Re-annotation of 191 developmental and epileptic encephalopathy-associated genes unmasks de novo variants in SCN1A
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Published:2019-12
Issue:1
Volume:4
Page:
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ISSN:2056-7944
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Container-title:npj Genomic Medicine
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language:en
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Short-container-title:npj Genom. Med.
Author:
Steward Charles A.ORCID, Roovers Jolien, Suner Marie-MartheORCID, Gonzalez Jose M., Uszczynska-Ratajczak BarbaraORCID, Pervouchine Dmitri, Fitzgerald Stephen, Viola MargaridaORCID, Stamberger Hannah, Hamdan Fadi F., Ceulemans Berten, Leroy Patricia, Nava Caroline, Lepine Anne, Tapanari Electra, Keiller Don, Abbs Stephen, Sanchis-Juan Alba, Grozeva Detelina, Rogers Anthony S., Diekhans MarkORCID, Guigó Roderic, Petryszak Robert, Minassian Berge A., Cavalleri Gianpiero, Vitsios Dimitrios, Petrovski Slavé, Harrow Jennifer, Flicek PaulORCID, Lucy Raymond F., Lench Nicholas J., Jonghe Peter De, Mudge Jonathan M., Weckhuysen Sarah, Sisodiya Sanjay M., Frankish Adam
Abstract
AbstractThe 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.
Publisher
Springer Science and Business Media LLC
Subject
Genetics(clinical),Genetics,Molecular Biology
Cited by
26 articles.
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