The QTc-Polygenic Risk Score (QTc-PRS) and its Contribution to Type 1, Type 2, and Type 3 Long QT Syndrome in Probands and Genotype-Positive Family Members.

Background - Long QT syndrome (LQTS) is characterized by a prolonged heart rate corrected QT interval (QTc). Genome-wide association studies identified common genetic variants that collectively explain ~8-10% of QTc variation in the general population. Methods - Overall, 423 patients with type 1-3 LQTS were genotyped for 61 QTc-associated genetic variants used in a prototype QTc-polygenic risk score (QTc-PRS). A weighted QTc-PRS (range = 0-154.8 ms) was calculated for each patient and the Framingham Heart Study (FHS) population-based reference cohort (n=853). Results - The average QTc-PRS in LQTS was 88.0 ± 7.2 and explained only ~2.0% of the QTc variability. The QTc-PRS in LQTS probands (n=137; 89.3 ± 6.8) was significantly greater than both FHS controls (87.2 ± 7.4, difference-in-means (DIM) ± standard error: 2.1 ± 0.7, P < 0.002) and LQTS genotype-positive family members (87.5 ± 7.4, DIM: 1.8 ± .7, P < 0.009). There was no difference in QTc-PRS between symptomatic (n=156, 88.6 ± 7.3) and asymptomatic patients (n=267; 87.7 ± 7.2, DIM: 0.9 ± 0.7, P = 0.15). LQTS patients with a QTc ≥ 480 ms (n=120) had a significantly higher QTc-PRS (89.3 ± 6.7) than patients with a QTc < 480 ms (n=303, 87.6 ± 7.4, DIM: 1.7 ± 0.8, P < 0.05). There was no difference in QTc-PRS or QTc between genotypes. Conclusions - The QTc-PRS explained < 2% of the QTc variability in our LQT1-3 cohort, contributing 5 times less to their QTc value than in the general population. This prototype QTc-PRS does not distinguish/predict the clinical outcomes of individuals with LQTS.