Genotype-phenotype correlation of rare variants in the SCN5A gene in children population
Authors: Martinez Barrios E , Sarquella Brugada G , Cruzalegui Gomez J , Cesar Diaz S , Chipa Ccasani F , Greco A , Fiol V , Cerralbo P , Brugada Terradellas J , Campuzano Larrea O 
Published: May 2023

Abstract

Funding Acknowledgements
Type of funding sources: None.

Background
Rare variants in the SCN5A gene have been associated with Brugada syndrome (BS), long QT syndrome type 3 (LQTS3), and other conduction disorders that can lead to life-threatening arrhythmias. Variable expressivity, incomplete penetrance and other modifying factors make it difficult to establish a genotype-phenotype correlation, especially in paediatric patients. This, together with the finding of variants of uncertain significance (VUS), makes the genetic diagnosis of arrhythmogenic syndromes challenging.

Purpose
To describe the phenotypes associated with rare variants in the SCN5A gene in children.

Methods
This is a retrospective, single-centre descriptive analysis of the phenotypes found in patients (≤18 years of age at diagnosis) carriers of rare variants in the SCN5A gene. Sixty-four children (75% male, median age 8 years – IQR: 3-13 years) from 41 families were included. The variants were classified according to the recommendations of the American College of Medical Genetics.

Results
82.8% of patients harboured pathogenic (P) or likely pathogenic (LP) variants and 17.2% VUS. 89.1% was diagnosed with BS, 6.3% with LQTS3, and one family presented atrial fibrillation. Two patients died before the first year of life. Of the patients, 41.9% had symptoms: 21.9% cardiac events (cardiac syncope, resuscitated sudden death, ventricular fibrillation and ventricular tachycardia), 7.9% conduction disorders (sinus node dysfunction, atrioventricular block, bifascicular block) and 4.7% supraventricular arrhythmias (supraventricular tachycardia, atrial fibrillation, flutter). Non-cardiac phenotypes included: epilepsy (10.9%) and febrile seizures (7.8%). 58.1% of patients remained asymptomatic during follow-up (median follow-up 5 years – IQR: 2.25-6). In total, 39 variants were identified, 87.2 were classified as P/LP. Segregation studies allowed the reclassification of 28.2% of VUS as P/LP, 12.8% of the variants remained as VUS. 53.8% of the variants were located in the cytosolic region (Figure 1).

Conclusions
The presence of rare variants in the SCN5A gene is associated with arrhythmic phenotypes that can trigger cardiac events and lead to sudden death. The most common cardiac symptom in children is syncope. Patients may present with neurological symptoms such as epilepsy and febrile seizures. Identified VUS should be considered and not discarded until a definitive classification is made. VUS segregation can help to clarify the meaning of these variants, but should not be used to identify individuals at risk in the family, nor in clinical decisions. The high number of asymptomatic patients may be explained by the fact that these are diseases in which the onset of symptoms usually occurs in adolescence and later. Most of the variants were found in mutational hot spots, mainly located in the cytosolic and extracellular region of the protein.