P335Genotype-driven phenotype differences in probands with long QT syndrome
Authors: Jancauskaite D , Sulskute K , Masiuliene R , Adomavicius T , Ramanauskaite I , Preiksaitiene E , Mikstiene V , Barysiene J 
Published: June 2020

Abstract
Background/Introduction. Genetic abnormalities in heart ion channels can predispose life-threatening arrhythmias. Pathogenic genotype is found in the majority of individuals with phenotype of cardiac channelopathies of which long QT syndrome (LQTS) is the most common. However, incomplete penetrance and substantial heterogeneity in genotype-phenotype relationship results in broad clinical disease spectrum.
Purpose. To review data gathered from Vilnius University Hospital Santaros klinikos (VUHSK) probands with LQTS and detect phenotypic differences between groups of individuals according to genetic testing results.
Methods. We retrospectively reviewed data from clinical records of study participants with suspected LQTS who were clinically evaluated and treated at VUHSK in 2013-2019 year period. Probands with performed genetic testing were included for the final evaluation. Based on genetic testing results, the participants were divided into group I, involving patients with established genetic diagnosis, and group II, which included patients with no clinically relevant variants identified. Patients with variants of uncertain significance (VUS) were excluded from further analysis. Main characteristics of clinical manifestation (age during first symptoms, syncope, cardiac arrest, etc), results of instrumental examination (ECG, Holter monitoring, exercise stress test), Schwatz & Crotti score were compared between groups I and II.
Results. LQTS was suspected for 137 patients; genetic testing was performed for 112 probands: 49 (43.8%) patients had pathogenic and likely pathogenic (P/LP) variant; 12 (10.7%) - VUS; 51 (45.5%) - no clinically relevant variant was determined. Phenotype differences of LQTS were compared between two groups: probands with P/PL variant (group I, n = 49); probands with no alteration found (group II, n = 51) (total of 100 patients). The median age of these two groups was 15 [6] years, 31 (31%) were adults, 56 (56%) were female. Most common P/LP variants among probands were identified in KCNQ1 (Type 1), KCNH2 (Type 2) and CACNA1C (Type 8) genes. Participants with P/PL variant had longer QTc interval on ECG (510 ms [37] vs. 500 ms [41], p = 0.011), 24-hour Holter monitoring (510 ms [34] vs. 500 ms [42], p = 0.013) and during 4th minute of recovery from exercise stress test (485 ms [35] vs. 458 ms [52], p = 0.021), compared to individuals without genetic alterations in LQTS genes. The Schwartz & Crotti score was higher in group I than in group II (3.5 [1.5] vs. 3 [1.25], p = 0.026). Other clinical findings did not differ statistically significantly.
Conclusions. Probands with P/PL variants of LQTS had longer QTc intervals and higher Schwartz & Crotti score than patients with no alteration found. Genotype can affect clinical manifestation in patients with LQTS and consequently determine patient’s prognosis and further medical care. Larger scale study is required for more detailed analysis of genotype-driven phenotype differences.