Variable expression of long QT syndrome among gene carriers from families with five different HERG mutations

Objectives: This study assessed the phenotypic variability of LQTS in carriers with the same and with different mutations in the LQT2 gene. Background: Mutations of ion-channel genes are known to cause the long QT syndrome (LQTS), a disorder associated with distinctive genotypic-specific electrocardiographic patterns and variable clinical expression. Methods: Clinical and electrocardiographic characteristics were assessed in five large LQTS families, each with a different mutation of the HERG gene (LQT2; n = 469, 69% genotyped, 102 carriers). One mutation was located on the N-terminus and the other four on the C-terminus of the HERG channel protein. Results: The QTc duration and the frequency of cardiac events (syncope and LQTS-related cardiac arrest/death) were similar among carriers with the five HERG mutations. QTc was as variable in carriers of the same mutation as it was among carriers with different HFRG mutations (P = 0.19). Qualitative assessment of the electrocardiograms revealed extensive intra-and interfamilial variability in T-wave morphology. Among carriers with multiple electrocardiograms extending over 2 to 7 years, variation in QTc over time was minimal. A strong association was found between QTc and the occurrence of cardiac events in carriers of all five mutations. Conclusions: The clinical expression of LQTS was equally variable in carriers from families with the same or different HERG mutations. These findings highlight the complexity of the clinical phenotype in this Mendelian dominant disorder and suggest that one or more modifier genes contribute to the variable expression of this syndrome.