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Am J Hum Genet. 2018 Dec 6;103(6):1022-1029. doi: 10.1016/j.ajhg.2018.10.023.

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

Author information

1
Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, IL 60610, USA.
2
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA; Department of Biochemistry and Molecular Genetics, Anschutz School of Medicine, University of Colorado Denver, Denver, CO 80204, USA.
3
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
4
Laboratory of Neurogenetics, Institute Born-Bunge, University of Antwerp, Antwerp 2610, Belgium; Neurogenetics Group, Center for Molecular Neurology, VIB, Antwerp 2610, Belgium; Department of Neurology, University Hospital Antwerp, Antwerp 2610, Belgium.
5
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA.
6
Epilepsy Research Centre, Department of Medicine, University of Melbourne, Austin Health, Heidelberg, VIC 3084, Australia.
7
Department of Development and Regeneration - Section Pediatric Neurology, University Hospitals KU Leuven, Leuven 3000, Belgium.
8
Department of Pediatric Neurology, University and University Hospital Antwerp, Antwerp 2610, Belgium.
9
University of Alabama at Birmingham, Birmingham, AL 35294, USA.
10
Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA.
11
Department of Neurology, University Hospital Antwerp, Antwerp 2610, Belgium; University of Melbourne, Royal Children's Hospital, Murdoch Children's Research Institute, Florey Institute, Melbourne, VIC 3084, Australia.
12
HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA. Electronic address: gcooper@hudsonalpha.org.
13
Division of Genetic Medicine, Department of Pediatrics, University of Washington, Seattle, WA 98195, USA. Electronic address: hmefford@uw.edu.

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.

KEYWORDS:

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

PMID:
30526861
PMCID:
PMC6288405
[Available on 2019-06-06]
DOI:
10.1016/j.ajhg.2018.10.023
[Indexed for MEDLINE]

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