Analysis of patients with two major forms of inherited J-wave syndrome (JWS) has uncovered novel variants of the SCN5A gene associated with different forms.
Published online Monday and in the Oct. 19 issue of the Journal of the American College of Cardiology, the study noted that JWSs – made up of the Brugada syndrome (BrS) and early repolarization syndrome (ERS) – are associated with vulnerability to the development of polymorphic ventricular tachycardia and ventricular fibrillation (VT/VF) leading to sudden cardiac death (SCD).
“The appearance of J-waves on the ECG is due to the presence of a prominent transient outward potassium current (Ito)–mediated action potential notch in the ventricular epicardium, but not the endocardium, causing a transmural voltage gradient during early ventricular repolarization,” said the team, led by Zhong-He Zhang, MD, from the Renmin Hospital of Wuhan University and the Hubei Key Laboratory of Cardiology, Wuhan.
The authors noted that delayed depolarization also plays a key role in the pathogenesis of JWS, and that the SCN5A gene encodes the alpha subunit of the voltage-gated Nav1.5 cardiac sodium channel.
“Loss of function in SCN5A has been associated with the development of JWS,” said Zhang and colleagues, noting that since its first identification in 1998 SCN5A has been found to account for 20%-30% of BrS all probands – with more than 350 variants reported.
“SCN5A is responsible for initiating the cardiac action potential,” they added. “Loss of function in SCN5A reduces the excitability of myocardial cells and slows impulse conduction throughout the myocardium.”
The new study aimed to assess distinct differences in features of patients with ERS and BrS carrying pathogenic variants in SCN5A. Zhang and colleagues used a combination of clinical evaluations and next-generation sequencing were to analyze the distinct features between 262 patients with ERS and BrS carrying pathogenic variants in the SCN5A gene.
They found that patients with ERS were more often male and presented at younger ages, but that ERS patients carried pathogenic SCN5A genetic variants less often than those with BrS (9.62% vs 22.90%; P = 0.004). However, patients diagnosed with ERS displayed shorter QRS and QTc than patients with BrS, they said.
“Our results indicate that ERS probands carry SCN5Aþ variants less often than BrS probands, but that SCN5A is nevertheless a major susceptibility gene in ERS as it is in BrS,” the authors said.
Furthermore, the study uncovered 10 novel SCN5A pathogenic variants in patients with ERS and 2 novel variants in BrS.
Five patients were found to have more than two pathogenic SCN5A variants, said the team, noting that these patients displayed longer PR intervals and QRS duration and experienced more major arrhythmia events (MAE) compared with those carrying only a single pathogenic variant.
“Our findings show that patients with multiple pathogenic variants in SCN5A display longer PR intervals and QRS durations and experience more MAE than those carrying only a single pathogenic variant,” said Zhang and colleagues.
“These findings point to SCN5A as a major susceptibility gene in ERS as much as it is in BrS, whereas the lower SCN5Aþ ratio in ERS indicates the difference in underlying electrophysiology,” they added. “Moreover, we identified the first case of fever induced ERS and the associated SCN5A variant.”
The authors added that further research is now needed to define the specific arrhythmic risks associated with the various pathogenic SCN5A variants – both alone and in combination – and their interactions with physiological changes such as fever, autonomic nervous system activity, and metabolic derangements.
Writing in an accompanying editorial Elijah R. Behr, MA, MBBS, MD, from St. George’s University Hospitals, London, noted that BrS and ERS are considered by many to be part of the same spectrum of disease, known as “the J-wave syndromes”, because of similarities in the ECG phenotype of J-point elevation but with differences in location.
“They also have similar therapeutic responses to isoprenaline and quinidine for the treatment of storms and prevention of recurrent ventricular fibrillation,” he noted. “However, sodium channel blocker testing in BrS augments J-point and ST-segment elevation, whereas the response is highly variable in ERS.”
The editorialist noted that the new study identifies yields of pathogenic and likely pathogenic loss-of function variants in the SCN5A gene responsible for the alpha subunit of the cardiac sodium channel—approximately 10% in patients with ERS and 23% in patients with BrS.
He added that his data suggest “there might actually be a common pathophysiological and genetic basis among patients with J-wave syndromes.”
However, he suggested that the differences in manifestation of the disease from people with the same genetic variants of SCN5A mean that “there must be other genetic, epigenetic, or environmental modifiers of phenotype that may alter the location of the putative substrate and associated ECG phenotype in patients with J-wave with SCN5A variants.”
Behr concluded that the “only way” to understand such issues further is to undertake deep phenotyping and genotyping of more patients and to establish genome wide association studies of a large cohort of patients.
“Identifying new loci will stimulate functional research studies and may also lead, in time, to new treatments and the prevention of sudden death,” he said.
Zhang Z-H, Barajas-Martínez H, Xia H, et al. Distinct Features of Probands With Early Repolarization and Brugada Syndromes Carrying SCN5A Pathogenic Variants. J Am Coll Cardiol 2021;78:1603-1617.
Behr ER. J-Wave Syndromes, SCN5A, and Cardiac Conduction Reserve: Two Sides of the Same Coin? J Am Coll Cardiol 2021;78:1618-1620.
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