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

Details

Serval ID
serval:BIB_91AED6A4F57A
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Genetic characterization of KCNQ1 variants improves risk stratification in type 1 long QT syndrome patients.
Journal
Europace
Author(s)
Morgat C., Fressart V., Porretta A.P., Neyroud N., Messali A., Temmar Y., Algalarrondo V., Surget E., Bloch A., Leenhardt A., Denjoy I., Extramiana F.
ISSN
1532-2092 (Electronic)
ISSN-L
1099-5129
Publication state
Published
Issued date
03/06/2024
Peer-reviewed
Oui
Volume
26
Number
6
Language
english
Notes
Publication types: Journal Article
Publication Status: ppublish
Abstract
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.
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].
Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events than other LQT1 patients.
Keywords
Humans, KCNQ1 Potassium Channel/genetics, Female, Male, Risk Assessment, Romano-Ward Syndrome/genetics, Romano-Ward Syndrome/physiopathology, Romano-Ward Syndrome/diagnosis, Risk Factors, Child, Electrocardiography, Child, Preschool, Heterozygote, Mutation, Jervell-Lange Nielsen Syndrome/genetics, Jervell-Lange Nielsen Syndrome/physiopathology, Genetic Predisposition to Disease, Infant, Adult, Adolescent, Phenotype, Retrospective Studies, Death, Sudden, Cardiac/etiology, Young Adult, Incidence, KCNQ1, Heterozygous carriers, Jervell and Lange–Nielsen syndrome, Risk stratification, Type 1 long QT syndrome
Pubmed
Open Access
Yes
Create date
14/06/2024 11:48
Last modification date
02/07/2024 8:36
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