Abstract Body (Do not enter title and authors here): Background: Congenital long QT syndrome (LQTS) is characterized by a prolongation of the heart rate-corrected QT interval (QTc) and an increased risk of syncope, seizure and sudden cardiac arrest/death (SCA/SCD). Genome-wide association studies have identified numerous QT interval-influencing loci of small effect sizes. Herein, we sought to investigate whether a polygenic background for the QT interval contributes to the phenotypic heterogeneity in patients with genotype-positive LQTS.

Methods: We used summary statistics from a recent genome-wide meta-analysis for QT interval (n = 117,532) to derive 160 different polygenic scores for QT interval (PGS_QT) using LDpred2-grid, each comprising ~1.4 million common variants with varying assumptions of the underlying genetic architecture. Next, we applied these PGS_QT to predict the QTc value in a genetically unrelated, European ancestry subset of the ‘All of Us’ cohort with available electrocardiogram and genetic data (n=6,404), where the best performing PGS_QT was determined based on explained variance. Next, using 225 patients with genetically confirmed LQTS who were evaluated in the Mayo Clinic Windland Smith Rice Genetic Heart Rhythm Clinic, we tested the effect of the best performing PGS_QT on QTc duration and LQTS-associated cardiac events (defined as a composite of syncope, seizures, sustained ventricular arrhythmia, appropriate ICD shocks, and SCA/SCD) using Bayesian regression models.

Results: Overall, the best performing PGS_QT explained 11.8% of the variance in the QTc in the ‘All of Us’ cohort. Among patients with genotype-positive LQTS (n [%]; KCNQ1 125 [55.6], KCHN2 76 [33.8], SCN5A 21 [9.3], Other 3 [1.3]), those with higher PGS_QT had a higher QTc (predicted mean QTc [95% uncertainty interval], 95^th percentile vs 50^th percentile for PGS_QT, 478 ms [464-491] vs 459 ms [449-468]). In comparison to the median PGS, those LQTS patients with a PGS_QT >95^th percentile were more than twice as likely to have experienced a LQTS-associated cardiac event (Odds ratio [95% UI], 95^th percentile vs 50^th percentile for PGS_QT; 2.16 [1.02-5.41]), (Figure).

Conclusions: Individuals with genotype-positive LQTS who have high polygenic susceptibility for QTc prolongation are more likely to phenotypically exhibit a higher QTc value and experience potentially life-threatening LQTS-associated cardiac events. Accounting for polygenic background may refine risk stratification strategies for patients with genotype-positive LQTS