KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

Show simple item record

dc.contributor.author Kapplinger, Jamie
dc.contributor.author Erickson, Anders
dc.contributor.author Asuri, Sirisha
dc.contributor.author Tester, David J.
dc.contributor.author McIntosh, Sarah
dc.contributor.author Kerr, Charles R.
dc.contributor.author Morrison, Julie
dc.contributor.author Tang, Anthony
dc.contributor.author Sanatani, Shubhayan
dc.contributor.author Arbour, Laura
dc.contributor.author Ackerman, Michael J.
dc.date.accessioned 2020-04-02T22:29:45Z
dc.date.available 2020-04-02T22:29:45Z
dc.date.copyright 2017 en_US
dc.date.issued 2017
dc.identifier.citation Kapplinger, J. D.; Erickson, A.; Asuri, S.; Tester, D. J.; McIntosh, S.; Kerr, C. R.; … & Ackerman, M. J. (2017). KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1. Journal of Medical Genetics, 54(6), 390-398. DOI: 10.1136/jmedgenet-2016-104153 en_US
dc.identifier.uri http://dx.doi.org/10.1136/jmedgenet-2016-104153
dc.identifier.uri http://hdl.handle.net/1828/11663
dc.description.abstract Background Variable expressivity and incomplete penetrance between individuals with identical long QT syndrome (LQTS) causative mutations largely remain unexplained. Founder populations provide a unique opportunity to explore modifying genetic effects. We examined the role of a novel synonymous KCNQ1 p.L353L variant on the splicing of exon 8 and on heart rate corrected QT interval (QTc) in a population known to have a pathogenic LQTS type 1 (LQTS1) causative mutation, p.V205M, in KCNQ1-encoded Kv7.1. Methods 419 adults were genotyped for p.V205M, p.L353L and a previously described QTc modifier (KCNH2-p.K897T). Adjusted linear regression determined the effect of each variant on QTc, alone and in combination. In addition, peripheral blood RNA was extracted from three controls and three p.L353L-positive individuals. The mutant transcript levels were assessed via qPCR and normalised to overall KCNQ1 transcript levels to assess the effect on splicing. Results For women and men, respectively, p.L353L alone conferred a 10.0 (p=0.064) ms and 14.0 (p=0.014) ms increase in QTc and in men only a significant interaction effect in combination with the p.V205M (34.6 ms, p=0.003) resulting in a QTc of ∼500 ms. The mechanism of p.L353L's effect was attributed to approximately threefold increase in exon 8 exclusion resulting in ∼25% mutant transcripts of the total KCNQ1 transcript levels. Conclusions Our results provide the first evidence that synonymous variants outside the canonical splice sites in KCNQ1 can alter splicing and clinically impact phenotype. Through this mechanism, we identified that p.L353L can precipitate QT prolongation by itself and produce a clinically relevant interactive effect in conjunction with other LQTS variants. en_US
dc.description.sponsorship This work was supported by the Windland Smith Rice Comprehensive Sudden Cardiac Death Program, Rochester, Minnesota (JDK, DJT, MJA). JDK is supported by a National Institutes of Health (NIH)/National Heart, Lung, and Blood Institute (NHLBI) National Research Service Awards (NRSA) Ruth L. Kirschstein individual predoctoral MD/PhD fellowship (F30HL127904) by the NIH grant GM72474-08. The clinical cohort work (LA, SA, AE, CRK, SS, AT) was funded through the Canadian Institutes of Health Research, Ottawa, Ontario, Research grant no. 81197 to LA and AT. en_US
dc.language.iso en en_US
dc.publisher Journal of Medical Genetics en_US
dc.title KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1 en_US
dc.type Article en_US
dc.description.scholarlevel Faculty en_US
dc.description.reviewstatus Reviewed en_US

Files in this item

This item appears in the following Collection(s)

Show simple item record

Search UVicSpace


My Account