Allelic variants in long-QT disease genes in patients with drug-associated torsades de pointes

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 approximately 10% to 15% of affected subjects, predominantly in genes encoding ancillary subunits.