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

Steward, Charles A. and Roovers, Jolien and Suner, Marie-Marthe and Gonzalez, Jose M. and Uszczynska-Ratajczak, Barbara and Pervouchine, Dmitri and Fitzgerald, Stephen and Viola, Margarida and Stamberger, Hannah and Hamdan, Fadi F. and Ceulemans, Berten and Leroy, Patricia and Nava, Caroline and Lepine, Anne and Tapanari, Electra and Keiller, Don and Abbs, Stephen and Sanchis-Juan, Alba and Grozeva, Detelina and Rogers, Anthony S. and Diekhans, Mark and Guigó, Roderic and Petryszak, Robert and Minassian, Berge A. and Cavalleri, Gianpiero and Vitsios, Dimitrios and Petrovski, Slavé and Harrow, Jennifer and Flicek, Paul and Raymond, F. Lucy and Lench, Nicholas J. and De Jonghe, Peter and Mudge, Jonathan M. and Weckhuysen, Sarah and Sisodiya, Sanjay M. and Frankish, Adam (2019) Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A. npj Genomic Medicine, 4 (1). p. 31. ISSN 2056-7944

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Official URL: https://doi.org/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 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.

Item Type: Journal Article
Faculty: Faculty of Science & Engineering
Depositing User: Lisa Blanshard
Date Deposited: 07 Jan 2020 12:47
Last Modified: 24 Apr 2020 15:46
URI: http://arro.anglia.ac.uk/id/eprint/705077

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