Analysis of Phenotypic and Genetic Characteristics of 37 Children with SCN5A Variants: from A Single Tertiary Medical Center in China

Analysis of Phenotypic and Genetic Characteristics of 37 Children with SCN5A Variants: from A Single Tertiary Medical Center in China | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Analysis of Phenotypic and Genetic Characteristics of 37 Children with SCN5A Variants: from A Single Tertiary Medical Center in China Huiming Zhou, Xiaomei Li, Yi Zhang, Meiting Li, Danlei Chen This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4453166/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract The clinical, electrocardiographic and genetic characteristics of children with SCN5A variants are complex and widely different from those of adults, but relevant reports are lacking. So, this study was designed to illustrate the characteristics of children with SCN5A variants in China with the largest sample size. Of arrhythmic children with SCN5A variants, clinical history and electrocardiographic and genetic results were integrated, and further follow-up was conducted to illustrate the disease spectrum, progression and genetics. Thirty-seven arrhythmic children with SCN5A variants were enrolled, whose electrocardiograms mainly presented as conduction disorders (60%), sinoatrial node dysfunction (46%), prolonged QT interval (38%) and Brugada pattern (5%). These electrocardiogram abnormalities could exist alone (54%) or form overlap syndrome (46%). Ventricular arrhythmia co-occurred in 57% of long QT syndrome patients. Of children with progressive cardiac conduction system disease (PCCD), 25% showed second-degree atrioventricular block (AVB) type II or third-degree AVB firstly and another 25% progressed from second-degree AVB type I to third-degree AVB. Forty-six percent of the sick sinus syndrome (SSS) children showed atrial tachycardia/flutter firstly, but sinus arrest/bradycardia was then triggered. Most of the overlap syndrome was SSS plus PCCD (65%) and the former took the predominance. The most prevalent culprit domain in N aV 1.5 channel was the pore-loop (26%) and followed by the II-III linker (18%). In conclusion, conduction disorders and sinoatrial node dysfunction are the most popular abnormal electrocardiograms. The pore-loop and II-III linker of N aV 1.5 channel are highly likely to be the key molecular structural regions determining the clinical phenotypes. children clinical phenotype genetics SCN5A variants Figures Figure 1 Figure 2 Introduction The SCN5A gene encodes the N aV 1.5 channel protein, which is the most important structural basis for regulating the inward sodium current in cardiomyocytes. 1 Its pathogenic variants are responsible for several forms of arrhythmias, such as Brugada syndrome (BrS), long QT syndrome (LQTS), progressive cardiac conduction system disease (PCCD) and sick sinus syndrome (SSS). 2 Clinical manifestations of these syndromes that can exist alone or in multiple combinations (known as overlap syndrome) in patients are diverse and intricate. In adults, BrS was reported by previous researches as the most prominent phenotype (52%) of SCN5A variants (c.4813+3_4813+6dupGGGT.), and conduction dysfunction existed in substantial part of them (65%). 3 SCN5A 1975insD variant can lead to QTc prolongation in nearly half of carriers, more J-point/ST elevations and cardiac conduction dysfunction patients. 4 However, corresponding studies in children are so scarce that the understandings of their clinical phenotypes and genetics are insufficient. Paradoxically, the diligent attention of pediatric physicians is intensely required as the high proportion (31%) of life-threatening cardiac events and the high degree of malignant nature. 5 So, our research is the largest sample size of SCN5A variants population in China so far, and it was aimed to analyze the clinical and genetic characteristics of children with SCN5A pathogenic variants in our medical center to deepen the insight of this disease spectrum and provide reasonable basis for clinical diagnosis and management. Methods A retrospective cohort study on 37 children with arrhythmia and SCN5A pathogenic variants recruited from the Department of Pediatric Cardiology at the First Hospital of Tsinghua University was conducted from November 2013 to October 2022. The detailed family and medical history, physical examination, laboratory tests, electrocardiogram (ECG), 24-h Holter, echocardiography, electroencephalogram, brain imaging examination, results of genetic testing and follow-up information were obtained for each patient and further analyzed. Types of arrhythmias were determined based on the recordings of ECGs and 24-h Holter. Those who met all of the following conditions were included: 1) clinical diagnosis of hereditary arrhythmia relevant to gene mutations; 2) at least one SCN5A variant by whole exome sequencing, considered “pathogenic/likely pathogenic” according to the 2015 ACMG guidelines; 6 and 3) age at first diagnosis ≤ 14 y. Those patients with 1) no SCN5A variants; 2) SCN5A variants defined as “uncertain significance”, “benign” or “likely benign”; or 3) other pathogenic variants causing the same clinical phenotype were excluded in this study. Prior to genetic investigation, written informed consent was obtained from a legal guardian of each pediatric patient, and this study was allowed by the Ethics Committee of the First Hospital of Tsinghua University (No.201612) and performed in agreement with the ethical standards in the Declaration of Helsinki. Diagnosis criteria of the phenotypes associated with SCN5A pathogenic variants were listed below. 7 , 8 BrS was identified with the presence of classic ST-segment elevation (coved type) in leads V 1 through V 3 on right chest at baseline or after administration of intravenous sodium channel blockers combined with ventricular tachycardia (VT), ventricular fibrillation (VF), self-terminating polymorphic VT, cardiogenic syncope, family history of sudden cardiac death or coved type ECG in families. Those subjects with normal heart structure were eliminated. We defined the diagnosis of LQTS in the presence of a QT interval corrected for heart rate using Bazett’s formula (QTc) ≥ 480 ms in repeated ECGs associated with an LQTS risk score of Schwartz ≥ 3.5 with or without ventricular arrhythmia or cardiac event. Those conditions with acquired QT prolongation caused by medicine, slow heart rate, electrolyte disturbance, heart dysfunction, etc. were abandoned. PCCD, a major conduction disturbance (such as atrioventricular node block or left/right bundle branch block) with progressive aggravation. SSS was considered with one or more of the following conditions: chronic sinus bradycardia inconsistent with the age, sinus pause longer than 1.8 s or frequent sinoatrial block and bradycardia-tachycardia syndrome. Patients with more than one of the above arrhythmogenic phenotypes were defined as cases of overlap syndrome. The first-visit age was referred to the age of the first visit to a doctor due to the unwell symptoms or the discovery of abnormal ECGs. And the age of diagnosis was defined as the age when genetic testing declared the pathogenic variants causing the relevant clinical phenotypes. Gain-of-function variants in SCN5A induce an elevated sodium current during the action potential plateau and result in LQTS. On the other side, loss-of-function variants induce a decreasing sodium current and result in an arrhythmic clinical spectrum, such as BrS, PCCD and SSS. A genetic testing was carried out using genomic DNA extracted from peripheral white blood cells of all participants and targeted sequence was captured by high-throughput sequencing technology using standard protocols (Illumina NovaSeq 6000, Illumina Inc., San Diego, CA, USA) and that of the pediatric patients and their parents was validated by Sanger sequencing. The Genome Analysis Tool Kit (version 4.0, https://gatk.broadinstitute.org ) was applied to identify variant sequences and ANNOVAR ( https://annovar.openbioinformatics.org ) was used to annotate all variants. The tools like dbscSNV1.1, spidex and SpliceAI were applied to presume the pathogenicity of novel variants and ACMG criteria were employed to clarify the classification of variants as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign. 6 A two-dimensional map was determined based on the locus of SCN5A variants in the Nav1.5 channel protein published in UniProt database, furthermore, on which the amino acid sequence coded by the altered nucleotides and the clinical phenotypes were depicted. Data analysis was performed using SPSS 22.0 (IBM Corp, Armonk, NY, USA). Quantitative values were described as means ± SD and categorical variables were expressed as counts and proportions. Results Thirty-seven pediatric patients [26 boys (70%) and 11 girls (30%)] with arrhythmias testified relevant to SCN5A variants were enrolled in this study, all of whom were probands. The demographics and basically clinical characteristics were presented in Table 1 . The duration from the first-visit to the time of genetic testing was 1.3 ± 1.8 (range, 0.1 to 8.0) y. Of all the participants, 22 (59%) had suspicious family history. Especially, 12 of them (55%) had the family history of syncope or sudden death. Table 1 Demographic and basically clinical characteristics (n = 37) Boys/girls 26/11 (70%/30%) First-visit age, y 4.4 ± 3.8 (range, prenatal to 12) In prenatal period 4 (11%) In infancy 8 (22%) In early childhood 6 (16%) In preschool period 6 (16%) In school period 13 (35%) Reasons for the first-visit Tachycardia or bradycardia in utero 4 (11%) Syncope 7 (19%) Discovered by chance * 26 (70%) History of syncope and/or sudden death 12 (32%) History of syncope only 3 (8%) History of sudden death only 3 (8%) Both 6 (16%) Values are means ± SD and n (%); * Abnormal heart rate or abnormal ECGs found during regular check-ups or visiting a physician for other reasons. As for electrocardiographic data, conduction defect was the most popular form (n = 22, 60%), followed by sinoatrial node dysfunction (SND) (n = 17, 46%) and prolonged QT interval (n = 14, 38%). Only two cases (5%) showed a coved-type BrS ECG pattern (Fig. 1 ). Isolated phenotypes (n = 20, 54%) and overlap phenotypes (n = 17, 46%) respectively accounted for almost the half. Exactly, there were 10 cases with isolated LQTS (27%), eight with isolated PCCD (22%) and two with isolated SSS (5%). Among the remaining patients with overlap syndrome, eleven cases (30%) had SSS and PCCD, two (5%) had LQTS and PCCD, two (5%) had LQTS and SSS, one (3%) had BrS and SSS, and the last one (3%) was persecuted by three combined phenotypes of BrS, PCCD and SSS. According to the function of SCN5A variants, 10 patients (27%) had gain-of-function phenotype and another 10 (27%) patients showed loss-of-function phenotype. Both phenotypes of gain- and loss-of-function were occurred in four children (11%) and more than one kind of loss-of-function phenotype did in 13 children (35%). The detailed information of the above mentioned four ECG abnormalities was described as follows (Table 2 ): Table 2 Clinical features of children with SCN5A variants Phenotypes Cases n (%) First-visit age, y Age at diagnosis, y QTc, ms AVB BBB SND Tachyarrhythmias Syncope n (%) Ⅰ/Ⅱ-Ⅰ n (%) Ⅱ-Ⅱ/Ⅲ n (%) RBBB n (%) Bradycardia n (%) Arrest n (%) Ventricular n (%) Atrial n (%) LQTS first 14 (38%) 5.7 ± 4.2 6.9 ± 4.7 578.6 ± 62.9 2 (9%) 0 (0%) 2(15%) 2 (15%) 0 (0%) 8 (67%) 1 (8%) 4 (33%) Isolated LQTS 10 (71%) 6.6 ± 4.2 8.1 ± 5.1 593.5 ± 74.5 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 6 (75%) 0 (0%) 2 (50%) LQTS + PCCD 2 (14%) 1.0 ± 0.7 1.9 ± 1.5 545.0 ± 7.1 2 (100%) 0 (0%) 2 (100%) 0 (0%) 0 (0%) 2 (25%) 0 (0%) 1 (25%) LQTS + SSS 2 (14%) 5.5 ± 2.1 6.0 ± 2.8 492.5 ± 10.6 0 (0%) 0 (0%) 0 (0%) 2 (100%) 0 (0%) 0 (0%) 1 (100%) 1 (25%) PCCD first 8 (22%) 2.2 ± 2.4 4.4 ± 4.3 444.0 ± 27.3 8 (36%) 4 (80%) 5 (38%) 0 (0%) 0 (0%) 2 (17%) 0 (0%) 3 (25%) Isolated PCCD 8 (100%) 2.2 ± 2.4 4.4 ± 4.3 437.0 ± 18.7 8 (100%) 4 (100%) 5 (100%) 0 (0%) 0 (0%) 2 (100%) 0 (0%) 3 (100%) SSS first 13 (35%) 5.0 ± 3.6 5.8 ± 3.1 435.4 ± 26.7 11 (50%) 0 (0%) 6 (46%) 9 (69%) 12 (92%) 0 (0%) 12 (92%) 4 (33%) Isolated SSS 2 (15%) 8.5 ± 4.9 8.7 ± 5.0 438.0 ± 14.1 0 (0%) 0 (0%) 0 (0%) 2 (22%) 2 (17%) 0 (0%) 1 (8%) 0 (0%) SSS + PCCD 11 (85%) 4.4 ± 3.3 5.2 ± 2.7 434.9 ± 32.3 11 (100%) 0 (0%) 6 (100%) 7 (78%) 10 (83%) 0 (0%) 11 (92%) 4 (100%) BrS first 2 (5%) 1.1 ± 0.6 1.4 ± 0.9 450.0 ± 14.1 1 (5%) 1 (20%) 0 (0%) 2 (15%) 1 (8%) 2 (17%) 0 (0%) 1 (8%) BrS + SSS 1 (50%) 1.5 2.0 440.0 0 (0%) 0 (0%) 0 (0%) 1 (50%) 1 (100%) 1 (50%) 0 (0%) 0 (0%) BrS + PCCD + SSS 1 (50%) 0.7 0.8 460.0 1 (100%) 1 (100%) 0 (0%) 1 (50%) 0 (0%) 1 (50%) 0 (0%) 1 (100%) AVB = atrioventricular block; BBB = bundle branch block; BrS = Brugada syndrome; LQTS = long QT syndrome; PCCD = progressive cardiac conduction disease; RBBB = right bundle branch block; SND = sinoatrial node dysfunction; SSS = sick sinus syndrome; Ⅰ/Ⅱ-Ⅰ = first-degree AVB or second-degree AVB type I; Ⅱ-Ⅱ/Ⅲ = second-degree AVB type II or third-degree AV. Conduction defect. Twenty-two patients (59%) were disturbed by conduction defect and all of them were accompanied by atrioventricular block (AVB). Exactly, first-degree AVB was discovered in 20 patients (91%), second-degree AVB in nine (41%) and third-degree AVB in three (14%). Meanwhile, 12 patients (55%) were also disturbed by bundle branch block (BBB), specifically 11 of whom (50%) by right BBB and the other one (5%) by both right and left BBB. Eight patients [5 boys (62%) and 3 girls (38%)] were diagnosed with isolated PCCD. Their first-visit age was 2.2 ± 2.4 (range, prenatal to 7) y. Two patients at their first-visit age of 0.6 and 1.3 y respectively displayed second-degree AVB type Ⅱ and third-degree AVB. Two more patients displayed second-degree AVB type Ⅰ respectively at their first-visit age of 4.5 and 3 y. However, both progressed to second-degree AVB type Ⅱ and eventually third-degree AVB during their respective nine and ten years of follow-up. The remaining four patients were characterized with first-degree AVB and BBB (right or both left and right), and no progress was discovered during their 6.2 ± 3.6 (range, 1 to 11) y of follow-up. Among the eight patients, three (38%) experienced syncope, one thought to ascribe to high degree AVB with the longest RR interval of 7.2 s and the others related to VT. Sinoatrial node dysfunction. Seventeen patients showed SND in ECGs, 76% (n = 13) of them had sinus bradycardia with the mean heart rate of 65 ± 8 (range, 54–83) bpm and 76% (n = 13) experienced sinus arrest with the longest RR interval of 4.2 ± 2.8 (range, 1.9–16.1) s. Taken together, both sinus bradycardia and sinus arrest occurred in nine patients (53%). Thirteen patients characterized with SND were diagnosed with SSS (two isolated cases and the others along with PCCD). Ten boys (77%) and three girls (23%) visit a doctor firstly at their age of 5.0 ± 3.6 (range, 0.4–12) y. Each of syncope and sinus bradycardia was reported in three patients (23%) as their chief complaint for visiting a doctor. Another one patient (8%) asked for help because of sinus arrest and the remaining six ones (46%) for tachycardia. To be exact, only one patient (8%) having disease onset in utero was characterized with sinus bradycardia [mean heart rate 54 (range, 35–128) bpm] rather than sinus arrest. All of the remaining 12 patients (92%) presented as bradycardia-tachycardia syndrome, half of whom were diagnosed with tachyarrhythmia (atrial flutter or sustained atrial tachycardia) at their first-visit and further showed SND after conversion to sinus rhythm by radiofrequency ablation, and the other half displayed the alternation of tachyarrhythmia (sustained atrial tachycardia or atrial flutter) and bradyarrhythmia (sinus arrest or sinus bradycardia) firstly. As for ECG phenotypes in the 12 patients, sinus arrest with the longest RR interval of 4.7 ± 3.9 (range, 2.1–10.5) s was found in four cases, who had normal heart rate during other times. And the other eight cases experienced both sinus bradycardia (mean heart rate 69 ± 8 bpm, the slowest heart rate 48 ± 10 bpm and the fastest heart rate 147 ± 29 bpm) and sinus arrest [the longest RR interval 4.5 ± 1.6 (range, 2.1–7.1) s]. On the other side, 11 of the 13 patients (85%) whose diseases centered on SSS also endured conduction dysfunction (first-degree AVB) and what was more, second-degree AVB type Ⅰ co-occurred in five of them and right BBB did in the others. Specifically, one patient diagnosed with isolated SSS at the first-visit progressively developed to first-degree AVB and right BBB, then eventually to second-degree AVB type Ⅰ during the following four years. In total, there were four patients experiencing syncopal episodes, two of whom showed sustained atrial flutter or atrial fibrillation in ECGs or Holter and the other two cases endured sinus arrest with the documented longest RR intervals of 3.5 s and 4.4 s, respectively. Prolongation of QT interval. Prolonged QTc intervals [565.9 ± 66.4 (range, 480–724) ms] were found in 14 patients, notably longer than 500 ms found in 12 of them (86%). LQTS was determined as the chief phenotype in all patients, including 10 isolated cases and four overlap cases. Exactly, two of the four overlap cases were combined with first-degree AVB and right BBB. And the remaining two cases displayed SND, one showing sinus bradycardia with heart rate ranging from 39 to 125 (mean 60) bpm at the age of seven years and the other one also showing sinus bradycardia with heart rate ranging from 58 to 113 (mean 73) bpm at the age of four years. The first-visit age of the 14 LQTS cases was 5.7 ± 4.2 (range, prenatal-12) y, 10 boys (71%) and 4 girls (29%). VT or VF was also documented in ECGs or Holter in eight cases and the QTc interval longer than 500 ms was recorded in seven of them (88%). Syncopal episodes happened to four cases (29%), all of whom were disturbed by both of VT/VF and obvious prolonged QTc interval (> 500 ms). Brugada syndrome. Both of the two patients diagnosed with BrS also manifested other phenotypes, whose detailed information was elaborated as follows: BrS plus SSS happened to one baby boy, who had disease onset at 1.5 y and were diagnosed at 2 y. VT was described as his chief complaint and elevated J wave (dome-shaped elevation in leads of V1 to V3) was observed in ECG under sinus rhythm. He also showed the characteristics of SND, namely sinus bradycardia with heart rate ranging from 52 to 148 (mean 84) bpm and sinus arrest with the longest RR interval of 16.1 s. Another baby girl was diagnosed with PCCD and SSS except for BrS, who had disease onset at the age of eight mo and was diagnosed at nine mo. Syncopal events accompanied by VT were reported as her chief complaint and the typical BrS ECG (elevated J wave with dome morphology in leads of V1 and V2 under sinus rhythm) was regarded as the main electrocardiographic phenotype, along with conduction defect (first-degree AVB with PR interval of 0.17–0.22 s and intermittent second-degree AVB type Ⅱ) and SND [sinus bradycardia with heart rate ranging from 50 to 188 (mean 83) bpm]. The 37 patients had 40 independent variants (three of them harboring a double heterozygous variants) of SCN5A gene, including 34 non-repeat variants (Supplementary Table 1). Eighteen non-repeat variants have been reported and eight of them were missense mutations. In total, among the 40 independent variants, missense mutations accounted for 75% (n = 30), frameshift/non-sense/splicing mutations for 25% (n = 10). As for their origins, 21 variants (53%) were inherited from the maternal line, 14 (35%) from the paternal line and the remaining five (12%) were regarded as de novo variants. What was notable, the same frameshift variant (c.611 + 1G > C) happened to the only two patients diagnosed with BrS. All of the amino acid sites and clinical phenotypes were presented in Fig. 2. The most prevalent domain in N aV 1.5 channel protein where amino acids encoded by SCN5A variants located was the pore-loop (26%), followed by II-III linker (18%), and the other domains were occupied by sporadic variants. Regarding the relationship of clinical phenotypes and variants locus of Na V 1.5, variants of isolated LQTS were mainly located at II-III linker (40%) and pore-loop (30%), and variants of isolated PCCD were mainly at II-III linker (30%) and pore-loop (30%). Whereas, the variants locus of overlap phenotype was dispersive. The clinical presentation of all the eight patients with the frameshift/non-sense/splicing mutations was determined as loss-of-function (5 PCCD + SSS, 3 PCCD, 1 BrS + SSS and 1 BrS + SSS + PCCD). Totally, 12 syncopal patients (two attacked by sudden death) had 12 variants most of which located at voltage-sensing domain (58%), and then II-III linker (17%). Discussion The structural abnormality of N aV 1.5 channel protein caused by SCN5A variants can lead to cardiac arrhythmias and structural abnormalities, and its correlation with cardiogenetic disorders has attracted more and more attention. Both of the electrocardiographic phenotypes and the clinical phenotypes associated with SCN5A variants are diverse, namely not only causing different isolated phenotypes but also causing overlap syndrome with various combinations. Moreover, high proportion of life-threatening cardiac events, high degree of malignancy and early disease onset at childhood deserve great attention from physicians. 5 Unfortunately, few studies on ECGs and clinical phenotypes related to SCN5A in children population have been reported, 5 , 9 so this study would enrich our understanding and offset this gap to some extent. In our population, the first-visit age of the 37 enrolled patients was 4.4 ± 3.8 y. Syncopal events were reported as the chief complaint in 19% patients and the major part (70%) visited a cardiologist because abnormal signs in physical examination or ECGs were found when visiting a doctor for other reasons. Thus, it can be seen that this spectrum of disorders is easy to be missed for its lack of specific clinical symptoms and signs. Genetic testing is helpful to clarify the association of genetic arrhythmias and SCN5A variants. The mean duration of 1.3 ± 1.8 y with the longest duration of eight years was spent to take genetic examinations since the first-visit to a doctor, implying doctors’ insufficient cognition on this spectrum of diseases is common. For children with hereditary arrhythmias, such as QT interval prolongation, sinus node dysfunction, conduction defect and Brugada-type ECG without clear secondary pathogenic reasons, whether with positive family history or not, genetic testing should be performed as early as possible to determine the suspicious disease-causing gene variants aiming to make early diagnosis, treatment scheme and prognosis assessment. 10 Hereditary cardiac conduction disorders are characterized by age-dependent progression, such as PR interval prolongation, QRS interval prolongation and bundle branch conduction block progressing with aging. 11 One research conducted in a mouse model found that at the same age, cardiac fibrosis caused by SCN5A variants is significantly more frequent than that of wild-type mice and the progress of conduction dysfunction is aggravated in a sequential manner, indicating that age-dependent cardiac fibrosis might be a crucial mechanism for the progress of conduction dysfunction with aging in PCCD. 12 In our study, the first-visit age of these PCCD patients was 2.2 ± 2.4 y. Two of them respectively showed second-degree AVB type II and third-degree AVB at their each first-visit age of 0.6 y and 1.3 y, and another two patients progressed from second-degree AVB type I to third-degree AVB in nine to ten years of follow-up, which indicated that PCCD patients caused by SCN5A variants could present as second-degree AVB type II or third-degree AVB in childhood, or even in infancy. However, the early clinical manifestations of PCCD are so lacking that it is easy to make missed diagnosis, so physicians should pay more attention to it and make careful and regular follow-up to observe its dormant progression. Observed in our study, 50% patients with PCCD had right BBB and only 5% had both left and right BBB. One plausible explanation may be that the expression of N aV 1.5 channel protein within the right bundle branch is relatively lower than that of the left bundle branch. 13 Consequently, the loss-of-function of N aV 1.5 has a greater impact on the right bundle branch conduction system, the risk of right BBB is much higher and the onset of right BBB is earlier than the left. In our study, 46% patients exhibited SSS, whose age of disease-onset was 5.0 ± 3.6 (range, 0.4–12) y. Some studies demonstrate the high incidence rate of SSS both in adults and children, 5 , 9 , 14 hinting the early onset of SSS in the young. One cohort study including 15 families in Japan found that 37% of SCN5A variants carriers exhibited SSS, and the mean disease-onset age of 35.5 ± 5.4 (range, 3–65) y in these probands was significantly younger than that in sporadic SSS patients (74.3 ± 0.4 y). 14 All electrocardiographic forms involving SSS took as high as 46%, however, only 5% presented as isolation and the vast majority of them presented as overlap, which combining with PCCD accounted for 30%. The possible reason is that both the pathogeneses of SSS and PCCD are impaired sodium current in cardiomyocytes. 15 And different expression degree of SCN5A in different part of the heart is the basis of pathological structure of them. 1 , 13 One study conducted by Villarreal-Molina T, et al. in children along with SCN5A variants showed that SSS happened to 77% recruited patients and 54% of them were disturbed by atrial tachycardia or atrial flutter. 9 The same phenomenon appeared in our study. Atrial tachyarrhythmias (atrial tachycardia or atrial flutter) were recorded as the first signs for visiting a doctor in 46% of the enrolled patients with SSS, and then atrial arrhythmias gradually developed into SND. Sinus bradycardia or sinus arrest cannot easily be diagnosed due to the lack of clinical manifestations, until it alters as tachyarrhythmia and affected patients often visit a doctor for obvious palpitations or even tachycardia cardiomyopathy. LQTS is also a common clinical phenotype in children and adult who carried SCN5A variants. 4 , 5 , 9 , 16 There are ten (27%) isolated LQTS patients and four (11%) overlap phenotype patients who were combine with PCCD or SSS, and these patients regarded LQTS as the major form. 86% of their QTc intervals were longer than 500ms and 57% of these LQTS patients occurred ventricular arrhythmias. The researchers found that the probability of cardiac event increased by 19% for every 10 ms increase in the QTc intervals before 500 ms, and this trend decreased after 500 ms. 16 Purkinje system hyperexcitability may be a major cause of ventricular arrhythmia in these patients. 17 BrS, which has been documented as one of the most popular phenotypes in adults, 3 , 4 took the least part (5%) in our participants. Baruteau AE, et al. also observed the likely phenomenon in another pediatric population and declared that isolated BrS only accounted for 1.8%. 5 So, it is suggested that onset of BrS is relatively late and it is rare in children. As a result, the incidence rates of children and adults are significantly different from each other. It is supposed that the pathophysiological basis for Brugada ECG patten is epicardial fibrosis in the right ventricular outflow tract and the conduction velocity of the fibrosis local is therefore delayed. 18 , 19 Furthermore, the formation of epicardial fibrosis in the right ventricular outflow tract has been proven to be associated with aging, 20 which is regarded as one probable reason for the low incidence rate of BrS in children. More rationally, one animal research conducted by David SP, et al. discovered that one kind of haploid loss-of-function SCN5A variants could lead to hypertrophy, disordered arrangement and even fibrosis of cardiomyocytes at cardiac conduction system or outflow tract in adult pigs, but not in the young. 13 In our study, the only two BrS patients were demonstrated to be both along with SSS and one of them also with PCCD, indicating that BrS, a type of functional impairment phenotypes, could overlap with other functional impairment phenotypes, like SSS and PCCD. 21 Another research in Japan also found that four BrS patients with SCN5A heterozygous variants were all complicated with SSS (and/or PCCD). 22 At the same time Villarreal-Molina T, et al. also reported that 67% BrS pediatric patients had combination with SSS (and/or PCCD). 9 Therefore, it seems to be some relationship among these three functional impairment phenotypes (BrS/PCCD/SSS) need to further research. Taken together, it can be concluded that the clinical manifestations caused by SCN5A variants are of complexity and diversity. Consequently, for children with SCN5A variants, we should not pay attention to only isolated phenotype but also overlap phenotype and should carefully distinguish them to avoid missed diagnosis. The variance of functional domains where variants locating may play a crucial role in the formation of different phenotypes. 23 According to the data observed in our work, up to 18 of the 34 non-repetitive variants are de novo, indicating that there may still be many de novo pathogenic variants in SCN5A gene even though more than 400 pathogenic missense mutations have been reported. 24 We found that pathogenic SCN5A variants are mainly located in pore-loop, and also common in II-III linker, hinting these regions are closely associated with clinical phenotypes. Here, we demonstrate the elaborate characteristics of arrhythmic children with SCN5A variants and broaden and deepen the understandings of this field. However, limited number of enrolled patients from one single center restricts its extrapolation. Meanwhile, the follow-up duration is not long enough to span adulthood to obtain a more detailed picture of disease progression. Further multicenter-based researches with larger populations are needed. Conclusively, the electrocardiographic manifestations of SCN5A variants in children are diverse, ranging from conduction defects, sinus node dysfunction, prolongation of QT interval to Brugada pattern. Various electrocardiographic abnormalities can present as isolated phenotypes or as overlap phenotypes. The clinical and electrocardiographic characteristics of children with SCN5A variants are different from those of adults, so it is indispensable to pay more attention and complete genetic screening as soon as possible to clarify the etiologies and estimate disease progression and prognosis. As for the roles of N aV 1.5 structure, the linkers (especially II-III linker) and pore-loop are inferred as crucial molecular regions determining the various phenotypes of this spectrum of diseases. Declarations Funding sources: The present study was supported by the Capital Clinical Characteristic Application Research (Z221100007422082) and Tsinghua University Yuyuan Medical Research Funding (202000591). Author Contribution Zhou wrote the main manuscript text; and prepared figures 1-2 and table 1-2. Zhang modified the manuscript for the first time.Li Mei-ting and Chen were responsible for part of the data collection.Li Xiao-mei provided study design and modified the manuscript finally.All authors reviewed the manuscript. Acknowledgements The authors appreciate the children who participated in this study as well as their guardians. References Rivaud MR, Delmar M, Remme CA (2020) Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms. Cardiovasc Res 116:1557–1570 Ruan Y, Liu N, Priori SG (2009) Sodium channel mutations and arrhythmias. Nat Rev Cardiol 6:337–348 Sieliwonczyk E, Alaerts M, Robyns T, Schepers D, Claes C, Corveleyn A, Willems R, Van Craenenbroeck M, Simons E, Nijak E, Vandendriessche A, Mortier B, Vrints G, Koopman C, Heidbuchel P, Laer H, Saenen LV, Loeys J (2021) Clinical characterization of the first Belgian SCN5A founder mutation cohort. 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Eur Heart J 39:2879–2887 Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hegde M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17:405–424 Priori SG, Wilde AA, Horie M, Cho Y, Behr ER, Berul C, Blom N, Brugada J, Chiang CE, Huikuri H, Kannankeril P, Krahn A, Leenhardt A, Moss A, Schwartz PJ, Shimizu W, Tomaselli G, Tracy C (2013) HRS/EHRA/APHRS expert consensus statement on the diagnosis and management of patients with inherited primary arrhythmia syndromes: document endorsed by HRS, EHRA, and APHRS in May 2013 and by ACCF, AHA, PACES, and AEPC in June 2013. Heart Rhythm 10:1932–1963 Kusumoto FM, Schoenfeld MH, Barrett C, Edgerton JR, Ellenbogen KA, Gold MR, Goldschlager NF, Hamilton RM, Joglar JA, Kim RJ, Lee R, Marine JE, McLeod CJ, Oken KR, Patton KK, Pellegrini CN, Selzman KA, Thompson A, Varosy PD (2019) 2018 ACC/AHA/HRS guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines, and the Heart Rhythm Society. J Am Coll Cardiol 74:932–987 Villarreal-Molina T, García-Ordóñez GP, Reyes-Quintero ÁE, Domínguez-Pérez M, Jacobo-Albavera L, Nava S, Carnevale A, Medeiros-Domingo A, Iturralde P (2021) Clinical spectrum of scn5a channelopathy in children with primary electrical disease and structurally normal hearts. Genes (Basel) 13:16 Wilde AAM, Semsarian C, Márquez MF, Sepehri Shamloo A, Ackerman MJ, Ashley EA, Sternick EB, Barajas-Martinez H, Behr ER, Bezzina CR, Breckpot J, Charron P, Chockalingam P, Crotti L, Gollob MH, Lubitz S, Makita N, Ohno S, Ortiz-Genga M, Sacilotto L, Schulze-Bahr E, Shimizu W, Sotoodehnia N, Tadros R, Ware JS, Winlaw DS, Kaufman ES, Document R, Aiba T, Bollmann A, Choi JI, Dalal A, Darrieux F, Giudicessi J, Guerchicoff M, Hong K, Krahn AD, MacIntyre C, Mackall JA, Mont L, Napolitano C, Ochoa JP, Peichl P, Pereira AC, Schwartz PJ, Skinner J, Stellbrink C, Tfelt-Hansen J, Deneke T (2022) Society (APHRS)/Latin American Heart Rhythm Society (LAHRS) expert consensus statement on the state of genetic testing for cardiac diseases. Heart Rhythm 19:e1–e60European Heart Rhythm Association (EHRA)/Heart Rhythm Society (HRS)/Asia Pacific Heart Rhythm Probst V, Kyndt F, Potet F, Trochu JN, Mialet G, Demolombe S, Schott JJ, Baró I, Escande D, Le Marec H (2003) Haploinsufficiency in combination with aging causes SCN5A-linked hereditary Lenègre disease. J Am Coll Cardiol 41:643–652 Papadatos GA, Wallerstein PM, Head CE, Ratcliff R, Brady PA, Benndorf K, Saumarez RC, Trezise AE, Huang CL, Vandenberg JI, Colledge WH, Grace AA (2002) Slowed conduction and ventricular tachycardia after targeted disruption of the cardiac sodium channel gene Scn5a. Proc Natl Acad Sci USA 99:6210–6215 Park DS, Cerrone M, Morley G, Vasquez C, Fowler S, Liu N, Bernstein SA, Liu FY, Zhang J, Rogers CS, Priori SG, Chinitz LA, Fishman GI (2015) Genetically engineered SCN5A variant pig hearts exhibit conduction defects and arrhythmias. J Clin Invest 125:403–412 Abe K, Machida T, Sumitomo N, Yamamoto H, Ohkubo K, Watanabe I, Makiyama T, Fukae S, Kohno M, Harrell DT, Ishikawa T, Tsuji Y, Nogami A, Watabe T, Oginosawa Y, Abe H, Maemura K, Motomura H, Makita N (2014) Sodium channelopathy underlying familial sick sinus syndrome with early onset and predominantly male characteristics. Circ Arrhythm Electrophysiol 7:511–517 Wu J, Zhang Y, Zhang X, Cheng L, Lammers WJ, Grace AA, Fraser JA, Zhang H, Huang CL, Lei M (2012) Altered sinoatrial node function and intra-atrial conduction in murine gain-of-function Scn5a+/∆KPQ hearts suggest an overlap syndrome. Am J Physiol Heart Circ Physiol 302:H1510–H1523 Wilde AA, Moss AJ, Kaufman ES, Shimizu W, Peterson DR, Benhorin J, Lopes C, Towbin JA, Spazzolini C, Crotti L, Zareba W, Goldenberg I, Kanters JK, Robinson JL, Qi M, Hofman N, Tester DJ, Bezzina CR, Alders M, Aiba T, Kamakura S, Miyamoto Y, Andrews ML, McNitt S, Polonsky B, Schwartz PJ, Ackerman MJ (2016) Clinical aspects of type 3 long-qt syndrome: an international multicenter study. Circulation 134:872–882 Barake W, Giudicessi JR, Asirvatham SJ, Ackerman MJ (2020) Purkinje system hyperexcitability and ventricular arrhythmia risk in type 3 long QT syndrome. Heart Rhythm 17:1768–1776 Nademanee K, Raju H, de Noronha SV, Papadakis M, Robinson L, Rothery S, Makita N, Kowase S, Boonmee N, Vitayakritsirikul V, Ratanarapee S, Sharma S, van der Wal AC, Christiansen M, Tan HL, Wilde AA, Nogami A, Sheppard MN, Veerakul G, Behr ER (2015) Fibrosis, connexin-43, and conduction abnormalities in the Brugada syndrome. J Am Coll Cardiol 66:1976–1986 Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, Likittanasombat K, Bhuripanyo K, Ngarmukos T (2011) Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 123:1270–1279 Cerrone M, Costa S, Delmar M (2022) The Genetics of Brugada Syndrome. Annu Rev Genomics Hum Genet 23:255–274 Probst V, Allouis M, Sacher F, Pattier S, Babuty D, Mabo P, Mansourati J, Victor J, Nguyen JM, Schott JJ, Boisseau P, Escande D, Le Marec H (2006) Progressive cardiac conduction defect is the prevailing phenotype in carriers of a Brugada syndrome SCN5A mutation. J Cardiovasc Electrophysiol 17:270–275 Makiyama T, Akao M, Tsuji K, Doi T, Ohno S, Takenaka K, Kobori A, Ninomiya T, Yoshida H, Takano M, Makita N, Yanagisawa F, Higashi Y, Takeyama Y, Kita T, Horie M (2005) High risk for bradyarrhythmic complications in patients with Brugada syndrome caused by SCN5A gene mutations. J Am Coll Cardiol 46:2100–2106 Jiang D, Banh R, Gamal El-Din TM, Tonggu L, Lenaeus MJ, Pomès R, Zheng N, Catterall WA (2021) Open-state structure and pore gating mechanism of the cardiac sodium channel. Cell 184:5151–5162e11 Pan X, Li Z, Jin X, Zhao Y, Huang G, Huang X, Shen Z, Cao Y, Dong M, Lei J, Yan N (2021) Comparative structural analysis of human Na(v)1.1 and Na(v)1.5 reveals mutational hotspots for sodium channelopathies. Proc Natl Acad Sci USA 118:e2100066118 Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4453166","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":309619454,"identity":"462665f5-f271-476d-91d9-a6bd9b5bdeea","order_by":0,"name":"Huiming Zhou","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Huiming","middleName":"","lastName":"Zhou","suffix":""},{"id":309619455,"identity":"0040d335-f853-4962-8f29-d82b8e1b6592","order_by":1,"name":"Xiaomei Li","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA60lEQVRIiWNgGAWjYBACPmYGhgMgBhsz+8EHHyoYeAhqYYNrYedJNpxxhhgtcBY/g5kwbxsRDgMabnjgR8U2OaAL0xhnzquTMWc/wPjhYw4+h7ElHOw5c9uYjZnx2IOP2w7zWPYkMEvO3IZPC/OBA7xttxPbmBnSDWduO8BjcCCBjZkXrxbGhoN/227XA7WYSfPOqeMxOP+AkBbmA4eBtgBNBmlpYOYxuEHQFraEwzJnbhu2MYMC+dhhoJaHzXj9ws9/xvjjm4rb8vL9x4FRWVNnb3A++eCHj3i0YAOMDaSpHwWjYBSMglGAAQAJgExNstTvcQAAAABJRU5ErkJggg==","orcid":"","institution":"Tsinghua University","correspondingAuthor":true,"prefix":"","firstName":"Xiaomei","middleName":"","lastName":"Li","suffix":""},{"id":309619456,"identity":"549830f3-9e3f-4d76-9fc6-d61e89bf7e0d","order_by":2,"name":"Yi Zhang","email":"","orcid":"","institution":"The First Hospital of Tsinghua University (Beijing Huaxin Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Yi","middleName":"","lastName":"Zhang","suffix":""},{"id":309619457,"identity":"705ec655-fafe-455b-86d6-e89fc32df049","order_by":3,"name":"Meiting Li","email":"","orcid":"","institution":"The First Hospital of Tsinghua University (Beijing Huaxin Hospital)","correspondingAuthor":false,"prefix":"","firstName":"Meiting","middleName":"","lastName":"Li","suffix":""},{"id":309619458,"identity":"e7f628bc-236d-4fe2-b2a5-c05fc725bf4d","order_by":4,"name":"Danlei Chen","email":"","orcid":"","institution":"Tsinghua University","correspondingAuthor":false,"prefix":"","firstName":"Danlei","middleName":"","lastName":"Chen","suffix":""}],"badges":[],"createdAt":"2024-05-21 08:09:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4453166/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4453166/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":57948749,"identity":"7e6ed578-179d-48ad-b44c-1cef43a58342","added_by":"auto","created_at":"2024-06-07 20:38:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":974708,"visible":true,"origin":"","legend":"\u003cp\u003eElectrocardiographic data and clinical phenotypes of pediatric patients with SCN5A variants (n = 37). (a) general diagram of enrolled patients characterized by ECG phenotypes and clinical phenotypes, (b) histogram of ECG phenotypes and (c) pie chart of clinical phenotypes. BrS = Brugada syndrome; ECG = electrocardiogram; LQTS = long QT syndrome; PCCD = progressive cardiac conduction system disease; SSS = sick sinus syndrome.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-4453166/v1/efa4367aa697e642f30a9040.png"},{"id":57948750,"identity":"f3c197c5-acc5-44f9-9462-1b34201287cf","added_by":"auto","created_at":"2024-06-07 20:38:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":744730,"visible":true,"origin":"","legend":"\u003cp\u003eSee image above for figure legend\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-4453166/v1/29038c14ff4ba42a9325bb57.png"},{"id":59940494,"identity":"ce9c2358-ee73-4f71-865e-1ac3b44647e7","added_by":"auto","created_at":"2024-07-09 14:48:16","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1636657,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4453166/v1/f9c73b4a-0371-44a5-ba57-bfd9beefa4b1.pdf"},{"id":57949594,"identity":"dee1bf9e-35b1-4cf0-a53a-4cca07a8dbbe","added_by":"auto","created_at":"2024-06-07 20:46:30","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":23772,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4453166/v1/4927edc6d424ef1efdeb04ca.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Analysis of Phenotypic and Genetic Characteristics of 37 Children with SCN5A Variants: from A Single Tertiary Medical Center in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe SCN5A gene encodes the N\u003csub\u003eaV\u003c/sub\u003e1.5 channel protein, which is the most important structural basis for regulating the inward sodium current in cardiomyocytes.\u003csup\u003e1\u0026nbsp;\u003c/sup\u003eIts pathogenic variants are responsible for several forms of arrhythmias, such as Brugada syndrome (BrS), long QT syndrome (LQTS), progressive cardiac conduction system disease (PCCD) and sick sinus syndrome (SSS).\u003csup\u003e2\u003c/sup\u003e Clinical manifestations of these syndromes that can exist alone or in multiple combinations (known as overlap syndrome) in patients are diverse and intricate.\u0026nbsp;In adults, BrS was reported by previous researches as the most prominent phenotype (52%) of SCN5A variants (c.4813+3_4813+6dupGGGT.), and conduction dysfunction existed in substantial part of them (65%).\u003csup\u003e3\u003c/sup\u003e SCN5A 1975insD variant can lead to QTc prolongation in nearly half of carriers, more J-point/ST elevations and cardiac conduction dysfunction patients.\u003csup\u003e4\u003c/sup\u003e However, corresponding studies in children are so scarce that the understandings of their clinical phenotypes and genetics are insufficient. Paradoxically, the diligent attention of pediatric physicians is intensely required as the high proportion (31%) of life-threatening cardiac events and the high degree of malignant nature.\u003csup\u003e5\u003c/sup\u003e So, our research is the largest sample size of SCN5A variants population in China so far, and it was aimed to analyze the clinical and genetic characteristics of children with SCN5A pathogenic variants in our medical center to deepen the insight of this disease spectrum and provide reasonable basis for clinical diagnosis and management.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA retrospective cohort study on 37 children with arrhythmia and SCN5A pathogenic variants recruited from the Department of Pediatric Cardiology at the First Hospital of Tsinghua University was conducted from November 2013 to October 2022. The detailed family and medical history, physical examination, laboratory tests, electrocardiogram (ECG), 24-h Holter, echocardiography, electroencephalogram, brain imaging examination, results of genetic testing and follow-up information were obtained for each patient and further analyzed. Types of arrhythmias were determined based on the recordings of ECGs and 24-h Holter. Those who met all of the following conditions were included: 1) clinical diagnosis of hereditary arrhythmia relevant to gene mutations; 2) at least one SCN5A variant by whole exome sequencing, considered \u0026ldquo;pathogenic/likely pathogenic\u0026rdquo; according to the 2015 ACMG guidelines;\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e and 3) age at first diagnosis \u0026le; 14 y. Those patients with 1) no SCN5A variants; 2) SCN5A variants defined as \u0026ldquo;uncertain significance\u0026rdquo;, \u0026ldquo;benign\u0026rdquo; or \u0026ldquo;likely benign\u0026rdquo;; or 3) other pathogenic variants causing the same clinical phenotype were excluded in this study. Prior to genetic investigation, written informed consent was obtained from a legal guardian of each pediatric patient, and this study was allowed by the Ethics Committee of the First Hospital of Tsinghua University (No.201612) and performed in agreement with the ethical standards in the Declaration of Helsinki.\u003c/p\u003e \u003cp\u003eDiagnosis criteria of the phenotypes associated with SCN5A pathogenic variants were listed below.\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e BrS was identified with the presence of classic ST-segment elevation (coved type) in leads V\u003csub\u003e1\u003c/sub\u003e through V\u003csub\u003e3\u003c/sub\u003e on right chest at baseline or after administration of intravenous sodium channel blockers combined with ventricular tachycardia (VT), ventricular fibrillation (VF), self-terminating polymorphic VT, cardiogenic syncope, family history of sudden cardiac death or coved type ECG in families. Those subjects with normal heart structure were eliminated. We defined the diagnosis of LQTS in the presence of a QT interval corrected for heart rate using Bazett\u0026rsquo;s formula (QTc) \u0026ge; 480 ms in repeated ECGs associated with an LQTS risk score of Schwartz \u0026ge; 3.5 with or without ventricular arrhythmia or cardiac event. Those conditions with acquired QT prolongation caused by medicine, slow heart rate, electrolyte disturbance, heart dysfunction, etc. were abandoned. PCCD, a major conduction disturbance (such as atrioventricular node block or left/right bundle branch block) with progressive aggravation. SSS was considered with one or more of the following conditions: chronic sinus bradycardia inconsistent with the age, sinus pause longer than 1.8 s or frequent sinoatrial block and bradycardia-tachycardia syndrome. Patients with more than one of the above arrhythmogenic phenotypes were defined as cases of overlap syndrome.\u003c/p\u003e \u003cp\u003eThe first-visit age was referred to the age of the first visit to a doctor due to the unwell symptoms or the discovery of abnormal ECGs. And the age of diagnosis was defined as the age when genetic testing declared the pathogenic variants causing the relevant clinical phenotypes.\u003c/p\u003e \u003cp\u003eGain-of-function variants in SCN5A induce an elevated sodium current during the action potential plateau and result in LQTS. On the other side, loss-of-function variants induce a decreasing sodium current and result in an arrhythmic clinical spectrum, such as BrS, PCCD and SSS.\u003c/p\u003e \u003cp\u003e A genetic testing was carried out using genomic DNA extracted from peripheral white blood cells of all participants and targeted sequence was captured by high-throughput sequencing technology using standard protocols (Illumina NovaSeq 6000, Illumina Inc., San Diego, CA, USA) and that of the pediatric patients and their parents was validated by Sanger sequencing. The Genome Analysis Tool Kit (version 4.0, \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://gatk.broadinstitute.org\u003c/span\u003e\u003cspan address=\"https://gatk.broadinstitute.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was applied to identify variant sequences and ANNOVAR (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://annovar.openbioinformatics.org\u003c/span\u003e\u003cspan address=\"https://annovar.openbioinformatics.org\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e) was used to annotate all variants.\u003c/p\u003e \u003cp\u003eThe tools like dbscSNV1.1, spidex and SpliceAI were applied to presume the pathogenicity of novel variants and ACMG criteria were employed to clarify the classification of variants as pathogenic, likely pathogenic, of uncertain significance, likely benign or benign.\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e A two-dimensional map was determined based on the locus of SCN5A variants in the Nav1.5 channel protein published in UniProt database, furthermore, on which the amino acid sequence coded by the altered nucleotides and the clinical phenotypes were depicted.\u003c/p\u003e \u003cp\u003eData analysis was performed using SPSS 22.0 (IBM Corp, Armonk, NY, USA). Quantitative values were described as means \u0026plusmn; SD and categorical variables were expressed as counts and proportions.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThirty-seven pediatric patients [26 boys (70%) and 11 girls (30%)] with arrhythmias testified relevant to SCN5A variants were enrolled in this study, all of whom were probands. The demographics and basically clinical characteristics were presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The duration from the first-visit to the time of genetic testing was 1.3 \u0026plusmn; 1.8 (range, 0.1 to 8.0) y. Of all the participants, 22 (59%) had suspicious family history. Especially, 12 of them (55%) had the family history of syncope or sudden death.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemographic and basically clinical characteristics (n\u0026thinsp;=\u0026thinsp;37)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"2\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoys/girls\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26/11 (70%/30%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFirst-visit age, y\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.8 (range, prenatal to 12)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn prenatal period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn infancy\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (22%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn early childhood\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn preschool period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIn school period\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (35%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eReasons for the first-visit\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTachycardia or bradycardia in utero\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e4 (11%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSyncope\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7 (19%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiscovered by chance\u003csup\u003e*\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26 (70%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of syncope and/or sudden death\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (32%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of syncope only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHistory of sudden death only\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3 (8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBoth\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6 (16%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are means \u0026plusmn; SD and n (%); \u003csup\u003e*\u003c/sup\u003eAbnormal heart rate or abnormal ECGs found during regular check-ups or visiting a physician for other reasons.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eAs for electrocardiographic data, conduction defect was the most popular form (n\u0026thinsp;=\u0026thinsp;22, 60%), followed by sinoatrial node dysfunction (SND) (n\u0026thinsp;=\u0026thinsp;17, 46%) and prolonged QT interval (n\u0026thinsp;=\u0026thinsp;14, 38%). Only two cases (5%) showed a coved-type BrS ECG pattern (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Isolated phenotypes (n\u0026thinsp;=\u0026thinsp;20, 54%) and overlap phenotypes (n\u0026thinsp;=\u0026thinsp;17, 46%) respectively accounted for almost the half. Exactly, there were 10 cases with isolated LQTS (27%), eight with isolated PCCD (22%) and two with isolated SSS (5%). Among the remaining patients with overlap syndrome, eleven cases (30%) had SSS and PCCD, two (5%) had LQTS and PCCD, two (5%) had LQTS and SSS, one (3%) had BrS and SSS, and the last one (3%) was persecuted by three combined phenotypes of BrS, PCCD and SSS. According to the function of SCN5A variants, 10 patients (27%) had gain-of-function phenotype and another 10 (27%) patients showed loss-of-function phenotype. Both phenotypes of gain- and loss-of-function were occurred in four children (11%) and more than one kind of loss-of-function phenotype did in 13 children (35%). The detailed information of the above mentioned four ECG abnormalities was described as follows (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e):\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eClinical features of children with SCN5A variants\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"15\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c12\" colnum=\"12\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c13\" colnum=\"13\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c14\" colnum=\"14\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c15\" colnum=\"15\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003ePhenotypes\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCases\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eFirst-visit\u003c/p\u003e \u003cp\u003eage, y\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eAge at diagnosis, y\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eQTc, ms\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c7\" namest=\"c6\"\u003e \u003cp\u003eAVB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eBBB\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c11\" namest=\"c10\"\u003e \u003cp\u003eSND\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c14\" namest=\"c13\"\u003e \u003cp\u003eTachyarrhythmias\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c15\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eSyncope\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003eⅠ/Ⅱ-Ⅰ\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eⅡ-Ⅱ/Ⅲ\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c8\"\u003e \u003cp\u003eRBBB\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c10\"\u003e \u003cp\u003eBradycardia\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c11\"\u003e \u003cp\u003eArrest\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c13\"\u003e \u003cp\u003eVentricular\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c14\"\u003e \u003cp\u003eAtrial\u003c/p\u003e \u003cp\u003en (%)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLQTS first\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.7\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e578.6\u0026thinsp;\u0026plusmn;\u0026thinsp;62.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (9%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2(15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e8 (67%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsolated LQTS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e10 (71%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.6\u0026thinsp;\u0026plusmn;\u0026thinsp;4.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.1\u0026thinsp;\u0026plusmn;\u0026thinsp;5.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e593.5\u0026thinsp;\u0026plusmn;\u0026thinsp;74.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e6 (75%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e2 (50%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLQTS\u0026thinsp;+\u0026thinsp;PCCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.0\u0026thinsp;\u0026plusmn;\u0026thinsp;0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e545.0\u0026thinsp;\u0026plusmn;\u0026thinsp;7.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e2 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e2 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2 (25%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLQTS\u0026thinsp;+\u0026thinsp;SSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (14%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.5\u0026thinsp;\u0026plusmn;\u0026thinsp;2.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6.0\u0026thinsp;\u0026plusmn;\u0026thinsp;2.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e492.5\u0026thinsp;\u0026plusmn;\u0026thinsp;10.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePCCD first\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e444.0\u0026thinsp;\u0026plusmn;\u0026thinsp;27.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (36%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (80%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 (38%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3 (25%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsolated PCCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e437.0\u0026thinsp;\u0026plusmn;\u0026thinsp;18.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e8 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e4 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e5 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e3 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSS first\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e13 (35%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e435.4\u0026thinsp;\u0026plusmn;\u0026thinsp;26.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6 (46%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e9 (69%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e12 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e12 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4 (33%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eIsolated SSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8.5\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e8.7\u0026thinsp;\u0026plusmn;\u0026thinsp;5.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e438.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (22%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e2 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSSS\u0026thinsp;+\u0026thinsp;PCCD\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11 (85%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.4\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e5.2\u0026thinsp;\u0026plusmn;\u0026thinsp;2.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e434.9\u0026thinsp;\u0026plusmn;\u0026thinsp;32.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e11 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e6 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e7 (78%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e10 (83%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e11 (92%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e4 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrS first\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e2 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.1\u0026thinsp;\u0026plusmn;\u0026thinsp;0.6\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.4\u0026thinsp;\u0026plusmn;\u0026thinsp;0.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e450.0\u0026thinsp;\u0026plusmn;\u0026thinsp;14.1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (5%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (20%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e2 (15%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e2 (17%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1 (8%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrS\u0026thinsp;+\u0026thinsp;SSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e440.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBrS\u0026thinsp;+\u0026thinsp;PCCD\u0026thinsp;+\u0026thinsp;SSS\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e460.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c7\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c8\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c9\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c10\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c11\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c12\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c13\"\u003e \u003cp\u003e1 (50%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c14\"\u003e \u003cp\u003e0 (0%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c15\"\u003e \u003cp\u003e1 (100%)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"15\"\u003eAVB\u0026thinsp;=\u0026thinsp;atrioventricular block; BBB\u0026thinsp;=\u0026thinsp;bundle branch block; BrS\u0026thinsp;=\u0026thinsp;Brugada syndrome; LQTS\u0026thinsp;=\u0026thinsp;long QT syndrome; PCCD\u0026thinsp;=\u0026thinsp;progressive cardiac conduction disease; RBBB\u0026thinsp;=\u0026thinsp;right bundle branch block; SND\u0026thinsp;=\u0026thinsp;sinoatrial node dysfunction; SSS\u0026thinsp;=\u0026thinsp;sick sinus syndrome; Ⅰ/Ⅱ-Ⅰ = first-degree AVB or second-degree AVB type I; Ⅱ-Ⅱ/Ⅲ = second-degree AVB type II or third-degree AV.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eConduction defect. Twenty-two patients (59%) were disturbed by conduction defect and all of them were accompanied by atrioventricular block (AVB). Exactly, first-degree AVB was discovered in 20 patients (91%), second-degree AVB in nine (41%) and third-degree AVB in three (14%). Meanwhile, 12 patients (55%) were also disturbed by bundle branch block (BBB), specifically 11 of whom (50%) by right BBB and the other one (5%) by both right and left BBB.\u003c/p\u003e \u003cp\u003eEight patients [5 boys (62%) and 3 girls (38%)] were diagnosed with isolated PCCD. Their first-visit age was 2.2 \u0026plusmn; 2.4 (range, prenatal to 7) y. Two patients at their first-visit age of 0.6 and 1.3 y respectively displayed second-degree AVB type Ⅱ and third-degree AVB. Two more patients displayed second-degree AVB type Ⅰ respectively at their first-visit age of 4.5 and 3 y. However, both progressed to second-degree AVB type Ⅱ and eventually third-degree AVB during their respective nine and ten years of follow-up. The remaining four patients were characterized with first-degree AVB and BBB (right or both left and right), and no progress was discovered during their 6.2 \u0026plusmn; 3.6 (range, 1 to 11) y of follow-up. Among the eight patients, three (38%) experienced syncope, one thought to ascribe to high degree AVB with the longest RR interval of 7.2 s and the others related to VT.\u003c/p\u003e \u003cp\u003eSinoatrial node dysfunction. Seventeen patients showed SND in ECGs, 76% (n\u0026thinsp;=\u0026thinsp;13) of them had sinus bradycardia with the mean heart rate of 65 \u0026plusmn; 8 (range, 54\u0026ndash;83) bpm and 76% (n\u0026thinsp;=\u0026thinsp;13) experienced sinus arrest with the longest RR interval of 4.2 \u0026plusmn; 2.8 (range, 1.9\u0026ndash;16.1) s. Taken together, both sinus bradycardia and sinus arrest occurred in nine patients (53%).\u003c/p\u003e \u003cp\u003eThirteen patients characterized with SND were diagnosed with SSS (two isolated cases and the others along with PCCD). Ten boys (77%) and three girls (23%) visit a doctor firstly at their age of 5.0 \u0026plusmn; 3.6 (range, 0.4\u0026ndash;12) y. Each of syncope and sinus bradycardia was reported in three patients (23%) as their chief complaint for visiting a doctor. Another one patient (8%) asked for help because of sinus arrest and the remaining six ones (46%) for tachycardia. To be exact, only one patient (8%) having disease onset in utero was characterized with sinus bradycardia [mean heart rate 54 (range, 35\u0026ndash;128) bpm] rather than sinus arrest. All of the remaining 12 patients (92%) presented as bradycardia-tachycardia syndrome, half of whom were diagnosed with tachyarrhythmia (atrial flutter or sustained atrial tachycardia) at their first-visit and further showed SND after conversion to sinus rhythm by radiofrequency ablation, and the other half displayed the alternation of tachyarrhythmia (sustained atrial tachycardia or atrial flutter) and bradyarrhythmia (sinus arrest or sinus bradycardia) firstly. As for ECG phenotypes in the 12 patients, sinus arrest with the longest RR interval of 4.7 \u0026plusmn; 3.9 (range, 2.1\u0026ndash;10.5) s was found in four cases, who had normal heart rate during other times. And the other eight cases experienced both sinus bradycardia (mean heart rate 69 \u0026plusmn; 8 bpm, the slowest heart rate 48 \u0026plusmn; 10 bpm and the fastest heart rate 147 \u0026plusmn; 29 bpm) and sinus arrest [the longest RR interval 4.5 \u0026plusmn; 1.6 (range, 2.1\u0026ndash;7.1) s].\u003c/p\u003e \u003cp\u003eOn the other side, 11 of the 13 patients (85%) whose diseases centered on SSS also endured conduction dysfunction (first-degree AVB) and what was more, second-degree AVB type Ⅰ co-occurred in five of them and right BBB did in the others. Specifically, one patient diagnosed with isolated SSS at the first-visit progressively developed to first-degree AVB and right BBB, then eventually to second-degree AVB type Ⅰ during the following four years. In total, there were four patients experiencing syncopal episodes, two of whom showed sustained atrial flutter or atrial fibrillation in ECGs or Holter and the other two cases endured sinus arrest with the documented longest RR intervals of 3.5 s and 4.4 s, respectively.\u003c/p\u003e \u003cp\u003eProlongation of QT interval. Prolonged QTc intervals [565.9 \u0026plusmn; 66.4 (range, 480\u0026ndash;724) ms] were found in 14 patients, notably longer than 500 ms found in 12 of them (86%). LQTS was determined as the chief phenotype in all patients, including 10 isolated cases and four overlap cases. Exactly, two of the four overlap cases were combined with first-degree AVB and right BBB. And the remaining two cases displayed SND, one showing sinus bradycardia with heart rate ranging from 39 to 125 (mean 60) bpm at the age of seven years and the other one also showing sinus bradycardia with heart rate ranging from 58 to 113 (mean 73) bpm at the age of four years. The first-visit age of the 14 LQTS cases was 5.7 \u0026plusmn; 4.2 (range, prenatal-12) y, 10 boys (71%) and 4 girls (29%). VT or VF was also documented in ECGs or Holter in eight cases and the QTc interval longer than 500 ms was recorded in seven of them (88%). Syncopal episodes happened to four cases (29%), all of whom were disturbed by both of VT/VF and obvious prolonged QTc interval (\u0026gt;\u0026thinsp;500 ms).\u003c/p\u003e \u003cp\u003eBrugada syndrome. Both of the two patients diagnosed with BrS also manifested other phenotypes, whose detailed information was elaborated as follows: BrS plus SSS happened to one baby boy, who had disease onset at 1.5 y and were diagnosed at 2 y. VT was described as his chief complaint and elevated J wave (dome-shaped elevation in leads of V1 to V3) was observed in ECG under sinus rhythm. He also showed the characteristics of SND, namely sinus bradycardia with heart rate ranging from 52 to 148 (mean 84) bpm and sinus arrest with the longest RR interval of 16.1 s. Another baby girl was diagnosed with PCCD and SSS except for BrS, who had disease onset at the age of eight mo and was diagnosed at nine mo. Syncopal events accompanied by VT were reported as her chief complaint and the typical BrS ECG (elevated J wave with dome morphology in leads of V1 and V2 under sinus rhythm) was regarded as the main electrocardiographic phenotype, along with conduction defect (first-degree AVB with PR interval of 0.17\u0026ndash;0.22 s and intermittent second-degree AVB type Ⅱ) and SND [sinus bradycardia with heart rate ranging from 50 to 188 (mean 83) bpm].\u003c/p\u003e \u003cp\u003eThe 37 patients had 40 independent variants (three of them harboring a double heterozygous variants) of SCN5A gene, including 34 non-repeat variants (Supplementary Table\u0026nbsp;1). Eighteen non-repeat variants have been reported and eight of them were missense mutations. In total, among the 40 independent variants, missense mutations accounted for 75% (n\u0026thinsp;=\u0026thinsp;30), frameshift/non-sense/splicing mutations for 25% (n\u0026thinsp;=\u0026thinsp;10). As for their origins, 21 variants (53%) were inherited from the maternal line, 14 (35%) from the paternal line and the remaining five (12%) were regarded as de novo variants. What was notable, the same frameshift variant (c.611\u0026thinsp;+\u0026thinsp;1G\u0026thinsp;\u0026gt;\u0026thinsp;C) happened to the only two patients diagnosed with BrS.\u003c/p\u003e \u003cp\u003eAll of the amino acid sites and clinical phenotypes were presented in Fig.\u0026nbsp;2. The most prevalent domain in N\u003csub\u003eaV\u003c/sub\u003e1.5 channel protein where amino acids encoded by SCN5A variants located was the pore-loop (26%), followed by II-III linker (18%), and the other domains were occupied by sporadic variants. Regarding the relationship of clinical phenotypes and variants locus of Na\u003csub\u003eV\u003c/sub\u003e1.5, variants of isolated LQTS were mainly located at II-III linker (40%) and pore-loop (30%), and variants of isolated PCCD were mainly at II-III linker (30%) and pore-loop (30%). Whereas, the variants locus of overlap phenotype was dispersive. The clinical presentation of all the eight patients with the frameshift/non-sense/splicing mutations was determined as loss-of-function (5 PCCD\u0026thinsp;+\u0026thinsp;SSS, 3 PCCD, 1 BrS\u0026thinsp;+\u0026thinsp;SSS and 1 BrS\u0026thinsp;+\u0026thinsp;SSS\u0026thinsp;+\u0026thinsp;PCCD). Totally, 12 syncopal patients (two attacked by sudden death) had 12 variants most of which located at voltage-sensing domain (58%), and then II-III linker (17%).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe structural abnormality of N\u003csub\u003eaV\u003c/sub\u003e1.5 channel protein caused by SCN5A variants can lead to cardiac arrhythmias and structural abnormalities, and its correlation with cardiogenetic disorders has attracted more and more attention. Both of the electrocardiographic phenotypes and the clinical phenotypes associated with SCN5A variants are diverse, namely not only causing different isolated phenotypes but also causing overlap syndrome with various combinations. Moreover, high proportion of life-threatening cardiac events, high degree of malignancy and early disease onset at childhood deserve great attention from physicians.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e Unfortunately, few studies on ECGs and clinical phenotypes related to SCN5A in children population have been reported,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e so this study would enrich our understanding and offset this gap to some extent. In our population, the first-visit age of the 37 enrolled patients was 4.4 \u0026plusmn; 3.8 y. Syncopal events were reported as the chief complaint in 19% patients and the major part (70%) visited a cardiologist because abnormal signs in physical examination or ECGs were found when visiting a doctor for other reasons. Thus, it can be seen that this spectrum of disorders is easy to be missed for its lack of specific clinical symptoms and signs. Genetic testing is helpful to clarify the association of genetic arrhythmias and SCN5A variants. The mean duration of 1.3 \u0026plusmn; 1.8 y with the longest duration of eight years was spent to take genetic examinations since the first-visit to a doctor, implying doctors\u0026rsquo; insufficient cognition on this spectrum of diseases is common. For children with hereditary arrhythmias, such as QT interval prolongation, sinus node dysfunction, conduction defect and Brugada-type ECG without clear secondary pathogenic reasons, whether with positive family history or not, genetic testing should be performed as early as possible to determine the suspicious disease-causing gene variants aiming to make early diagnosis, treatment scheme and prognosis assessment.\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eHereditary cardiac conduction disorders are characterized by age-dependent progression, such as PR interval prolongation, QRS interval prolongation and bundle branch conduction block progressing with aging.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e One research conducted in a mouse model found that at the same age, cardiac fibrosis caused by SCN5A variants is significantly more frequent than that of wild-type mice and the progress of conduction dysfunction is aggravated in a sequential manner, indicating that age-dependent cardiac fibrosis might be a crucial mechanism for the progress of conduction dysfunction with aging in PCCD.\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e In our study, the first-visit age of these PCCD patients was 2.2 \u0026plusmn; 2.4 y. Two of them respectively showed second-degree AVB type II and third-degree AVB at their each first-visit age of 0.6 y and 1.3 y, and another two patients progressed from second-degree AVB type I to third-degree AVB in nine to ten years of follow-up, which indicated that PCCD patients caused by SCN5A variants could present as second-degree AVB type II or third-degree AVB in childhood, or even in infancy. However, the early clinical manifestations of PCCD are so lacking that it is easy to make missed diagnosis, so physicians should pay more attention to it and make careful and regular follow-up to observe its dormant progression. Observed in our study, 50% patients with PCCD had right BBB and only 5% had both left and right BBB. One plausible explanation may be that the expression of N\u003csub\u003eaV\u003c/sub\u003e1.5 channel protein within the right bundle branch is relatively lower than that of the left bundle branch.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e Consequently, the loss-of-function of N\u003csub\u003eaV\u003c/sub\u003e1.5 has a greater impact on the right bundle branch conduction system, the risk of right BBB is much higher and the onset of right BBB is earlier than the left.\u003c/p\u003e \u003cp\u003eIn our study, 46% patients exhibited SSS, whose age of disease-onset was 5.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.6 (range, 0.4\u0026ndash;12) y. Some studies demonstrate the high incidence rate of SSS both in adults and children,\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e hinting the early onset of SSS in the young. One cohort study including 15 families in Japan found that 37% of SCN5A variants carriers exhibited SSS, and the mean disease-onset age of 35.5 \u0026plusmn; 5.4 (range, 3\u0026ndash;65) y in these probands was significantly younger than that in sporadic SSS patients (74.3 \u0026plusmn; 0.4 y).\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e All electrocardiographic forms involving SSS took as high as 46%, however, only 5% presented as isolation and the vast majority of them presented as overlap, which combining with PCCD accounted for 30%. The possible reason is that both the pathogeneses of SSS and PCCD are impaired sodium current in cardiomyocytes.\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e And different expression degree of SCN5A in different part of the heart is the basis of pathological structure of them.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e One study conducted by Villarreal-Molina T, et al. in children along with SCN5A variants showed that SSS happened to 77% recruited patients and 54% of them were disturbed by atrial tachycardia or atrial flutter.\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e The same phenomenon appeared in our study. Atrial tachyarrhythmias (atrial tachycardia or atrial flutter) were recorded as the first signs for visiting a doctor in 46% of the enrolled patients with SSS, and then atrial arrhythmias gradually developed into SND. Sinus bradycardia or sinus arrest cannot easily be diagnosed due to the lack of clinical manifestations, until it alters as tachyarrhythmia and affected patients often visit a doctor for obvious palpitations or even tachycardia cardiomyopathy.\u003c/p\u003e \u003cp\u003eLQTS is also a common clinical phenotype in children and adult who carried SCN5A variants.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e There are ten (27%) isolated LQTS patients and four (11%) overlap phenotype patients who were combine with PCCD or SSS, and these patients regarded LQTS as the major form. 86% of their QTc intervals were longer than 500ms and 57% of these LQTS patients occurred ventricular arrhythmias. The researchers found that the probability of cardiac event increased by 19% for every 10 ms increase in the QTc intervals before 500 ms, and this trend decreased after 500 ms.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e Purkinje system hyperexcitability may be a major cause of ventricular arrhythmia in these patients.\u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eBrS, which has been documented as one of the most popular phenotypes in adults,\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e took the least part (5%) in our participants. Baruteau AE, et al. also observed the likely phenomenon in another pediatric population and declared that isolated BrS only accounted for 1.8%.\u003csup\u003e5\u003c/sup\u003e So, it is suggested that onset of BrS is relatively late and it is rare in children. As a result, the incidence rates of children and adults are significantly different from each other. It is supposed that the pathophysiological basis for Brugada ECG patten is epicardial fibrosis in the right ventricular outflow tract and the conduction velocity of the fibrosis local is therefore delayed.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e,\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Furthermore, the formation of epicardial fibrosis in the right ventricular outflow tract has been proven to be associated with aging,\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e which is regarded as one probable reason for the low incidence rate of BrS in children. More rationally, one animal research conducted by David SP, et al. discovered that one kind of haploid loss-of-function SCN5A variants could lead to hypertrophy, disordered arrangement and even fibrosis of cardiomyocytes at cardiac conduction system or outflow tract in adult pigs, but not in the young.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e In our study, the only two BrS patients were demonstrated to be both along with SSS and one of them also with PCCD, indicating that BrS, a type of functional impairment phenotypes, could overlap with other functional impairment phenotypes, like SSS and PCCD.\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e Another research in Japan also found that four BrS patients with SCN5A heterozygous variants were all complicated with SSS (and/or PCCD).\u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e At the same time Villarreal-Molina T, et al. also reported that 67% BrS pediatric patients had combination with SSS (and/or PCCD).\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e Therefore, it seems to be some relationship among these three functional impairment phenotypes (BrS/PCCD/SSS) need to further research. Taken together, it can be concluded that the clinical manifestations caused by SCN5A variants are of complexity and diversity. Consequently, for children with SCN5A variants, we should not pay attention to only isolated phenotype but also overlap phenotype and should carefully distinguish them to avoid missed diagnosis.\u003c/p\u003e \u003cp\u003eThe variance of functional domains where variants locating may play a crucial role in the formation of different phenotypes.\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e According to the data observed in our work, up to 18 of the 34 non-repetitive variants are de novo, indicating that there may still be many de novo pathogenic variants in SCN5A gene even though more than 400 pathogenic missense mutations have been reported.\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e We found that pathogenic SCN5A variants are mainly located in pore-loop, and also common in II-III linker, hinting these regions are closely associated with clinical phenotypes.\u003c/p\u003e \u003cp\u003eHere, we demonstrate the elaborate characteristics of arrhythmic children with SCN5A variants and broaden and deepen the understandings of this field. However, limited number of enrolled patients from one single center restricts its extrapolation. Meanwhile, the follow-up duration is not long enough to span adulthood to obtain a more detailed picture of disease progression. Further multicenter-based researches with larger populations are needed.\u003c/p\u003e \u003cp\u003eConclusively, the electrocardiographic manifestations of SCN5A variants in children are diverse, ranging from conduction defects, sinus node dysfunction, prolongation of QT interval to Brugada pattern. Various electrocardiographic abnormalities can present as isolated phenotypes or as overlap phenotypes. The clinical and electrocardiographic characteristics of children with SCN5A variants are different from those of adults, so it is indispensable to pay more attention and complete genetic screening as soon as possible to clarify the etiologies and estimate disease progression and prognosis. As for the roles of N\u003csub\u003eaV\u003c/sub\u003e1.5 structure, the linkers (especially II-III linker) and pore-loop are inferred as crucial molecular regions determining the various phenotypes of this spectrum of diseases.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding sources:\u0026nbsp;\u003c/strong\u003eThe present study was supported by the Capital Clinical Characteristic Application Research (Z221100007422082) and Tsinghua University Yuyuan Medical Research Funding (202000591).\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eZhou wrote the main manuscript text; and prepared figures 1-2 and table 1-2. Zhang modified the manuscript for the first time.Li Mei-ting and Chen were responsible for part of the data collection.Li Xiao-mei provided study design and modified the manuscript finally.All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eThe authors appreciate the children who participated in this study as well as their guardians.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eRivaud MR, Delmar M, Remme CA (2020) Heritable arrhythmia syndromes associated with abnormal cardiac sodium channel function: ionic and non-ionic mechanisms. Cardiovasc Res 116:1557\u0026ndash;1570\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRuan Y, Liu N, Priori SG (2009) Sodium channel mutations and arrhythmias. 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Proc Natl Acad Sci USA 118:e2100066118\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"children, clinical phenotype, genetics, SCN5A variants","lastPublishedDoi":"10.21203/rs.3.rs-4453166/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4453166/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe clinical, electrocardiographic and genetic characteristics of children with SCN5A variants are complex and widely different from those of adults, but relevant reports are lacking. So, this study was designed to illustrate the characteristics of children with SCN5A variants in China with the largest sample size. Of arrhythmic children with SCN5A variants, clinical history and electrocardiographic and genetic results were integrated, and further follow-up was conducted to illustrate the disease spectrum, progression and genetics. Thirty-seven arrhythmic children with SCN5A variants were enrolled, whose electrocardiograms mainly presented as conduction disorders (60%), sinoatrial node dysfunction (46%), prolonged QT interval (38%) and Brugada pattern (5%). These electrocardiogram abnormalities could exist alone (54%) or form overlap syndrome (46%). Ventricular arrhythmia co-occurred in 57% of long QT syndrome patients. Of children with progressive cardiac conduction system disease (PCCD), 25% showed second-degree atrioventricular block (AVB) type II or third-degree AVB firstly and another 25% progressed from second-degree AVB type I to third-degree AVB. Forty-six percent of the sick sinus syndrome (SSS) children showed atrial tachycardia/flutter firstly, but sinus arrest/bradycardia was then triggered. Most of the overlap syndrome was SSS plus PCCD (65%) and the former took the predominance. The most prevalent culprit domain in N\u003csub\u003eaV\u003c/sub\u003e1.5 channel was the pore-loop (26%) and followed by the II-III linker (18%). In conclusion, conduction disorders and sinoatrial node dysfunction are the most popular abnormal electrocardiograms. The pore-loop and II-III linker of N\u003csub\u003eaV\u003c/sub\u003e1.5 channel are highly likely to be the key molecular structural regions determining the clinical phenotypes.\u003c/p\u003e","manuscriptTitle":"Analysis of Phenotypic and Genetic Characteristics of 37 Children with SCN5A Variants: from A Single Tertiary Medical Center in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-06-07 20:38:25","doi":"10.21203/rs.3.rs-4453166/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7bea1528-1cb5-477b-9921-b73d5d77ebe0","owner":[],"postedDate":"June 7th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-07-09T14:40:06+00:00","versionOfRecord":[],"versionCreatedAt":"2024-06-07 20:38:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4453166","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4453166","identity":"rs-4453166","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}