Objectives Long QT syndrome (LQTS) is an inherited cardiac disorder characterised by QT prolongation and increased risks of torsade de pointes and sudden death. To date, mutations in 13 genes, including the genes encoding ion channels and their associated proteins, have been identified in hereditary LQTS. However, only 60%–70% of the individuals affected with LQTS could be detected to have mutations in these genes. Approximately 90% of the known mutations were on LQTS1-3 causing genes (KCNQ1, KCNH2 and SCN5A). Since the vast majority of mutation carriers of LQT1-3 presented with genetype-specific ECG patterns, in this study we tested its utility in targeted genotyping in a large cohort of Chinese patients with LQTS.
Methods The ECG pattern guided genotyping was conducted in 75% (112/149) probands with LQTS enrolled in the Chinese Channelopathy Register Study. Probands with atypical ECG patterns were excluded from this study (n = 37). Blood samples of study participants were obtained under written consents. The initial 12-lead ECG of each patient was evaluated. Individuals were considered affected if they have a prolonged QT interval (QTc > 450 ms in male and > 470 ms in females). Patients were predicted as possible LQT1, 2 or 3 (ECG-diagnosis) based on the presence of ECG patterns typical to each genotype. The ECG results were read by two experienced LQTS investigators. Based on the ECG predictions, mutational screening of KCNQ1 or KCNH2 or SCN5A were performed using polymerase chain reaction (PCR) and direct DNA sequence analysis. DNA samples from 50 healthy Han Chinese were served as controls.
Results A total of 67 mutations, including 29 novel mutations, were identified. Of which 26 were KCNQ1, 39 KCNH2 and 2 SCN5A mutations, respectively. Among the 112 patients, the ECG-diagnosis results showed that there were 38 LQT1, 65 LQT2 and 9 LQT3, while gene screening results showed that 26, 48 and 2 patients could be diagnosed genetically as LQT1, LQT2 and LQT3, respectively. The mutational positive rate was 67.9% (76/112) for all patients. To be specific, the ECG predicted genotype matched the mutation results in 68.4% (26/38), 73.8% (48/65) and 22.2% (2/9) for LQT1, LQT2 and LQT3, respectively.
Conclusions The present study shows that the majority mutations harbored by LQTS patients are on LQT1-3 causing genes and LQT2 is the most common in Chinese. ECG prediction-guided genotyping is proven time and economically efficient, except for a low predictable rate of ECG-diagnosis in LQT3. Our experience sheds lights in LQTS studies in developing countries.