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

Jamie D. Kapplinger, Anders Erickson, Sirisha Asuri, David J. Tester, Sarah McIntosh, Charles R. Kerr, Julie Morrison, Anthony Tang, Shubhayan Sanatani, Laura Arbour, Michael John Ackerman

Research output: Contribution to journalArticle

6 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)390-398
Number of pages9
JournalJournal of Medical Genetics
Volume54
Issue number6
DOIs
StatePublished - Jun 1 2017

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Romano-Ward Syndrome
Long QT Syndrome
Exons
Phenotype
Mutation
Penetrance
Population
Linear Models
Heart Rate
RNA

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1. / Kapplinger, Jamie D.; Erickson, Anders; Asuri, Sirisha; Tester, David J.; McIntosh, Sarah; Kerr, Charles R.; Morrison, Julie; Tang, Anthony; Sanatani, Shubhayan; Arbour, Laura; Ackerman, Michael John.

In: Journal of Medical Genetics, Vol. 54, No. 6, 01.06.2017, p. 390-398.

Research output: Contribution to journalArticle

Kapplinger, JD, Erickson, A, Asuri, S, Tester, DJ, McIntosh, S, Kerr, CR, Morrison, J, Tang, A, Sanatani, S, Arbour, L & Ackerman, MJ 2017, 'KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1', Journal of Medical Genetics, vol. 54, no. 6, pp. 390-398. https://doi.org/10.1136/jmedgenet-2016-104153
Kapplinger, Jamie D. ; Erickson, Anders ; Asuri, Sirisha ; Tester, David J. ; McIntosh, Sarah ; Kerr, Charles R. ; Morrison, Julie ; Tang, Anthony ; Sanatani, Shubhayan ; Arbour, Laura ; Ackerman, Michael John. / KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1. In: Journal of Medical Genetics. 2017 ; Vol. 54, No. 6. pp. 390-398.
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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.",
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T1 - KCNQ1 p.L353L affects splicing and modifies the phenotype in a founder population with long QT syndrome type 1

AU - Kapplinger, Jamie D.

AU - Erickson, Anders

AU - Asuri, Sirisha

AU - Tester, David J.

AU - McIntosh, Sarah

AU - Kerr, Charles R.

AU - Morrison, Julie

AU - Tang, Anthony

AU - Sanatani, Shubhayan

AU - Arbour, Laura

AU - Ackerman, Michael John

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N2 - 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.

AB - 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.

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