# Clinical Presentation and Outcomes of Patients with biallelic SCN5A Variants: A systematic review

Elodie Surget, Alexis Hermida, Alice Maltret, James Marchant, Isabelle

Denjoy, Laure Champ-Rigot, Estelle Gandjbakhch, Charles Morgat,

Alessandra Pia Porretta, Véronique Fressart, et al.

► To cite this version:

Elodie Surget, Alexis Hermida, Alice Maltret, James Marchant, Isabelle Denjoy, et al. Clinical Presentation and Outcomes of Patients with biallelic SCN5A Variants: A systematic review. Heart Rhythm O2, 2025, 10.1016/j.hroo.2025.06.010. hal-05132945

HAL Id: hal-05132945

https://u-picardie.hal.science/hal-05132945v1

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# Clinical presentation and outcomes of patients with biallelic SCN5A variants: A systematic review

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Elodie Surget, MD, PhD,<sup>1,2</sup> Alexis Hermida, MD,<sup>3</sup> Alice Maltret, MD,<sup>4</sup>

James Marchant, PhD,<sup>5</sup> Isabelle Denjoy, MD,<sup>1,2</sup> Laure Champ-Rigot, MD,<sup>6</sup>

Estelle Gandjbakhch, MD, PhD,<sup>7</sup> Charles Morgat, MD,<sup>1</sup>

Alessandra Pia Porretta, MD, PhD,<sup>1,8</sup> Véronique Fressart, MD,<sup>9</sup> Antoine Leenhardt, MD,<sup>1</sup>

Fabrice Extramiana, MD, PhD<sup>1</sup>

From the <sup>1</sup>Reference Center for Inherited Arrhythmic Syndromes, Hôpital Bichat, APHP, Université Paris Cité, Paris, France, <sup>2</sup>Centre hospitalier universitaire Robert Debré, Université Paris Cité, Paris, France, <sup>3</sup>Centre hospitalier universitaire Amiens-Picardie, CHU Amiens, Amiens, France, <sup>4</sup>Department of Congenital Heart Diseases, M3C-Marie Lannelongue, Hôpital Marie Lannelongue, Groupe Hospitalier Paris Saint Joseph, Le Plessis Robinson, France, <sup>5</sup>Development, Aging and Regeneration Program, Center for Genetic Disorders and Aging Research, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, California, <sup>6</sup>Normandie Univ, UNICAEN, CHU de Caen Normandie, Service de Cardiologie, Caen, France, <sup>7</sup>Department of Cardiology, La Pitié-Salpêtrière Hospital, Paris, France, <sup>8</sup>Service of Cardiology, Heart and Vessel Department, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland, and <sup>9</sup>APHP, Referral Center for Cardiac Hereditary Diseases, Sorbonne University, Pitié-Salpêtrière Hospital, Paris, France.

**BACKGROUND** Heterozygous *SCN5A* variants are associated with a wide spectrum of inherited arrhythmic disorders. However, little is known about the clinical phenotypes associated with biallelic (ie, homozygous or compound heterozygous) *SCN5A* variants.

**OBJECTIVE** The purpose of this study was to systematically review the clinical characteristics, outcomes, and genotype-phenotype correlations in patients with biallelic *SCN5A* variants.

**METHODS** We reviewed the available literature on patients with biallelic *SCN5A* variants and evaluated their demographic characteristics, medical history, and prognosis.

**RESULTS** A total of 33 articles were selected, comprising 61 patients from 43 families. Most were symptomatic at diagnosis (29/36, 81%), with common presentations including syncope (15/36, 42%) and cardiac arrest (10/36, 28%). Sinus node dysfunction was the most prevalent phenotype (35/54, 65%), often associated with atrial standstill (20/34, 59%). Other electrocardiographic abnormalities included progressive cardiac conduction disease (17/52, 33%), Brugada syndrome (12/52, 23%), overlap phenotypes

(7/52, 13%), and long QT syndrome (2/52, 4%). During follow-up (median 5 ± 7 years), arrhythmias were common, and 76% (39/51) of patients required device implantation. Major cardiac events occurred in 50%, and 15% (8/55) died at a young age (mean 9 ± 15 years). Genotype analysis revealed 21 patients with homozygous *SCN5A* variants (34%) and 40 with compound heterozygous variants (66%). The type of variant, rather than zygosity, correlated with prognosis: a non-missense variant was associated with earlier onset and increased risk of major cardiac events.

**CONCLUSION** Patients with biallelic *SCN5A* variants display early-onset severe arrhythmic phenotypes with high morbidity and mortality. Improved recognition and international collaboration are essential to optimize diagnosis, management, and prevention of sudden cardiac death in this rare but high-risk population.

**KEYWORDS** *SCN5A*; Sudden death; Atrial standstill; Stroke; Brugada (Heart Rhythm 0<sup>2</sup> 2025;6:1372–1381) © 2025 Heart Rhythm Society. Published by Elsevier Inc. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

## Introduction

The voltage-gated cardiac sodium channel Na<sub>v</sub>1.5 is involved in phase 0 of the action potential and is essential for the initiation and propagation of cardiac depolarization.<sup>1</sup>

Variants in the *SCN5A* gene, which encodes the cardiac sodium channel α subunit, are associated with a wide spectrum of inherited arrhythmic disorders. Gain-of-function variants that increase the late inward sodium current are associated with long QT syndrome (LQTS) type 3<sup>2</sup> and multifocal ectopic premature Purkinje-related complexes.<sup>3</sup> Conversely, loss-of-function variants, leading to a decreased peak late inward sodium current, are associated with multiple clinical phenotypes, such as Brugada syndrome (BrS),<sup>4</sup> progressive

<footnote>**Address reprint requests and correspondence:** Dr Elodie Surget, Reference Center for Inherited Arrhythmic Syndromes, Hôpital Bichat, APHP, Université Paris Cité, 46 rue Henri Huchard, 75018 Paris, France. E-mail address: elodie.surget@aphp.fr.</footnote>
## KEY FINDINGS

* The most frequent cardiac phenotypes in patients with biallelic *SCN5A* variants are sinus node dysfunction, progressive cardiac conduction disease, and Brugada syndrome.

* Patients with biallelic *SCN5A* variants frequently present with early-onset and severe cardiac phenotypes.

* Non-missense variants are associated with worse outcomes. They are significantly associated with younger age at diagnosis, proband status, and a higher risk of major cardiac events.

* Despite a high prevalence of stroke, only 5% of patients received anticoagulation, suggesting that the risk of cardioembolic complications may be underestimated in this population.

cardiac conduction disease (PCCD),⁵ sinus node dysfunction (SND),⁶ atrial fibrillation,⁷ and dilated cardiomyopathy.⁸ However, a single *SCN5A* variant may confer heterogeneous biophysical properties, which, by accounting for both gain- and loss-of-function effects, may lead to overlapping phenotypes.⁹

Although several studies have already described the clinical characteristics of heterozygous *SCN5A* variants,¹⁰⁻¹² little is known about biallelic *SCN5A* variants. Hence, we performed a literature review to evaluate the clinical presentation and prognosis of these patients.

## Methods

### Protocol and registration

This systematic review was designed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines.¹³ The review protocol (registration number CRD420251012866) was registered in the International Prospective Register of Systematic Reviews.

### Eligibility criteria

Inclusion criteria were established as follows: articles published in English that included patients with pathogenic or likely pathogenic biallelic *SCN5A* variants. The pathogenicity of these variants was determined according to the American College of Medical Genetics and Genomics¹⁴ guidelines. Biallelic *SCN5A* variants included homozygous and compound heterozygous variants. Exclusion criteria encompassed articles involving patients with common genetic variants in *SCN5A* (eg, H558R or S1103Y) or variants in additional genes.

### Literature retrieval

A thorough literature search was performed using PubMed and Google Scholar from their inception to February 2025. The search strategy incorporated the MeSH (Medical Subject Headings) terms "homozygous *SCN5A* variant" or "compound heterozygote *SCN5A* variant." Reference lists of the included articles were also scanned to identify any studies that may have been missed during the initial search.

## Study selection and data extraction

Duplicate records were identified and removed. Full-text articles of potentially relevant studies were assessed for inclusion. Data extraction included data on demographic and clinical characteristics (age, sex, symptoms, etc), electrocardiography (ECG), echocardiography, and treatment (antiarrhythmics, anticoagulation, and device implantation). The prognosis of patients with biallelic *SCN5A* variants was evaluated on the basis of the occurrence of major cardiac events (MCEs; including ventricular tachycardia, cardiac arrest [CA], or death) and stroke.

## Statistical analysis

Continuous variables are presented as mean ± standard deviation and categorical variables as count and percentage. Comparisons between categorical variables were performed using the $\chi^2$ test or Fisher exact test, as appropriate. For continuous variables, the Mann-Whitney *U* test was used for comparisons between 2 groups and the Kruskal-Wallis test for comparisons among more than 2 groups.

Logistic regression analyses were performed to assess associations between categorical variables and clinical outcomes. Binary logistic regression was used for variables with 2 categories, while multinomial logistic regression was applied for variables with more than 2 categories. A *P* value less than .05 was considered statistically significant. Statistical analyses were performed using R++ software (Toulouse, France, https://www.rplusplus.com/en/home).

## Results

### Study selection

A comprehensive literature search identified a total of 116 articles from PubMed (n = 57) and Google Scholar (n = 59) (Figure 1). After excluding 8 duplicates, 108 unique records were screened on the basis of titles and abstracts. During this screening, 1 article was not retrieved and 62 other records were excluded for not meeting the inclusion criteria. Consequently, 45 studies were reviewed at the full-text level, with 12 excluded (7 for including multiple gene variants, 3 for nonpathogenic variants, 1 with unknown zygosity, and 1 with a patient already included) (Table 1).⁶,⁹,¹⁰,¹⁵⁻⁴⁴

### Baseline characteristics

We selected 33 articles for inclusion in our systematic review, comprising a total of 61 patients (35 males [65%]; median age 9 ± 10 years) from 43 distinct families. Most patients, especially those 10 years or younger (*P* = .04) (Table 2), were probands (40/58, 69%) and symptomatic (29/36, 81%) at diagnosis. The most common first clinical presentations were syncope (15/36, 42%) and CA (10/36, 28%). SND was described in the majority (35/54, 65%) of patients, including 20 with atrial standstill (59%). SND was
<figure><img src="image_3.png" /><figcaption>**Figure 1** Flowchart of literature search and screening.</figcaption></figure>

rarely isolated (14/52, 27%) but usually associated with other ECG phenotypes. The 4 other ECG phenotypes were PCCD (17/52, 33%), BrS (12/52, 23%), overlap phenotype (7/52, 13%), and LQTS (2/52, 4%). Patients with isolated SND were predominantly male (P = .02) (Table 3).

## Clinical outcomes

Follow-up periods varied, with a median of 5 ± 7 years. Arrhythmias were frequent, with atrial arrhythmias in 13 (24%) and ventricular arrhythmias in 18 (33%) patients. Nine patients received antiarrhythmic treatment, and 3 received anti-coagulation. A device was implanted in 76% of patients (pacemaker: n = 30; implantable cardioverter-defibrillator:

n = 9) at a mean age of 12 ± 11 years. Eight patients (15%) died at a mean age of 9 ± 15 years. Of note, 2 patients who initially received a pacemaker experienced CA later in the course: one developed ventricular tachycardia followed by heart failure and ventricular fibrillation,¹⁸ and the other presented with ventricular tachycardia and ventricular fibrillation during hospitalization.³⁷ Other complications such as heart failure (4%) and stroke (11%) were also frequent in this young population. Among the reviewed cases, stroke occurred in 11% of patients. Those who experienced stroke appeared to be diagnosed later (21 ± 18 years vs 8 ± 8 years; P = .06). There was no significant correlation between stroke and ECG phenotype, zygosity (P = .7), or variant type (P > .99). The presence of atrial standstill or supraventricular
<table><caption>**Table 1** Characteristics of the included studies</caption><thead><tr><th>Study</th><th>Age at first symptom, P</th><th>First symptom</th><th>Stroke</th><th>CA/HF</th><th>Atrial standstill</th><th>ECG</th><th>Conduction abnormalities</th><th>TTE</th><th>Device</th><th>Variant</th></tr></thead><tbody><tr><td rowspan="5">Alkorashy and colleagues<sup>15</sup></td><td>4 Patients: 19-y-o girl</td><td>NA</td><td>No</td><td>No/Yes</td><td>Yes</td><td>SND, LQT interval 535 ms</td><td>Complete heart block</td><td>Severe TR, DA<br>EF 50%</td><td>PM<br>PM</td><td rowspan="5">Hom p.Cys1850Arg in all 4</td></tr><tr><td>17-y-o boy</td><td>NA</td><td>No</td><td>No/No</td><td>No</td><td>SND, LQT interval 558 ms</td><td>No</td><td>EF 50%, DA</td><td>PM</td></tr><tr><td>1-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>SND, QTC interval 449 ms</td><td>No</td><td>Normal</td><td>PM</td></tr><tr><td>16-y-o boy</td><td>NA</td><td>Yes</td><td>No/No</td><td>No</td><td>SND, LQT interval 457 ms</td><td>No</td><td></td><td></td></tr><tr><td>2 Patients: 9-y-o girl, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>No</td><td>Normal</td><td>PM</td></tr><tr><td rowspan="2">Tan and colleagues<sup>16</sup></td><td>4-y-o girl</td><td>Asympt</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>No</td><td>NA</td><td>No</td><td>Hom p.Val1340Leu</td></tr><tr><td>2 Patients: 6-y-o girl, P</td><td>NA</td><td>No</td><td>Yes (PVT and VF)/</td><td>Yes</td><td>SND, AT</td><td>IV conduction delay</td><td>EF 20% after CA</td><td>ICD<br>ICD</td><td rowspan="2">Hom c.1924A&gt;T</td></tr><tr><td rowspan="2">Lopez and colleagues<sup>17</sup></td><td>6-y-o girl (twin)</td><td>Syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>No</td><td></td><td></td><td></td></tr><tr><td>4 Patients: 6-y-o boy, P</td><td>Dyspnea</td><td>No</td><td>Yes/Yes</td><td>No</td><td>SND, VT</td><td>RBBB, prolonged PR interval</td><td>Ebstein, NC,<br>↓ EF</td><td>PM<br>PM</td><td rowspan="5">Hom p.Ile230Thr in all</td></tr><tr><td rowspan="4">Neu and colleagues<sup>18</sup></td><td>4-y-o girl</td><td>NA</td><td>No</td><td>No/No</td><td>No</td><td>SND, VT</td><td>RBBB, prolonged PR interval</td><td>Normal</td><td>PM</td></tr><tr><td>Girl</td><td>NA</td><td>No</td><td>No/No</td><td>No</td><td>SND, VT</td><td>RBBB, prolonged PR interval</td><td>Normal</td><td>No</td></tr><tr><td>Girl</td><td>NA</td><td>No</td><td>No/No</td><td>No</td><td>SND</td><td>RBBB, prolonged PR interval</td><td>Normal</td><td>No</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td>RBBB, prolonged PR interval</td><td>Normal</td><td>No</td></tr><tr><td rowspan="2">Frigo and colleagues<sup>19</sup></td><td>25-y-o boy, P</td><td>NA</td><td>No</td><td>No/No</td><td>No</td><td>Brugada syndrome, VT</td><td>RBBB, prolonged PR interval</td><td>Dilated RV</td><td>No*</td><td rowspan="2">Hom p.Arg814Gln</td></tr><tr><td>2 Patients: 5-mo-o boy, P</td><td>Lethargy</td><td>No</td><td>No/No</td><td>NA</td><td>Brugada syndrome, VT, AT SND</td><td>Prolonged PR interval</td><td>NA</td><td>ICD</td></tr><tr><td rowspan="2">Wang and colleagues<sup>20</sup></td><td>NA</td><td>Asympt</td><td>No</td><td>No/No</td><td>NA</td><td></td><td>Prolonged PR interval and QRS duration</td><td>NA</td><td>No</td><td>Hom p.Arg1309His</td></tr><tr><td>18-y-o girl, P</td><td>Palpitations</td><td>Yes</td><td>No/No</td><td>Yes</td><td>SND, AFL and AF</td><td>No</td><td>Biatrial dilation</td><td>PM</td><td>Hom p.Arg219Cys</td></tr><tr><td>De Regibus and colleagues<sup>21</sup></td><td>3 Patients</td><td>NA</td><td>No</td><td>NA/NA</td><td>NA</td><td>Brugada syndrome</td><td>NA</td><td>NA</td><td>NA</td><td>Hom p.Arg551Thr, p.Asn592Lys p.Arg1193Gln</td></tr><tr><td>Juang and colleagues<sup>22</sup></td><td>5-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>LQT interval 526 ms</td><td>2:1 Functional AVB</td><td>Normal</td><td>No</td><td>Hom p.Val1777Met</td></tr><tr><td>Lupoglazoff and colleagues<sup>23</sup></td><td>11-y-o girl, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>Prolonged QRS duration</td><td>NA</td><td>PM</td><td>Com.Het p.Pro1048SerfsX97 and p.Thr220Ile</td></tr><tr><td>Baskar and colleagues<sup>24</sup></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>

(Continued)
<table><caption>**Table 1** (Continued)</caption><thead><tr><th>Study</th><th>Age at first symptom, P</th><th>First symptom</th><th>Stroke</th><th>CA/HF</th><th>Atrial standstill</th><th>ECG</th><th>Conduction abnormalities</th><th>TTE</th><th>Device</th><th>Variant</th></tr></thead><tbody><tr><td rowspan="6">Benson and colleagues<sup>6</sup></td><td>5 Patients: 6-y-o boy, P</td><td>NA</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>Prolonged QRS duration</td><td>Normal</td><td>PM</td><td>Com.Het p.Gly1408Arg and p.Pro1298Leu in the first 3</td></tr><tr><td>7-y-o boy</td><td>NA</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>Prolonged QRS duration</td><td>Normal</td><td>PM</td><td>Com.Het p.Thr220Ile and p.Arg1623X</td></tr><tr><td>2-y-o girl</td><td>Syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND, VT</td><td>NA</td><td>Normal</td><td>ICD</td><td>Com.Het del p.Phe1617 and p.Arg1632His</td></tr><tr><td>9-y-o boy, P</td><td>NA</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>Prolonged QRS duration</td><td>Normal</td><td>PM</td><td>Com.Het p.Phe1617 and p.Arg1632His</td></tr><tr><td>5-y-o boy, P</td><td>NA</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>Prolonged QRS duration</td><td>Normal</td><td>PM</td><td>Com.Het p.Phe1617 and p.Arg1632His</td></tr><tr><td>2 Patients: Newborn boy, P</td><td>Severe distress</td><td>No</td><td>No/No</td><td>NA</td><td>Wide QRS tachycardia</td><td>Broad P waves, prolonged PR interval and QRS duration</td><td>Small VSD</td><td>No</td><td>Com.Het p.Trp156X and p.Arg225Trp in both</td></tr><tr><td>Bezzina and colleagues<sup>9</sup></td><td>1-y-o girl</td><td>CA</td><td>No</td><td>Yes/No</td><td>NA</td><td>Wide QRS tachycardia</td><td>Broad P waves, prolonged PR interval and QRS duration, 2:1 AVB</td><td>NA</td><td>No</td><td>Com.Het p.Trp156X and p.Arg225Trp in both</td></tr><tr><td>Kodama and colleagues<sup>25</sup></td><td>5-y-o boy, P</td><td>Asympt</td><td>No</td><td>No/No</td><td>Yes</td><td>SND, AF</td><td>Prolonged PR interval</td><td>Normal</td><td>PM</td><td>Com.Het p.Asp349Asn and p.Asp1790Asn</td></tr><tr><td>Medeiros-Domingo and colleagues<sup>26</sup></td><td>2-y-o boy, P</td><td>Syncope</td><td>No</td><td>Yes/No</td><td>NA</td><td>LQT interval 519 ms, VT</td><td>No</td><td>Normal</td><td>No</td><td>Com.Het p.Arg34fs/60 and p.Arg1195His</td></tr><tr><td>Sacilotto and colleagues<sup>27</sup></td><td>4-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>SND, Brugada syndrome, AF, wide QRS tachycardia</td><td>Prolonged PR interval, increased HV interval</td><td>Normal</td><td>PM</td><td>Com.Het p.Gly400Arg and p.Thr1461Ser</td></tr><tr><td>Selly and colleagues<sup>28</sup></td><td>10-y-o boy, P</td><td>Asympt</td><td>No</td><td>No/No</td><td>NA</td><td>SND, AFL</td><td>HV interval 72 ms</td><td>Normal</td><td>PM</td><td>Com.Het p.Ala735Val and p.Asp1792Asn</td></tr><tr><td>Thongnak and colleagues<sup>29</sup></td><td>18-mo-o girl, P</td><td>NA</td><td>No</td><td>NA/No</td><td>NA</td><td>Complete AVB</td><td>Complete AVB</td><td>NA</td><td>PM</td><td>Com.Het p.Arg34His and p.Val1278Ile</td></tr><tr><td>Tan and colleagues<sup>30</sup></td><td>11-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>Brugada syndrome, polymorphic VT</td><td>Prolonged PR interval and QRS duration</td><td>Normal</td><td>No</td><td>Com.Het p.Ala226Val and p.Arg1629X</td></tr><tr><td>Cordeiro and colleagues<sup>31</sup></td><td>Boy, P</td><td>Asympt</td><td>No</td><td>No/No</td><td>NA</td><td>Brugada syndrome</td><td>Prolonged PR interval</td><td>NA</td><td>ICD</td><td>Com.Het p.Pro336Leu and p.Ile1660Val</td></tr><tr><td rowspan="2">Robyns and colleagues<sup>32</sup></td><td>2 Patients: 14-y-o girl, P</td><td>Palpitation</td><td>No</td><td>No/No</td><td>NA</td><td>SND, AFL</td><td>Prolonged HV interval</td><td>Normal</td><td>PM</td><td>Com.Het p.Arg1632His and p.Met858Leu in both</td></tr><tr><td>13-y-o boy</td><td>NA</td><td>No</td><td>No/No</td><td>Yes</td><td>SND, AFL</td><td>Prolonged QRS duration</td><td>NA</td><td>PM</td><td>Com.Het p.Arg1632His and p.Met858Leu in both</td></tr><tr><td rowspan="4">Howard and colleagues<sup>33†</sup></td><td>3 Patients: 6-y-o boy, P</td><td>NA</td><td>Yes</td><td>NA/NA</td><td>Yes</td><td>Brugada syndrome, AFL, VT, VF</td><td>NA</td><td>NA</td><td>ICD</td><td>Hom p.Arg1309His</td></tr><tr><td>4-y-o girl, P</td><td>NA</td><td>No</td><td>NA/NA</td><td>Yes</td><td>JT</td><td>NA</td><td>NA</td><td>PM</td><td>Com.Het p.Leu227Pro and p.Met1793Lys</td></tr><tr><td>10-y-o boy, P</td><td>NA</td><td>No</td><td>NA/NA</td><td>Yes</td><td>AT, VT</td><td>NA</td><td>NA</td><td>ICD</td><td>Com.Het p.Ala735Val and p.Arg1512Trp</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr></tbody></table>
<table><tr><td>Abe and colleagues<sup>34</sup></td><td>4-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND</td><td>No</td><td>NA</td><td>PM</td><td>Com.Het c.2401_2409delinsTCC and P.Met1880Val</td></tr><tr><td>Calloe and colleagues<sup>35</sup></td><td>44-y-o man, P</td><td>Syncope</td><td>Yes</td><td>Yes/No</td><td>NA</td><td>Brugada syndrome, VT</td><td>Prolonged PR interval</td><td>NA</td><td>ICD</td><td>Com.Het p.Arg620His and p.Arg811His</td></tr><tr><td>Moreau and colleagues<sup>36</sup></td><td>9-y-o boy, P</td><td>Pre syncope</td><td>No</td><td>No/No</td><td>Yes</td><td>SND, AFL and AF</td><td>No</td><td>Normal</td><td>PM</td><td>Com.Het c.1141-2 A>G and p.Pro1053Lys</td></tr><tr><td rowspan="3">Villarreal-Molina and colleagues<sup>37</sup></td><td>3 Patients: 22-mo-o boy P</td><td>CA</td><td>No</td><td>Yes/No</td><td>NA</td><td>LQT interval 519 ms, VT</td><td>Yes</td><td>NA</td><td>No</td><td>Com.Het p.Arg34fs*60 and p.Arg1195His</td></tr><tr><td>4-y-o boy, P</td><td>Syncope</td><td>No</td><td>Yes/No</td><td>NA</td><td>SND, VT, AF, LQT interval 495 ms</td><td>RBBB, prolonged PR interval</td><td>NA</td><td>PM</td><td>p.Asp1741Glyfs*48 and p.Val240Met</td></tr><tr><td>3-y-o girl, P</td><td>Syncope</td><td>No</td><td>Yes/No</td><td>NA</td><td>SND, VT, Brugada syndrome, AF and AFL, LQT interval 630 ms</td><td>RBBB and LBBB, third-degree AVB, prolonged PR interval</td><td>NA</td><td>PM</td><td>p.Trp1345_Ser1349delinsPhe and p.Pro1730Leu</td></tr><tr><td>Sommariva and colleagues<sup>38</sup></td><td>3-y-o boy, P</td><td>Asympt</td><td>No</td><td>No/No</td><td>No</td><td>Brugada syndrome, VT</td><td>No</td><td>Normal</td><td>No</td><td>Com.Het c.3258_3261del4 and p.Phe1293Ser</td></tr><tr><td>Nijak and colleagues<sup>39</sup></td><td>2-y-o boy, P</td><td>Syncope</td><td>Yes</td><td>No/No</td><td>Yes</td><td>SND, Brugada syndrome</td><td>No</td><td>Normal</td><td>ICD</td><td>Com.Het c.4813+3_4813+6dupGGGT and p.Phe1571Leu</td></tr><tr><td>Nof and colleagues<sup>40</sup></td><td>16-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>SND</td><td>HV interval 75 ms</td><td>Normal</td><td>PM</td><td>Com.Het p.Lys1493del and p.Ala1924Thr</td></tr><tr><td rowspan="2">Wang and colleagues<sup>41</sup></td><td>2 Sisters: 5-y-o, P</td><td>REEC</td><td>No</td><td>No/No</td><td>NA</td><td>SND</td><td>No</td><td>Normal</td><td>PM</td><td>Com.Het p.Arg965Cys and p.Arg811Cys in both</td></tr><tr><td>12-y-o</td><td>NA</td><td>No</td><td>NA/No</td><td>NA</td><td>SND</td><td>NA</td><td>NA</td><td>PM</td><td>p.Arg811Cys in both</td></tr><tr><td rowspan="3">Lin and colleagues<sup>42</sup></td><td>2 Patients: 10-y-o boy, P</td><td>Syncope</td><td>No</td><td>No/No</td><td>No</td><td>SND, AF</td><td>Third-degree AVB</td><td>NA</td><td>PM</td><td>Com.Het p.Arg965Cys and p.Arg1309His in both</td></tr><tr><td>41-y-o man</td><td>NA</td><td>Yes</td><td>No/No</td><td>Yes</td><td>SND, AF</td><td>Third-degree AVB</td><td>NA</td><td>PM</td><td>p.Arg1309His in both</td></tr><tr><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td rowspan="4">Baruteau and colleagues<sup>10</sup></td><td>3 Patients: &lt;1-y-o, P</td><td>NA</td><td>NA</td><td>NA/NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>&lt;1-y-o, P</td><td>NA</td><td>NA</td><td>NA/NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>&lt;1-y-o, P</td><td>NA</td><td>NA</td><td>NA/NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>&gt;1-y-o, P</td><td>NA</td><td>NA</td><td>NA/NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td rowspan="4">Chockalingam and colleagues<sup>43</sup></td><td>2 Families: A male infant P</td><td>NA</td><td>NA</td><td>Yes/No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>and his sibling</td><td>NA</td><td>NA</td><td>No/No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>A male neonate P</td><td>NA</td><td>NA</td><td>Yes/No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>and his sister</td><td>NA</td><td>NA</td><td>Yes/No</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>NA</td><td>Com.Het exact variant NA</td></tr><tr><td>Postema and colleagues<sup>44</sup></td><td>46-y-o man, P</td><td>NA</td><td>No</td><td>No/No</td><td>NA</td><td>LQT interval 500 ms, Brugada syndrome</td><td>Prolonged PR interval and QRS duration</td><td>NA</td><td>No</td><td>Com.Het Ile1660Val and ΔKPQ variant</td></tr></table>

AF = atrial fibrillation; AFL = atrial flutter; Asympt = asymptomatic; AT = atrial tachycardia; AVB = atrioventricular block; CA = cardiac arrest; Com.Het = compound heterozygous; DA = dilated atria; ECG = electrocardiography; EF = ejection fraction; HF = heart failure; Hom = homozygous; ICD = intracardiac defibrillator; IV = intraventricular; JT = junctional tachycardia; LBBB = left bundle branch block; LQT = long QT; mo-o = month-old; NA = not available; NC = noncompaction; P = proband; PM = pacemaker; PVT = polymorphic ventricular tachycardia; QTc = corrected QT; RBBB = right bundle branch block; REEC = reduced endurance exercise capacity; RV = right ventricle; SND = sinus node dysfunction; TR = tricuspid regurgitation; TTE = transthoracic echocardiography; VF = ventricular fibrillation; VSD = ventricular septal defect; VT = ventricular tachycardia; y-o = year-old.

*Patient refused ICD implantation.

†Patients from this cohort already reported in other cited articles have been excluded.
<table><caption>**Table 2** Clinical characteristics according to age at diagnosis</caption><thead><tr><th>Characteristic</th><th>Age ≤10 y (n = 36)</th><th>Age >10 y (n = 14)</th><th>P</th></tr></thead><tbody><tr><td>Clinical characteristics</td><td></td><td></td><td></td></tr><tr><td>Sex (47): male</td><td>22 (67)</td><td>9 (64)</td><td>&gt;.99</td></tr><tr><td>Proband (50)</td><td>30 (83)</td><td>7 (50)</td><td>.04</td></tr><tr><td>Mode of presentation at diagnosis (31)</td><td></td><td></td><td>.3</td></tr><tr><td>Asymptomatic</td><td>5 (21)</td><td>0 (0)</td><td></td></tr><tr><td>Syncope</td><td>12 (50)</td><td>3 (43)</td><td></td></tr><tr><td>CA</td><td>5 (21)</td><td>2 (29)</td><td></td></tr><tr><td>Others</td><td>2 (8)</td><td>2 (29)</td><td></td></tr><tr><td>ECG phenotypes (47)</td><td></td><td></td><td></td></tr><tr><td>LQT3</td><td>2 (6)</td><td>0 (0)</td><td>.9</td></tr><tr><td>BrS</td><td>5 (15)</td><td>3 (21)</td><td>.9</td></tr><tr><td>PCCD</td><td>14 (42)</td><td>4 (29)</td><td>.6</td></tr><tr><td>Isolated SND</td><td>9 (27)</td><td>5 (36)</td><td>.8</td></tr><tr><td>Overlap phenotype</td><td>3 (9)</td><td>4 (29)</td><td>.2</td></tr><tr><td>Atrial standstill (32)</td><td>15 (68)</td><td>5 (50)</td><td>.6</td></tr><tr><td>Arrhythmias (47)</td><td></td><td></td><td></td></tr><tr><td>SVT</td><td>9 (27)</td><td>4 (29)</td><td>&gt;.99</td></tr><tr><td>VT</td><td>14 (42)</td><td>3 (21)</td><td>.3</td></tr><tr><td>Device (47)</td><td>26 (79)</td><td>11 (79)</td><td>&gt;.99</td></tr><tr><td>Heart failure (44)</td><td>1 (3)</td><td>1 (7)</td><td>&gt;.99</td></tr><tr><td>MCE (40)</td><td>16 (57)</td><td>4 (33)</td><td>0.3</td></tr><tr><td>Stroke (47)</td><td>2 (6)</td><td>4 (29)</td><td>0.1</td></tr><tr><td>Death (47)</td><td>4 (12)</td><td>1 (7)</td><td>&gt;.99</td></tr><tr><td>Zygosity (50)</td><td></td><td></td><td>.8</td></tr><tr><td>Homozygous</td><td>10 (28)</td><td>26 (72)</td><td></td></tr><tr><td>Compound heterozygous</td><td>5 (36)</td><td>9 (64)</td><td></td></tr><tr><td>Variant type (47)</td><td></td><td></td><td>.6</td></tr><tr><td>Biallelic missense pathogenic variant</td><td>22 (67)</td><td>11 (33)</td><td></td></tr><tr><td>Missense + non-missense pathogenic variant</td><td>11 (79)</td><td>3 (21)</td><td></td></tr></tbody></table>

Values are presented as n (%).

BrS = Brugada syndrome; CA = cardiac arrest; ECG = electrocardiographic; LQT3 = long QT syndrome type 3; MCE = major cardiac event; PCCD = progressive cardiac conduction disease; SND = sick sinus node dysfunction; SVT = supraventricular tachycardia; VT = ventricular tachycardia.

tachycardia did not significantly influence stroke occurrence (55% vs 80%; P = .4 and 21% vs 50%; P = .1, respectively), likely owing to the small number of patients and the short

follow-up duration (atrial standstill: 10 ± 9 years with 8 ± 8 years of follow-up; supraventricular tachycardia: 11 ± 11 years with 7 ± 6 years of follow-up). Notably, 3 of the 6 patients who suffered a stroke had both supraventricular tachycardia and atrial standstill.

## Genotype-prognosis correlation

Of the 61 patients, 21 (34%) had homozygous variants and 40 (66%) compound heterozygous variants. Consanguinity was identified in a majority (57%) of patients with homozygous SCN5A variants. Overall, variants were mostly (82 [86%]) located in domains DI–DIV (67 localized to either DI S1–S4, DII S1–S4, DIII S1–S4, or DIV S1–S4 and 15 localized to the S5, P-loop, and S6 regions containing the pore filter of the sodium channel). Three variants (3%) were localized in N-terminal domains and 10 (11%) in C-terminal domains. Zygosity was not a prognostic factor, in contrast to variant type (Tables 4 and 5). Most variants were missense (40/54, 74%), whereas 26% (14/54) were not (truncation variants: 10%; in-frame variants: 4%). A non-missense variant was more frequently identified in probands (P = .04) and younger patients (P = .01) (Table 5). The risk of ventricular tachycardia and MCEs was significantly increased in patients with a non-missense variant (P = .008 and P = .01, respectively).

## Discussion

SND and PCCD were the most prevalent phenotypes. Looking more broadly across all 61 cases, we showed that the phenotype was severe, with MCEs in half of the cases, especially in patients with non-missense SCN5A variants.

## Cardiac phenotype of patients with biallelic SCN5A variants

Having homozygous or compound heterozygous SCN5A variants is a rare condition, representing less than 2% of all patients with SCN5A variants across different cohorts.¹⁰,⁴⁵ A high degree of phenotypic variability has been associated with heterozygous SCN5A variants owing to their effect on NaV1.5 biophysical properties⁴⁶ and other modulating

<table><caption>**Table 3** Clinical characteristics according to ECG phenotypes</caption><thead><tr><th>Characteristic</th><th>LQT3</th><th>BrS</th><th>PCCD</th><th>Isolated SND</th><th>Overlap phenotype</th><th>P</th></tr></thead><tbody><tr><td>Sex (48): male</td><td>0 (0)</td><td>9 (100)</td><td>11 (69)</td><td>4 (29)</td><td>5 (71)</td><td>.02</td></tr><tr><td>Proband (49)</td><td>2 (100)</td><td>9 (100)</td><td>10 (59)</td><td>9 (64)</td><td>3 (43)</td><td>.04</td></tr><tr><td>Syncope (31)</td><td>2 (100)</td><td>5 (71)</td><td>3 (33)</td><td>6 (60)</td><td>2 (67)</td><td>.5</td></tr><tr><td>CA (46)</td><td>1 (50)</td><td>1 (13)</td><td>2 (13)</td><td>1 (8)</td><td>3 (43)</td><td>.6</td></tr><tr><td>Arrhythmias</td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>SVT (52)</td><td>0 (0)</td><td>3 (25)</td><td>3 (18)</td><td>5 (36)</td><td>2 (29)</td><td>.3</td></tr><tr><td>VT (52)</td><td>1 (50)</td><td>7 (58)</td><td>6 (35)</td><td>0 (0)</td><td>3 (43)</td><td>.1</td></tr><tr><td>Heart failure (48)</td><td>0 (0)</td><td>0 (0)</td><td>1 (6)</td><td>0 (0)</td><td>1 (14)</td><td>.4</td></tr><tr><td>MCE (42)</td><td>2 (100)</td><td>5 (71)</td><td>4 (31)</td><td>6 (46)</td><td>3 (43)</td><td>.2</td></tr><tr><td>Stroke (52)</td><td>0 (0)</td><td>3 (25)</td><td>1 (6)</td><td>1 (7)</td><td>1 (14)</td><td>.5</td></tr><tr><td>Death (49)</td><td>1 (50)</td><td>0 (0)</td><td>2 (12)</td><td>0 (0)</td><td>2 (29)</td><td>.9</td></tr></tbody></table>

Values are presented as n (%).

BrS = Brugada syndrome; CA = cardiac arrest; ECG = electrocardiographic; LQT3 = long QT syndrome type 3; MCE = major cardiac event; PCCD = progressive cardiac conduction defect; SND = sinus node dysfunction; SVT = supraventricular tachycardia; VT = ventricular tachycardia.
<table><caption>**Table 4** Risk of MCEs</caption><thead><tr><th>Characteristic</th><th>No MCE<br>(n = 23)</th><th>MCE<br>(n = 23)</th><th>P</th></tr></thead><tbody><tr><td><strong>Clinical characteristics</strong></td><td></td><td></td><td></td></tr><tr><td>Sex (45): male</td><td>15 (68)</td><td>17 (74)</td><td>.9</td></tr><tr><td>Proband (46)</td><td>11 (48)</td><td>21 (91)</td><td>.003</td></tr><tr><td>Age at diagnosis (y)</td><td>12 ± 12</td><td>8 ± 10</td><td>.2</td></tr><tr><td>Age ≤ 1 y at diagnosis (44)</td><td>1 (5)</td><td>4 (17)</td><td>.3</td></tr><tr><td><strong>ECG phenotypes (42)</strong></td><td></td><td></td><td></td></tr><tr><td>LQT3</td><td>0 (0)</td><td>2 (10)</td><td>.4</td></tr><tr><td>BrS</td><td>2 (9)</td><td>5 (25)</td><td>.3</td></tr><tr><td>PCCD</td><td>10 (45)</td><td>6 (30)</td><td>.5</td></tr><tr><td>Isolated SND</td><td>7 (32)</td><td>6 (30)</td><td>&gt;.99</td></tr><tr><td>Overlap phenotype</td><td>4 (18)</td><td>3 (15)</td><td>&gt;.99</td></tr><tr><td>Atrial standstill (27)</td><td>10 (71)</td><td>7 (54)</td><td>.4</td></tr><tr><td>SVT (42)</td><td>5 (23)</td><td>7 (35)</td><td>.6</td></tr><tr><td>Zygosity (46)</td><td></td><td></td><td>.5</td></tr><tr><td>Homozygous</td><td>8 (35)</td><td>5 (22)</td><td></td></tr><tr><td>Compound heterozygous</td><td>15 (65)</td><td>18 (78)</td><td></td></tr><tr><td><strong>Variant type (42)</strong></td><td></td><td></td><td>.01</td></tr><tr><td>Biallelic missense pathogenic<br>variant</td><td>19 (86)</td><td>9 (45)</td><td></td></tr><tr><td>Missense + non-missense<br>pathogenic variant</td><td>3 (14)</td><td>11 (55)</td><td></td></tr></tbody></table>

Values are presented as mean ± standard deviation or n (%).
BrS = Brugada syndrome; ECG = electrocardiographic; LQT3 = long QT syndrome type 3; MCE = major cardiac event; PCCD = progressive cardiac conduction disease; SND = sinus node dysfunction; SVT = supraventricular tachycardia.

factors such as age, sex, or time of day. Gain-of-function variants are associated with LQTS type 3,² whereas loss-of-function variants are associated with BrS⁴ or abnormal cardiac conduction. This pleiotropy of cardiac phenotypes was also observed in patients with biallelic *SCN5A* variants, with BrS in 12 (23%), LQTS in 2 (4%), and overlap phenotype in 7 (13%) patients. Conduction defects were frequently observed, with atrial standstill in 20 (59%), SND in 35 (65%), and PCCD in 17 (33%) patients. Although our findings support a key role for *SCN5A* variant type in determining phenotype severity, they also fit within a broader and evolving understanding of BrS as a complex disorder not solely explained by rare monogenic variants. Recent genome-wide association studies⁴⁷ have shown that common genetic variants, quantified using polygenic risk scores, may contribute to susceptibility to the Brugada ECG pattern, particularly in the absence of a rare *SCN5A* variant. This suggests that *SCN5A*-independent mechanisms may play a role in disease expression and supports a more integrated approach to genetic risk assessment. Interestingly, beyond genetic variants, recent evidence⁴⁸ suggests that immunological mechanisms may modulate sodium channel function. In particular, the presence of anti-NaV1.5 autoantibodies has been reported in the majority of patients with BrS, including those without *SCN5A* variants. These autoantibodies were shown to reduce sodium current density and reproduce

<table><caption>**Table 5** Clinical characteristics according to *SCN5A* variant zygosity and variant type</caption><thead><tr><th>Characteristic</th><th>Homozygous<br>(n = 21)</th><th>Compound heterozygous<br>(n = 40)</th><th>P</th><th>Missense<br>(n = 40)</th><th>Missense + non-missense<br>(n = 14)</th><th>P</th></tr></thead><tbody><tr><td><strong>Clinical characteristics</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>Sex (54, 50): male</td><td>8 (47)</td><td>27 (73)</td><td>.1</td><td>21 (58)</td><td>11 (79)</td><td>.3</td></tr><tr><td>Proband (58, 51)</td><td>9 (50)</td><td>31 (78)</td><td>.07</td><td>22 (59)</td><td>13 (93)</td><td>.04</td></tr><tr><td>Age at diagnosis (y)</td><td>9 ± 7</td><td>9 ± 12</td><td>.8</td><td>12 ± 12</td><td>5 ± 5</td><td>.01</td></tr><tr><td>Age ≤1 y at diagnosis (54, 47)</td><td>2 (13)</td><td>5 (13)</td><td>1</td><td>2 (6)</td><td>2 (14)</td><td>.6</td></tr><tr><td><strong>Mode of presentation at<br>diagnosis<br>(36, 33)</strong></td><td></td><td></td><td>.4</td><td></td><td></td><td>.3</td></tr><tr><td>Asymptomatic</td><td>3 (27)</td><td>4 (16)</td><td></td><td>6 (30)</td><td>1 (8)</td><td></td></tr><tr><td>Syncope</td><td>5 (45)</td><td>10 (40)</td><td></td><td>8 (40)</td><td>7 (54)</td><td></td></tr><tr><td>CA</td><td>1 (9)</td><td>9 (36)</td><td></td><td>3 (15)</td><td>4 (31)</td><td></td></tr><tr><td>Others</td><td>2 (19)</td><td>2 (8)</td><td></td><td>3 (15)</td><td>1 (8)</td><td></td></tr><tr><td><strong>ECG phenotypes (54, 54)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>LQT3</td><td>1 (5)</td><td>1 (3)</td><td>1</td><td>1 (3)</td><td>1 (7)</td><td>&gt;.99</td></tr><tr><td>BrS</td><td>6 (29)</td><td>6 (18)</td><td>.6</td><td>9 (23)</td><td>3 (21)</td><td>&gt;.99</td></tr><tr><td>PCCD</td><td>8 (38)</td><td>13 (39)</td><td>1</td><td>15 (38)</td><td>6 (43)</td><td>&gt;.99</td></tr><tr><td>Isolated SND</td><td>6 (29)</td><td>8 (24)</td><td>1</td><td>12 (30)</td><td>2 (14)</td><td>.4</td></tr><tr><td>Overlap phenotype</td><td>3 (14)</td><td>4 (12)</td><td>1</td><td>4 (10)</td><td>3 (21)</td><td>.5</td></tr><tr><td>Atrial standstill (34, 34)</td><td>7 (44)</td><td>13 (72)</td><td>.2</td><td>15 (58)</td><td>5 (63)</td><td>&gt;.99</td></tr><tr><td><strong>Arrhythmias (54, 54)</strong></td><td></td><td></td><td></td><td></td><td></td><td></td></tr><tr><td>SVT</td><td>4 (19)</td><td>9 (27)</td><td>.7</td><td>11 (28)</td><td>2 (14)</td><td>.5</td></tr><tr><td>VT</td><td>6 (29)</td><td>12 (36)</td><td>.8</td><td>9 (23)</td><td>9 (64)</td><td>.008</td></tr><tr><td>Device (51, 51)</td><td>13 (72)</td><td>26 (79)</td><td>.9</td><td>31 (84)</td><td>8 (57)</td><td>.07</td></tr><tr><td>Heart failure (52, 48)</td><td>2 (12)</td><td>0 (0)</td><td>.2</td><td>2 (6)</td><td>0 (0)</td><td>.9</td></tr><tr><td>MCE (46, 42)</td><td>5 (38)</td><td>18 (55)</td><td>.5</td><td>9 (32)</td><td>11 (79)</td><td>.01</td></tr><tr><td>Stroke (54, 54)</td><td>3 (14)</td><td>3 (9)</td><td></td><td>5 (13)</td><td>1 (7)</td><td>&gt;.99</td></tr><tr><td>Death (55, 51)</td><td>2 (11)</td><td>8 (16)</td><td>.9</td><td>2 (5)</td><td>3 (21)</td><td>.2</td></tr></tbody></table>

Values are presented as mean ± standard deviation or n (%).
BrS = Brugada syndrome; CA = cardiac arrest; ECG = electrocardiographic; LQT3 = long QT syndrome type 3; MCE = major cardiac event; PCCD = progressive cardiac conduction disease; SND = sinus node dysfunction; SVT = supraventricular tachycardia; VT = ventricular tachycardia.
Brugada-like ECG abnormalities in animal models, suggesting an immune-mediated contribution to disease expression. This emerging concept may help explain the phenotypic variability observed even among individuals sharing the same *SCN5A* genotype and represents a potentially confounding factor when interpreting genotype-phenotype correlations.

## Therapeutic management of patients with biallelic *SCN5A* variants

Three types of complications can occur in patients with biallelic *SCN5A* variants: cardioembolic, arrhythmic (SND with bradycardia or ventricular arrhythmias), and hemodynamic complications. CA occurred in 28%, and a device was implanted in three-quarters of cases. The indication for pacemaker or implantable cardioverter-defibrillator implantation followed standard guidelines, with a young mean age at implantation (12 ± 11 years). Of note, 2 patients who initially received a pacemaker experienced CA later in the course: one developed ventricular tachycardia followed by heart failure and ventricular fibrillation,¹⁸ and the other presented with ventricular tachycardia and ventricular fibrillation during hospitalization.³⁷ This observation suggests that pacemaker implantation may not provide sufficient protection against ventricular arrhythmias in some cases, reinforcing the importance of careful risk stratification. These results corroborated previous studies demonstrating that patients with biallelic *SCN5A* variants present with a more severe phenotype, experience more cardiac events, and are diagnosed at a younger age at diagnosis.

Furthermore, our results demonstrated a high occurrence of stroke (11%). Moreau and colleagues³⁶ recently highlighted the association between *SCN5A* variants and stroke in young patients. This association was described in 2 children aged 11 and 14 years, both with severe atrial arrhythmias. The 14-year-old patient also exhibited atrial standstill. In our study, only 3 patients received anticoagulation, and 59% and 24% had atrial standstill and atrial arrhythmias, respectively. These findings raise the question of whether anticoagulation should be considered in these specific patients.

## Genotype-phenotype correlation

Zygosity and variant type were not significantly correlated with ECG phenotype. However, unlike zygosity, variant type affected the risk of MCEs. Indeed, 79% of patients with a non-missense variant experienced MCEs (vs 32% with missense variants; *P* = .01). Also, non-missense variants were more frequently identified in probands (*P* = .04) and younger patients (*P* = .01). Importantly, no patients with 2 non-missense variants have been reported in the literature, suggesting that this genotype may be incompatible with life. This hypothesis is supported by experimental studies⁴⁹ and underlines the severity of phenotypes associated with a single non-missense variant. This is an important finding that may have significant implications for refining therapeutic strategies in affected patients and their relatives.

## Limitations

This study had several limitations and potential biases. First, the primary limitation is that data analysis was based on incomplete information. Not all articles consistently reported clinical data, such as sex, first symptoms, or age at diagnosis. Second, there is publication bias, as an unknown number of patients may have died without undergoing genetic testing. Finally, the patients included in this study had relatively short follow-up periods, limiting insight into long-term disease progression.

## Conclusion

This study provides valuable insights into the clinical spectrum and prognosis of patients with biallelic *SCN5A* variants. These patients are at high risk of life-threatening arrhythmias and stroke from an early age. Given the severity and rarity of this condition, international registries and collaborative research are essential to improve risk stratification, guide personalized management, and ultimately prevent sudden cardiac death in affected individuals.

**Funding Sources:** This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

**Disclosures:** The authors have no conflicts of interest to disclose.

**Authorship:** All authors attest they meet the current ICMJE criteria for authorship.

**Patient Consent:** The patient gave written informed consent.

**Ethics Statement:** This systematic review was designed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta Analyses) guidelines.

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