Introduction:
Voltage-gated Na+ channels are crucial for the amplitude and upstroke of cardiac action potentials (AP), which are important determinants for driving AP propagation and conduction velocity throughout the working myocardium1. Mutations in SCN5A , the gene that encodes Nav1.5, the predominant cardiac Na+ channel, have been implicated in rare familial forms of cardiac arrhythmias such as type 3 long QT syndrome (LQT3) , Brugada syndrome (BS ), progressive cardiac conduction disorder (PCCD ), atrial fibrillation (AFib), and sudden infant death syndrome (SIDS) . Another SCN5Amutation has recently been reported to be involved in dilated cardiomyopathy, a structural heart disease2,3. In addition to their role in changing gating characteristics, there is growing recognition that such mutations may also be associated with alterations in channel protein trafficking and expression levels. SCN5A gene is also the only gene to have a definitive evidence, for clinical validity of BS4.
Long QT syndrome (LQTS) is an inherited cardiac channelopathy that may lead to syncope and even sudden cardiac death as a result of polymorphic ventricular tachycardia known as torsade de pointes. LQTS manifests as a prolonged corrected QT (QTc) interval exceeding 450 ms on 12-lead electrocardiograms (ECG). To date, seventeen genes have been linked to inherited LQTS but only three have shown a definitive evidence as a genetic cause for typical LQTS. Those genes are KCNQ1, KCNH2 and SCN5A5.
LQT3 is caused by mutations in SCN5A genes mapped to chromosome 3q21-24, which encodes the α-subunits of the cardiac Na+ channel6,7. SCN5Amutations have been identified in about 10% of genotyped LQTS patients8. When a patient presents a LQTS, a genetic testing is used to identify the gene that cause the disease. If the gene is identified, then the clinician knows the type of LQTS (LQT1, LQT2 or LQT3)9. The development of arrhythmias is often associated with bradycardia during sleep or relaxation, when the QTc interval is prolonged. The most common mechanism for QT interval prolongation in LQT3 is due to a persistent or a late Na+ current leading to an increase in AP plateau duration6. This can be a substrate for early after depolarizations (EADs), which can potentially trigger ventricular tachyarrhythmias. Most mutations linked to LQT3 are located in exons 23, 26, and 28, which encode the III-IV linker or inactivation gate, the voltage sensor domain, and the C-terminus of the Na+channel, all of which are involved in fast inactivation. These mutations impede the proper closure of the channel during this critical process, resulting in an increase in the number of channels that are unable to reach a stable inactivated state. This leads to a rise in persistent Na+ currents unlike the normal inactivation of WT Na+ channels.
Although SIDS is the leading cause of death in the first year of life, its cause is still unknown. The only recommended preventive measure is to avoid placing infants on their stomachs or sides for sleep10. Several studies have linked SIDS to LQTS11 and have shown that 50% of infants who die of SIDS have a prolonged QTc interval and that a prolonged QTc interval over 440 ms in the first week of life increases the risk of SIDS by a factor of 4112,13.
We report here on two infants who presented with a prolonged QTc interval and who died suddenly, most likely after experiencing ventricular fibrillation. Although the 5- and 12-week-old infants were within the age range during which the incidence of SIDS peaks, their deaths were not attributed to SIDS. A sequencing analysis revealed a heterozygous G‐to‐T base substitution at position 4473 in exon 23 that resulted in a glutamate (E)‐to‐histidine (H) substitution at residue 1491 and a heterozygous G‐to‐T base substitution at position 4442 in exon 23 that resulted in a glycine (G)‐to‐valine (V) substitution at residue 1481. We recorded macroscopic Na+ currents in transfected mammalian cells using the whole-cell configuration of the patch-clamp technique. The data revealed a marked shift of inactivation to more positive potentials, the presence of a persistent Na+ current, and a large increase in the window current. All these characteristics point toward a gain-of-function due to the mutations.