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 language | English (US) |
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Pages (from-to) | 1022-1029 |
Number of pages | 8 |
Journal | American journal of human genetics |
Volume | 103 |
Issue number | 6 |
DOIs | |
State | Published - Dec 6 2018 |
Funding
We thank the affected individuals and their families for participating in our research programs. G.L.C. is supported by the NIH (NINDS R00 NS089858) and the Junior Investigator Kevin's Fellows Award sponsored by the American Epilepsy Society and the Epilepsy Foundation. H.C.M. is supported by the NIH (NINDS R01 NS069605). I.E.S. and S.F.B. are supported by funding from the National Health and Medical Research Council of Australia. Work by authors at HudsonAlpha was supported by grants from the National Human Genome Research Institute (UM1HG007301) and National Cancer Institute (R01CA197139). We thank the affected individuals and their families for participating in our research programs. G.L.C. is supported by the NIH ( NINDS R00 NS089858 ) and the Junior Investigator Kevin’s Fellows Award sponsored by the American Epilepsy Society and the Epilepsy Foundation . H.C.M. is supported by the NIH ( NINDS R01 NS069605 ). I.E.S. and S.F.B. are supported by funding from the National Health and Medical Research Council of Australia . Work by authors at HudsonAlpha was supported by grants from the National Human Genome Research Institute ( UM1HG007301 ) and National Cancer Institute ( R01CA197139 ).
Keywords
- Dravet syndrome
- SCN1A
- alternative splicing
- epilepsy
- genome sequencing
- noncoding
- poison exon
- variant interpretation
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)