We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies.
Atrial fibrillation (AF) and sinus bradycardia have been reported in patients with short QT syndrome variant 2 (SQT2), which is underlain by gain-of-function mutations in <i>KCNQ1</i> encoding the α subunit of channels carrying slow delayed rectifier potassium current, <i>I</i><sub>Ks</sub>.
Loss-of-function mutations in the gene KCNQ1 encoding the Kv7.1 K(+) channel cause long QT syndrome type 1 (LQT1), whereas gain-of-function mutations are associated with short QT syndrome as well as familial atrial fibrillation (FAF).
This simulation study identifies mechanisms by which cellular electrophysiological changes in the SQT2 (slow delayed rectifier, IKs, -linked) SQTS variant increases arrhythmia risk.
Hence, unlike the known mutations in the two other SQTS forms (N588K in HERG and V307L in KvLQT1), simulations using the D172N and WT/D172N mutations fully accounted for the ECG phenotype of tall and asymmetrically shaped T waves.
Three different gain-of-function mutations in genes encoding for cardiac potassium channels (KCNH2, KCNQ1, and KCNJ2) have been identified up to now to cause short QT syndrome.
A benign variety of the disease has been observed in children with atrial fibrillation and a KCNH2-V141M mutation, and recently a mutation in the cardiac Cl/HCO<sub>3</sub> exchanger AE3 was found to cause SQTS.
Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed.
We obtained high-quality DNA from 70 cases, which were then sequenced for a custom panel of 35 genes, 12 for inherited long- and short-QT syndrome genes (LQT1-LQT12 and SQT1-3), and 23 additional candidate genes derived from genome-wide association studies.
SQT1 variant (linked to the rapid delayed rectifier potassium channel current, IKr) of SQTS, results from an inactivation-attenuated, gain-of-function mutation (N588K) in the KCNH2-encoded potassium channels.
The LQT2 was produced by intravenous infusion with dofetilide (n = 6), quinidine (n = 6) and sotalol (n = 6) whereas the SQTS was induced by intravenous escalating concentrations of nicorandil (n = 7), pinacidil (n = 5) and cromakalim (n = 5).
Gain-of-function mutations to potassium channels mediating the rapid delayed rectifier current, <i>I</i><sub>Kr</sub>, underlie SQTS variant 1 (SQT1), in which treatment with Na<sup>+</sup> and K<sup>+</sup> channel blocking class Ia anti-arrhythmic agents has demonstrated some efficacy.
The average QTc was 314 ± 23 ms. A mutation in genes related to SQTS was found in 23% of the probands; most of them had a gain of function mutation in HERG (SQTS1).
To evaluate the possible diagnosis of SQTS, DNA sequencing of genes known to be associated with SQTS was performed and identified a novel mutation in the KCNH2 gene.
Here, for the first time, electrophysiological effects were studied of a gain-of-function hERG mutation (N588K; responsible for the 'SQT1' variant of the short QT syndrome) on current (I(hERG1a/1b)) carried by co-expressed hERG1a/1b channels.
Although the gain of function for KCNH2 shortened APD in the short-QT syndrome, this simulation study suggested that arrhythmogenesis was associated not only with gain of function, but also with accelerated deactivation of KCNH2.
Oral quinidine is effective in suppressing the gain of function in IKr responsible for some cases of short QT syndrome with a mutation in HERG and thus restoring normal rate dependence of the QT interval and rendering ventricular tachycardia/ventricular fibrillation noninducible.