Abstract 3091: The Clinical and Electrocardiographic Phenotype of Unrelated Patients with Genotype-Negative Long QT Syndrome
Long QT syndrome (LQTS) is a heterogeneous group of channelopathies characterized by increased risk of potentially lethal ventricular arrhythmias. LQT1, LQT2, and LQT3 comprise 95% of genetically proven cases and exhibit a number of established genotype-phenotype correlations. The study aimed at examining the phenotypes of genotype-negative LQTS, accounting for ~25% of LQTS cases. An IRB-approved retrospective analysis was conducted on 56 patients (39 female, 25 ± 17 years) who, after genetic testing either in our sudden death genomics laboratory or with the commercially available Familion test, were negative for mutations in the 3 principal LQTS-susceptibility genes (KCNQ1, KCNH2, and SCN5A), and the minor genes underlying LQT5 and LQT6. All had been diagnosed with LQTS, with a clinical diagnostic score of ≥ 3.5 or QTc ≥ 480 ms. The mean diagnostic score was 4.4 (95% CI 4.2 – 4.7); mean QTc was 525 ms (95% CI 508 – 543 ms). Two-thirds were symptomatic (syncope, cardiac arrest, and/or seizures) with exercise-triggered events in 10 (26%). Twenty-one (38%) had a family history of sudden cardiac arrest. ECG showed a T wave pattern suggestive of LQT1 in 32%, LQT2 in 43%, and LQT3 in 18%. In those with exercise-induced symptoms, the ECG was LQT2-like in 50% and LQT1-like in 30%. One patient had post-partum syncope with an LQT2-like ECG. None had an auditory trigger, but 3 patients, all with an LQT2-like ECG, had a family history of auditory-triggered events. One-third of the patients had received an ICD, 58% as secondary prevention. Over 2/3 were on beta-blockers. Among the 45 patients so far tested for mutations in minor LQTS-susceptibility genes, 2 had LQTS-causing mutations in ANKB (LQT4), 1 in SCN4B (LQT10), 1 in AKAP9 (LQT11) and 2 in SNTA1 (LQT12). Genotype-negative patients with a firm LQTS diagnosis show marked phenotypic heterogeneity, suggesting multiple underlying pathogenic pathways. Only a few patients have LQTS-causing mutations in minor genes after complete LQT1–12 genetic testing. Classifying genotype negative patients into LQT1-, LQT2-, or LQT3-like profiles may guide the discovery of novel genes encoding channel interacting proteins corresponding to those specific signaling pathways.