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. 2017 Jun;54(6):390-398.
doi: 10.1136/jmedgenet-2016-104153. Epub 2017 Mar 6.

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

Jamie D Kapplinger  1   2 , Anders Erickson  3 , Sirisha Asuri  4 , David J Tester  5 , Sarah McIntosh  4 , Charles R Kerr  6 , Julie Morrison  7 , Anthony Tang  8 , Shubhayan Sanatani  9 , Laura Arbour  3   4 , Michael J Ackerman  1   2   5   10
Affiliations

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

Jamie D Kapplinger et al. J Med Genet. 2017 Jun.

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.

Keywords: KCNQ1; First Nations; exon skipping; long QT syndrome; modifier.

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Conflict of interest statement

Competing interests: MJA is a consultant for Boston Scientific, Gilead Sciences, Medtronic and St. Jude Medical. MJA and Mayo Clinic receive royalties from Transgenomic for their FAMILION-LQTS and FAMILION-CPVT genetic tests. However, none of these commercial entities supported this research work.

Figures

Figure 1
Figure 1
Pedigree of Family 1 harbouring the KCNQ1 p.V205M, p.L353L and KCNH2 p.K897T variants. The arrow indicates the proband. Note symbols representing the variant status and corrected QT (QTc) values (ms) below each participant.
Figure 2
Figure 2
(A) Adjusted predicted corrected QT (QTc) in interaction regression model in Men. Predicted effects of expected QTc in men with p.V205M and p.L353L variants above baseline QTc of 418.4 ms. (B) Adjusted predicted QTc in interaction regression model in women. Predicted effects of expected QTc in women with p.V205M, p.L353L and p.K879T above 444.3 ms. Both models were adjusted conditionally for age, cardiovascular diseases, past and current alcohol abuse and QT-prolonging drugs. The predicted QTc is shown on the Y-axis in ms and variant status on the X-axis.
Figure 3
Figure 3
Pedigree of Family 2 harbouring the KCNQ1 p.V205M, p.L353L and KCNH2 p.K897T variants. Note three male siblings with p.V205M*p.L353L and high corrected QT (QTc). The arrow indicates the proband. QTc values (ms) are listed below each participant.
Figure 4
Figure 4
Assessment of p.L353L mutant KCNQ1 transcript levels. (A) Gel electrophoresis (amplified using 5F and 10R primers) showing the full-length sequence and alternatively spliced product skipping exon 8 (Δ8). (B) Schematic of primers designed for the selective amplification of the Δ8 transcript (7.9F and 10R), the full-length transcript (8.9F and 10R) and total KCNQ1 transcript (9F and 10R). (C) Graph showing the percentage of KCNQ1 transcripts in p.L353L-positive versus p.L353L-negative individuals. (D) Chart and schematic of the statistical model fitted to a binomial distribution used to predict the likelihood of functional Kv7.1 tetramer formation. WT, wild-type.
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