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. 2024 Jun 3;26(6):euae136.
doi: 10.1093/europace/euae136.

Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients

Charles Morgat  1 , Véronique Fressart  2 , Alessandra Pia Porretta  1   3 , Nathalie Neyroud  4 , Anne Messali  1 , Yassine Temmar  5 , Vincent Algalarrondo  1 , Elodie Surget  1 , Adrien Bloch  2 , Antoine Leenhardt  1 , Isabelle Denjoy  1 , Fabrice Extramiana  1
Affiliations

Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients

Charles Morgat et al. Europace. .

Abstract

Aims: KCNQ1 mutations cause QTc prolongation increasing life-threatening arrhythmias risks. Heterozygous mutations [type 1 long QT syndrome (LQT1)] are common. Homozygous KCNQ1 mutations cause type 1 Jervell and Lange-Nielsen syndrome (JLNS) with deafness and higher sudden cardiac death risk. KCNQ1 variants causing JLNS or LQT1 might have distinct phenotypic expressions in heterozygous patients. The aim of this study is to evaluate QTc duration and incidence of long QT syndrome-related cardiac events according to genetic presentation.

Methods and results: We enrolled LQT1 or JLNS patients with class IV/V KCNQ1 variants from our inherited arrhythmia clinic (September 1993 to January 2023). Medical history, ECG, and follow-up were collected. Additionally, we conducted a thorough literature review for JLNS variants. Survival curves were compared between groups, and multivariate Cox regression models identified genetic and clinical risk factors. Among the 789 KCNQ1 variant carriers, 3 groups were identified: 30 JLNS, 161 heterozygous carriers of JLNS variants (HTZ-JLNS), and 550 LQT1 heterozygous carriers of non-JLNS variants (HTZ-Non-JLNS). At diagnosis, mean age was 3.4 ± 4.7 years for JLNS, 26.7 ± 21 years for HTZ-JLNS, and 26 ± 21 years for HTZ-non-JLNS; 55.3% were female; and the mean QTc was 551 ± 54 ms for JLNS, 441 ± 32 ms for HTZ-JLNS, and 467 ± 36 ms for HTZ-Non-JLNS. Patients with heterozygous JLNS mutations (HTZ-JLNS) represented 22% of heterozygous KCNQ1 variant carriers and had a lower risk of cardiac events than heterozygous non-JLNS variant carriers (HTZ-Non-JLNS) [hazard ratio (HR) = 0.34 (0.22-0.54); P < 0.01]. After multivariate analysis, four genetic parameters were independently associated with events: haploinsufficiency [HR = 0.60 (0.37-0.97); P = 0.04], pore localization [HR = 1.61 (1.14-1.2.26); P < 0.01], C-terminal localization [HR = 0.67 (0.46-0.98); P = 0.04], and group [HR = 0.43 (0.27-0.69); P < 0.01].

Conclusion: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.

Keywords: KCNQ1; Heterozygous carriers; Jervell and Lange–Nielsen syndrome; Risk stratification; Type 1 long QT syndrome.

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Conflict of interest statement

Conflict of interest: none declared.

Figures

Graphical Abstract
Graphical Abstract
Figure 1
Figure 1
Flow chart. JLNS, Jervell and Lange–Nielsen syndrome; LQT1, long QT syndrome type 1; HTZ-JLNS, heterozygous carriers of variants found in the JLNS population; HTZ-Non-JLNS, heterozygous carriers of variants not found in the JLNS population.
Figure 2
Figure 2
Box plot of the distribution of QTc according to the groups at diagnosis.
Figure 3
Figure 3
Survival curves without arrhythmic events (A) and severe arrhythmic events (B) according to the groups. JLNS, Jervell and Lange–Nielsen syndrome; HTZ-JLNS, heterozygous carriers of variants found in the JLNS population; HTZ-Non-JLNS, heterozygous carriers of variants not found in the JLNS population.
Figure 4
Figure 4
Free-event survival curves related to LQT1 JLNS variant carriers (HTZ-Non-Relative-JLNS), relatives of JLNS-affected patients (HTZ-Relative-JLNS) and others LQT1 patients (HTZ-Non-JLNS).
Figure 5
Figure 5
Algorithm for the 15-year AE rate based on QTc, HI, and pore location. HI, haploinsufficiency.
See this image and copyright information in PMC

References

    1. Crotti L, Brugada P, Calkins H, Chevalier P, Conte G, Finocchiaro G et al. From gene-discovery to gene-tailored clinical management: 25 years of research in channelopathies and cardiomyopathies. Europace 2023;25:euad180. - PMC - PubMed
    1. Mousavi Nik A, Gharaie S, Jeong Kim H. Cellular mechanisms of mutations in Kv7.1: auditory functions in Jervell and Lange-Nielsen syndrome vs. Romano Ward syndrome. Front Cell Neurosci 2015;9:32, Available from: http://journal.frontiersin.org/Article/10.3389/fncel.2015.00032/abstract. - DOI - PMC - PubMed
    1. Schwartz PJ, Priori SG, Spazzolini C, Moss AJ, Vincent GM, Napolitano C et al. Genotype-phenotype correlation in the long-QT syndrome: gene-specific triggers for life-threatening arrhythmias. Circulation 2001;103:89–95. - PubMed
    1. Moore JP, Gallotti RG, Shannon KM, Bos JM, Sadeghi E, Strasburger JF et al. Genotype predicts outcomes in fetuses and neonates with severe congenital long QT syndrome. JACC Clin Electrophysiol 2020;6:1561–70. - PMC - PubMed
    1. Yang WP, Levesque PC, Little WA, Conder ML, Shalaby FY, Blanar MA. KvLQT1, a voltage-gated potassium channel responsible for human cardiac arrhythmias. Proc Natl Acad Sci USA 1997;94:4017–21. - PMC - PubMed

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