Clinical Course of Patients with Long-QT Syndrome: Is There a Genotype–Phenotype Relationship?

Objectives: Long-QT syndrome (LQTS) is a cardiac channelopathy with high risk of malignant ventricular arrhythmias and sudden cardiac death (SCD). Although the disease is known for many years, data correlating genotype with clinical phenotype and outcome are limited. We report the clinical course of our patients with LQTS.

Methods: Retrospective chart review of all patients with LQTS who were in care at our institution from July 2007 to December 2018. Biometric data, results of genetic testing, drug, surgical and device therapy, and outcome data were analyzed. Cardiac events (CE) were defined as syncope or documented ventricular arrhythmias prior to initiation of medical therapy. Breakthrough CE (BCE) were recognized after initiation of medical therapy.

Result: Seventy-seven subjects were included. Median age at diagnosis was 13.5 (range, 0–75) years. Genetic testing was performed in all subjects. Causative mutation was detected in 65 of 77 (84.8%) patients, while 9 of 77 (11.6%) were genotype negative. VUS (variant of uncertain significance) were found in 3 of 77 (3.8%) subjects. Locus of mutation was KCNQ1 in 20 of 65 (30.7%), KCNH2 in 19 of 65 (29%), SCN5A in 7 of 65 (11%), KCNE1 in 6 of 65 (9%), KCNE2 in 4 of 65 (6%), KCNJ2 in 4 of 65 (6%), CACNA1C in 2 of 65 (3%), and combined KCNQ1/KCNQ2, DSP/ANK2, KCNQ1/KCNH2 in one subject each. Median QTc (Bazett) was 492 ms (IQR: 455–562 ms). The majority of patients (75 of 77, 97%) was treated with &β-blockers: propranolol in 56 of 77 (73%), metoprolol in 17 of 77 (22%), nadolol 2 of 77 (2.6%). Four of seven patients with an SCN5A mutation were treated with mexiletin in addition to &β-blocker therapy. All patients (4 of 77) with a KCNJ2 mutation were treated with &β-blockers and flecainide. Thirty-nine patients (50.6%) had a CE and 11 of 77 (14.2%) had at least one BCE. Of those 11 subjects, 10 had their BCE under adequately dosed &β-blocker medication. Fifteen of 77 patients left cardiac sympathetis denervation (LCSD), either after BCE under adequate antiarrhytmic medication or as primary prophylaxis to prevent life-threatening VT. Only one subject with LQTS, one had a BCE after LCSD. Thirty-one of 77 of our patients got an ICD. No association/correlation between genotype and clinical phenotype (i.e., incidence of CE or BCE was found).

Conclusion: The present analysis did not reveal an association between LQTS genotype and the subjects’ clinical phenotype with respect to incidence of CE and BCE. However, the results have to be interpreted carefully as this was a single-center analysis and patient number was low. &β-blockers and LCSD were effective in the prevention of BCE in the present population.