Abstract 17871: Heterozygous Carriers of KCNQ1 Variants Associated With the Jervell-Lange-Nielsen Syndrome Have a Better Outcome When Compared to Other Type 1 LQTS Patients

Abstract

Background: KCNQ1 mutations are associated with a risk of life-threatening torsade de Pointes. In the most common presentation, the mutation is heterozygous (type 1 LQTS). The homozygous expression causes type 1 Jervell-Lange-Nielsen syndrome (JLNS) with deafness and higher risk of sudden cardiac death. Hypothesis: Heterozygous carriers of JLN mutations would have different phenotype expression than patients carrying other KCNQ1 variants. Aims: To evaluate QTc duration and incidence of LQTS-related cardiac events according to genetic presentation. Methods: All patients with class 4 or 5 KCNQ1 variants for LQT1 or JLNS followed in our center (September 1993 to January 2023) were included. Lifelong Severe Cardiac events (ACA, SCD, appropriate shocks) and cardiac events (severe event + cardiac syncope) were collected.Quantitative data were compared between groups by ANOVA. Kaplan-Meier survival curves with the log-rank test were used to compare survival between the groups. Results: Three groups were identified among 741 LQT1 patients (55.3% female, age at diagnosis 25.2 years); 30 JLNS (group 1), 557 LQT1 carrying heterozygous mutations not found in the JLNS population (group 2), and 154 heterozygous carriers of mutations found in the JLNS population (group 3). QTc interval duration was different between groups (548±60ms, 467±36ms and 450±31ms in group 1, 2, 3 respectively, p<0.001).Patients carrying heterozygous JLN mutations (group 3) had a lower risk for cardiac events than patients with heterozygous non JLN mutations (group2) (HR 0.36 [0.23-0.57]; p<0.01) (Figure). Four parameters were independently associated with cardiac events: QTc (HR 1.01 [1.01-1.01]; p<0.01, haploinsufficiency (HR 0.57 [0.36-0.92]; p<0.05), pore localization (HR 1.63 [1.16-2.30]; p<0.01), and group (HR 0.50 [0.32-0.81]; p<0.01). Conclusion: Heterozygous carriers of JLNS variants have a lower risk of cardiac arrhythmic events that other type 1 LQTS patients.