@article{cd265088c82443e4b7ffb575fca161fc,
title = "Aberrant Inclusion of a Poison Exon Causes Dravet Syndrome and Related SCN1A-Associated Genetic Epilepsies",
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",
author = "{EuroEPINOMICS Rare Epilepsy Syndrome, Myoclonic-Astatic Epilepsy, and Dravet Working Group} and Carvill, {Gemma L.} and Engel, {Krysta L.} and Aishwarya Ramamurthy and Cochran, {J. Nicholas} and Jolien Roovers and Hannah Stamberger and Nicholas Lim and Schneider, {Amy L.} and Georgie Hollingsworth and Holder, {Dylan H.} and Regan, {Brigid M.} and James Lawlor and Lieven Lagae and Berten Ceulemans and Bebin, {E. Martina} and John Nguyen and Pasquale Striano and Federico Zara and Ingo Helbig and M{\o}ller, {Rikke S.} and {von Spiczak}, Sarah and Hiltrud Muhle and Hande Caglayan and Katalin Sterbova and Dana Craiu and Dorota Hoffman and Lehesjoki, {Anna Elina} and Kaja Selmer and Christel Depienne and Johannes Lemke and Carla Marini and Renzo Guerrini and Bernd Neubauer and Tiina Talvik and Eric Leguern and {de Jonghe}, Peter and Sarah Weckhuysen and Barsh, {Gregory S.} and Sarah Weckhuysen and Miriam Meisler and Berkovic, {Samuel F.} and {De Jonghe}, Peter and Scheffer, {Ingrid E.} and Myers, {Richard M.} and Cooper, {Gregory M.} and Mefford, {Heather C.}",
note = "Funding Information: 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). Funding Information: 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{\textquoteright}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 ). Publisher Copyright: {\textcopyright} 2018 American Society of Human Genetics",
year = "2018",
month = dec,
day = "6",
doi = "10.1016/j.ajhg.2018.10.023",
language = "English (US)",
volume = "103",
pages = "1022--1029",
journal = "American Journal of Human Genetics",
issn = "0002-9297",
publisher = "Cell Press",
number = "6",
}