The congenital LQTS is characterized by prolongation of the ventricular myocardial action potential due to the increase in sodium and calcium input currents (INa and ICaL) or the decrease in potassium outflow currents (IKs, IKr and IK1). Molecular genetic studies identified mutations in 20 different genes that encode the subunits of cardiac ion channels and/or modulator proteins that directly or indirectly intervene in the formation of these currents [7, 14].
The KCNH2 (potassium voltage-gated channel subfamily H member 2) gene also known as hERG (human Ether-à-go-go-Related Gene) which is located on chromosome 7 (locus 7q35–36) is composed of 15 exons that encode the alpha subunit of the voltage-dependent potassium channel called Kv11.1 of 1159 amino acids. Four alpha subunits of Kv11.1 assemble a tetrameric ionic channel that generates the rapidly activating delayed rectifier potassium current (IKr) during phase 3 of the repolarization of myocardial cells. The loss of ion channel function results in increase in the duration of myocardial action potentials manifested as prolonged QT intervals in the ECG of patients with LQTS type 2 [15, 16].
Approximately 40% of KCNH2 gene mutations related to LQTS type 2 are: (a) nonsense mutations (point mutation in a sequence of DNA that results in a premature stop codon) or (b) frameshift mutation caused by the insertion or deletion of nucleotides in a DNA sequence and results a completely different reading frame from the original [15]. These mutations alter protein synthesis and generate defective alpha subunits of Kv11.1 channel. The remaining 60% of the mutations of KCNH2 gene are missense mutations, where a single nucleotide change alters an amino acid codon causing loss of channel function by disrupting the intracellular traffic of Kv11.1 to the cell membrane, altering channel gating or negatively affecting ion permeability [15, 17].
In heterozygous mutations of KCNH2 encoding truncated alpha subunits of Kv11.1 or disrupting intracellular traffic, the defective proteins are degraded by proteasomes. If alpha subunits encoded from the wild-type allele are still homomerized to form functional channels, the affected individuals manifest a less severe phenotype (haploinsufficiency). In contrast, individuals with point mutations that alter channel permeability or gating can assemble Kv11.1 heteromeric dysfunctional channels with alpha subunits encoded by both alleles (wild-type and mutant) and manifest a more severe phenotype (negative dominance) [18, 19].
In the sudden death risk stratification of patients with long QT syndrome, all patients with a mutation at the KCNQ1 gene (LQT1 locus) who have a QTc of 500 ms or more, male patients with a mutation at the KCNH2 gene (LQT2 locus) who have a QTc of 500 ms or more, all female patients with a mutation at the LQT2 locus irrespective of the QTc, and all patients with a mutation at the SCN5A gene (LQT3 locus) are considered high risk [20]. Most members of proband’s family, irrespective of the sex, had QT interval of 500 ms or more (Fig. 1b) and recurrent episodes of syncope.
At present, the beneficial effect of beta blockers in the treatment of patients with LQTS is clear. There is consensus that nadolol, unfortunately not available in all countries (including Argentina since 2016), is probably one of the most effective drugs. The efficacy of other more commonly prescribed beta-blockers such as propranolol, metoprolol, and atenolol is in dispute, especially in symptomatic patients [21, 22].
For patients with symptomatic LQTS in whom the beta-blocker is ineffective or poorly tolerated, left cardiac sympathetic denervation (LCSD) and/or an ICD are recommended [3, 13]. LCSD may be more effective in patients with long QT syndrome type 1. Although a marked reduction in the incidence of aborted cardiac arrest and syncope is usually seen after LCSD, 20% to 50% of patients with high-risk LQTS have experienced at least 1 recurrent arrhythmic event after LCSD [23, 24]. Therefore, LCSD is an important therapeutic option for the management of patients with a first episode of syncope that occurs despite beta-blocker therapy, but it should not be considered as a curative or alternative to ICD in patients with high risk of sudden cardiac death [25].
The genetic variant identified in this family is due to a heterozygous mutation resulting in a premature stop codon. According to the literature, these mutations would lead to haploinsufficiency causing a mild phenotype because there would be up to 50% loss of function, while the remaining wild-type Kv11.1 channels function normally [15, 18, 19].
However, the clinical and genetic findings of this family demonstrate that the mutations that cause haploinsufficiency can result in LQTS with a severe phenotypic manifestation and risk of arrhythmic events.