TY - JOUR
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 J.
N1 - Funding Information:
We acknowledge our continued partnership with the Gitxsan Health Society and extend our gratitude to the participants and local healthcare providers. JDK thanks the Mayo Clinic Medical Scientist Training Program for fostering an outstanding environment for physician-scientist training. We appreciate Beatrixe Whittome's assistance with data collection and figures and Sorcha Collins' assistance with final formatting. We appreciate Dr Jason D. Roberts' assistance with ECG assessments. 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.
PY - 2017/6/1
Y1 - 2017/6/1
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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U2 - 10.1136/jmedgenet-2016-104153
DO - 10.1136/jmedgenet-2016-104153
M3 - Article
C2 - 28264985
AN - SCOPUS:85019686834
VL - 54
SP - 390
EP - 398
JO - Journal of Medical Genetics
JF - Journal of Medical Genetics
SN - 0022-2593
IS - 6
ER -