Clinical Spectrum of SCN5A Channelopathy in Children with Primary Electrical Disease and Structurally Normal Hearts.

Teresa Villarreal-Molina,Argelia Medeiros-Domingo,Pedro Iturralde,Mayra Domínguez-Pérez,Álvaro E Reyes-Quintero,Leonor Jacobo-Albavera,Gabriela Paola García-Ordóñez,Alessandra Carnevale,Santiago Nava

doi:10.3390/genes13010016

Teresa Villarreal-Molina, Argelia Medeiros-Domingo + Show 7 more

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https://doi.org/10.3390/genes13010016

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Abstract

Sodium voltage-gated channel α subunit 5 (SCN5A)-mutations may cause an array of arrhythmogenic syndromes most frequently as an autosomal dominant trait, with incomplete penetrance, variable expressivity and male predominance. In the present study, we retrospectively describe a group of Mexican patients with SCN5A-disease causing variants in whom the onset of symptoms occurred in the pediatric age range. The study included 17 patients with clinical diagnosis of primary electrical disease, at least one SCN5A pathogenic or likely pathogenic mutation and age of onset <18 years, and all available first- and second-degree relatives. Fifteen patients (88.2%) were male, and sixteen independent variants were found (twelve missense, three truncating and one complex inframe deletion/insertion). The frequency of compound heterozygosity was remarkably high (3/17, 17.6%), with early childhood onset and severe disease. Overall, 70.6% of pediatric patients presented with overlap syndrome, 11.8% with isolated sick sinus syndrome, 11.8% with isolated Brugada syndrome (BrS) and 5.9% with isolated type 3 long QT syndrome (LQTS). A total of 24/45 SCN5A mutation carriers were affected (overall penetrance 53.3%), and penetrance was higher in males (63.3%, 19 affected/30 mutation carriers) than in females (33.3%, 5 affected/15 carriers). In conclusion, pediatric patients with SCNA-disease causing variants presented mainly as overlap syndrome, with predominant loss-of-function phenotypes of sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD) and ventricular arrhythmias.

Highlights

The function of the cardiac voltage-gated sodium channel α subunit protein (NaV 1.5)is crucial because it initiates the cardiac action potential by generating the inward sodium current (INa ), which mediates cardiomyocyte excitability and impulse conduction in the myocardium and specialized conduction system
Sodium channel α-subunits are traditionally believed to form functional monomers, some SCN5A mutation studies in patients with inherited arrhythmias indicate that oligomerization of the sodium channel α-subunits may occur, and recent experiments suggested that sodium channel α-subunits physically interact, assemble, function and gate as a dimer [3]
These mutations cause an array of arrhythmogenic syndromes including dilated, arrhythmogenic or non-compaction cardiomyopathy, or arrhythmogenic syndromes with minimal or no structural defects such as sick sinus syndrome (SSS), progressive cardiac conduction disease (PCCD), type 1 Brugada syndrome (BrS), familial atrial fibrillation, idiopathic ventricular tachycardia (VT), multifocal ectopic Purkinje-related premature contractions (MEPPC), and type 3 long QT

Summary

Introduction

Is crucial because it initiates the cardiac action potential by generating the inward sodium current (INa ), which mediates cardiomyocyte excitability and impulse conduction in the myocardium and specialized conduction system. This channel generates the late sodium current (INaL ), which plays a role in repolarization and refractoriness [1]. The α subunit of NaV 1.5 is a 220 kDa transmembrane protein encoded by the sodium voltage-gated channel α subunit (SCN5A) gene, consisting of a cytoplasmic N-terminal domain, four homologous transmembrane domains (TMD, DI-DIV) and a cytoplasmic C-terminal domain. SCN5A-mutations may cause several arrhythmogenic phenotypes most frequently inherited in an autosomal dominant fashion [4,5]. SCN5A disease-causing mutations show incomplete penetrance, variable expressivity and male predominance for reasons that are not fully understood, which include both genetic background and environmental factors [7]

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