Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes

TLDR

DNA variants in congenital long‑QT genes have been reported to predispose individuals to drug‑associated long‑QT syndrome. The study aimed to quantify how frequently these genetic risk factors occur in a large cohort of patients with drug‑associated long‑QT syndrome. The authors screened the coding regions of KvLQT1, HERG, and SCN5A in 92 aLQTS patients and in control groups of drug‑tolerant patients and population samples. In the aLQTS cohort, 10–15 % carried pathogenic variants—mostly in ancillary subunit genes—while common polymorphisms were equally frequent in controls, and functional assays showed that KvLQT1 and HERG missense mutations reduced K⁺ currents but SCN5A variants had no effect on Na⁺ currents.

Abstract

Background — DNA variants appearing to predispose to drug-associated “acquired” long-QT syndrome (aLQTS) have been reported in congenital long-QT disease genes. However, the incidence of these genetic risk factors has not been systematically evaluated in a large set of patients with aLQTS. We have previously identified functionally important DNA variants in genes encoding K + channel ancillary subunits in 11% of an aLQTS cohort. Methods and Results — The coding regions of the genes encoding the pore-forming channel proteins KvLQT1, HERG, and SCN5A were screened in (1) the same aLQTS cohort (n=92) and (2) controls, drawn from patients tolerating QT-prolonging drugs (n=67) and cross sections of the Middle Tennessee (n=71) and US populations (n=90). The frequency of three common nonsynonymous coding region polymorphisms was no different between aLQTS and control subjects, as follows: 24% versus 19% for H558R (SCN5A), 3% versus 3% for R34C (SCN5A), and 14% versus 14% for K897T (HERG). Missense mutations (absent in controls) were identified in 5 of 92 patients. KvLQT1 and HERG mutations (one each) reduced K + currents in vitro, consistent with the idea that they augment risk for aLQTS. However, three SCN5A variants did not alter I Na , which argues that they played no role in the aLQTS phenotype. Conclusions — DNA variants in the coding regions of congenital long-QT disease genes predisposing to aLQTS can be identified in ≈10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.