental and epileptic.....pdf (1.33 MB)

Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A

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journal contribution
posted on 2021-04-16, 11:10 authored by 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 CavalleriGianpiero 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
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 close phenotype/genotype correlation with Dravet syndrome, we screened 122 people with Dravet syndrome or a similar phenotype with a panel of exon sequences representing eight established genes and identified two de novo SCN1A variants that now - through improved gene annotation - are ascribed to residing among our exons. These two (from 122 screened people, 1.6%) molecular diagnoses carry significant clinical implications. Furthermore, we identified a previously classified SCN1A intronic Dravet syndrome-associated variant that now lies within a deeply conserved exon. Our findings illustrate the potential gains of thorough gene annotation in improving diagnostic yields for genetic disorders.


National Human Genome Research Institute (NHGRI) (2U41HG007234)

Wellcome Trust (WT108749/Z/15/Z)

European Molecular Biology Laboratory

Department of Health’s NIHR Biomedical Research Centres funding scheme

Epilepsy Society

Agency for Innovation by Science and Technology

Fund for Scientific Research Flanders (FWO, 1125416N)

Science Foundation Ireland (SFI)

European Regional Development Fund, grant number 16/RC/3948

BOF-University of Antwerp (FFB180053) and FWO (1861419N)



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Published Citation

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 SCN1A. NPJ Genomic Medicine. 2019;4:31.

Publication Date

2 December 2019

PubMed ID



  • FutureNeuro Centre
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Neurological and Psychiatric Disorders


Springer Nature Limited


  • Published Version (Version of Record)