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

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. RogersMark 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

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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.

Original languageEnglish (US)
Article number31
Journalnpj Genomic Medicine
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)


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