Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome
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Hammer, Michael F.
Ishii, Atsushi
Johnstone, Laurel
Tchourbanov, Alexander
Lau, Branden
Sprissler, Ryan
Hallmark, Brian
Zhang, Miao
Zhou, Jin
Watkins, Joseph
Hirose, Shinichi
Affiliation
Univ Arizona, ARL Div BiotechnolUniv Arizona, Neurol Dept
Univ Arizona, Interdisciplinary Program Stat
Univ Arizona, Coll Publ Hlth
Univ Arizona, Dept Math
Issue Date
2017-07-07
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PUBLIC LIBRARY SCIENCECitation
Rare variants of small effect size in neuronal excitability genes influence clinical outcome in Japanese cases of SCN1A truncation-positive Dravet syndrome 2017, 12 (7):e0180485 PLOS ONEJournal
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© 2017 Hammer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.Collection Information
This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at repository@u.library.arizona.edu.Abstract
Dravet syndrome (DS) is a rare, devastating form of childhood epilepsy that is often associated with mutations in the voltage-gated sodium channel gene, SCN1A. There is considerable variability in expressivity within families, as well as among individuals carrying the same primary mutation, suggesting that clinical outcome is modulated by variants at other genes. To identify modifier gene variants that contribute to clinical outcome, we sequenced the exomes of 22 individuals at both ends of a phenotype distribution (i. e., mild and severe cognitive condition). We controlled for variation associated with different mutation types by limiting inclusion to individuals with a de novo truncation mutation resulting in SCN1A haploinsufficiency. We performed tests aimed at identifying 1) single common variants that are enriched in either phenotypic group, 2) sets of common or rare variants aggregated in and around genes associated with clinical outcome, and 3) rare variants in 237 candidate genes associated with neuronal excitability. While our power to identify enrichment of a common variant in either phenotypic group is limited as a result of the rarity of mild phenotypes in individuals with SCN1A truncation variants, our top candidates did not map to functional regions of genes, or in genes that are known to be associated with neurological pathways. In contrast, we found a statistically-significant excess of rare variants predicted to be damaging and of small effect size in genes associated with neuronal excitability in severely affected individuals. A KCNQ2 variant previously associated with benign neonatal seizures is present in 3 of 12 individuals in the severe category. To compare our results with the healthy population, we performed a similar analysis on whole exome sequencing data from 70 Japanese individuals in the 1000 genomes project. Interestingly, the frequency of rare damaging variants in the same set of neuronal excitability genes in healthy individuals is nearly as high as in severely affected individuals. Rather than a single common gene/variant modifying clinical outcome in SCN1A-related epilepsies, our results point to the cumulative effect of rare variants with little to no measurable phenotypic effect (i.e., typical genetic background) unless present in combination with a disease-causing truncation mutation in SCN1A.Note
Open access journal.ISSN
1932-6203Version
Final published versionSponsors
Dravet Syndrome FoundationAdditional Links
http://dx.plos.org/10.1371/journal.pone.0180485ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0180485
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Except where otherwise noted, this item's license is described as © 2017 Hammer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License.