Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies

EuroEPINOMICS Rare Epilepsy Syndrome, Myoclonic-Astatic Epilepsy, and Dravet Working Group

Research output: Contribution to journalArticlepeer-review

36 Scopus citations

Abstract

Developmental and epileptic encephalopathies (DEEs) are a group of severe epilepsies characterized by refractory seizures and developmental impairment. Sequencing approaches have identified causal genetic variants in only about 50% of individuals with DEEs.1–3 This suggests that unknown genetic etiologies exist, potentially in the ∼98% of human genomes not covered by exome sequencing (ES). Here we describe seven likely pathogenic variants in regions outside of the annotated coding exons of the most frequently implicated epilepsy gene, SCN1A, encoding the alpha-1 sodium channel subunit. We provide evidence that five of these variants promote inclusion of a “poison” exon that leads to reduced amounts of full-length SCN1A protein. This mechanism is likely to be broadly relevant to human disease; transcriptome studies have revealed hundreds of poison exons,4,5 including some present within genes encoding other sodium channels and in genes involved in neurodevelopment more broadly.6 Future research on the mechanisms that govern neuronal-specific splicing behavior might allow researchers to co-opt this system for RNA therapeutics.

Original languageEnglish (US)
Pages (from-to)1022-1029
Number of pages8
JournalAmerican journal of human genetics
Volume103
Issue number6
DOIs
StatePublished - Dec 6 2018

Keywords

  • Dravet syndrome
  • SCN1A
  • alternative splicing
  • epilepsy
  • genome sequencing
  • noncoding
  • poison exon
  • variant interpretation

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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