Initial clinical presentation and laboratory examination

The study was approved by the ethics committee of West China Second University Hospital of Sichuan University (approval number 2021-069). In addition, we obtained written informed consent from the patients’ parents prior to performing WES and for inclusion of the clinical and imaging details of the patients in the publication.

The proband was initially diagnosed with bradycardia during a routine kindergarten physical examination at 5 years of age. The patient remained asymptomatic, denying dyspnoea, chest discomfort, palpitations, syncopal episodes, seizure activity, or exercise intolerance. Physical examination revealed heart rate variability ranging from 32–61 beats per minute, with nocturnal resting bradycardia of 30–40 bpm. Vital signs demonstrated a respiratory rate of 23 breaths per minute and a blood pressure of 110/66 mmHg. The patient appeared chronically ill but maintained comfort with preserved mental status. Physical examination was notable for the absence of generalised oedema, lymphadenopathy, respiratory distress, or oropharyngeal abnormalities. Cardiovascular examination revealed irregular rhythm with accentuated first heart sound (S1) and absence of murmurs. Water-hammer pulse and positive capillary pulsation sign were present. Abdominal and neurological examinations yielded normal findings. Initial electrocardiogram (ECG) demonstrated severe bradycardia (32 bpm) with sinus arrest, junctional escape rhythm, intermittent sinus capture, left axis deviation, nonspecific ST-T wave abnormalities, and QT interval prolongation. Twenty-four-hour Holter monitoring confirmed severe bradycardia with prolonged sinus arrest episodes (maximum duration 6.5 s) (Figure 1( a )). Transthoracic echocardiography revealed mild left ventricular enlargement (Figure 1( b )). Cardiac magnetic resonance imaging demonstrated left ventricular dilatation with mildly reduced systolic function (LVEF 47.31%), without evidence of delayed myocardial enhancement in the interventricular septum or left ventricular perfusion defects (Figure 1( c )). Laboratory investigations, including stool analysis, hepatorenal function, serum electrolytes, rheumatologic markers, metabolic parameters (pyruvate, β-hydroxybutyrate), comprehensive thyroid function panel, and cardiac biomarkers, were within normal limits. Parental cardiac screening revealed normal cardiac structure and function. Family history was negative for sudden cardiac death or significant cardiovascular disease.

Figure 1.

The clinical manifestation of the proband at the initially pacemaker implantation. ( a ). ECG demonstrated long duration sinus arrest and severe bradycardia. ( b ). Echocardiography demonstrated mild left ventricular enlargement. ( c ). Cardiac MRI presented no delayed myocardial enhancement or perfusion defects. ( d ). The chest X-ray after pacemaker implantation.

Figure 1. Long description

The image contains four distinct medical images. The first image is an electrocardiogram (ECG) showing long duration sinus arrest and severe bradycardia. The second image is an echocardiogram demonstrating mild left ventricular enlargement. The third image is a cardiac MRI scan presenting no delayed myocardial enhancement or perfusion defects. The fourth image is a chest X-ray taken after pacemaker implantation, showing the device in place. These images collectively illustrate the clinical manifestation of a patient at the time of initial pacemaker implantation.

Subsequently, the patient underwent single-chamber pacemaker implantation (Figure 1( d )) with the establishment of a structured follow-up protocol. At 11 years of age, the patient was scheduled for a dual-chamber pacemaker system upgrade due to battery depletion and concerns regarding potential adverse effects associated with chronic right ventricular apical pacing in the ventricular demand mode. This upgrade was indicated to optimise haemodynamic function and mitigate long-term complications of single-chamber ventricular pacing, including pacemaker syndrome and deleterious ventricular remodelling.

Intraoperative electrophysiological assessment and clinical decision-making

During the planned dual-chamber pacemaker upgrade procedure, initial attempts were made to establish atrial pacing capability through right atrial lead placement. Despite systematic exploration of multiple anatomical sites within the right atrium, adequate atrial capture could not be achieved, raising suspicion for extensive atrial conduction abnormalities involving both atria. To comprehensively evaluate atrial electrophysiological function, coronary sinus electrode mapping was performed. Initial positioning of the coronary sinus electrode within the right atrium (Figure 2( a )) demonstrated a complete absence of electrical activity along the anterior right atrial wall (Figure 2( b )). Subsequently, the electrode was advanced across the mitral valve (Figure 2( c )), revealing only ventricular electrograms (V waves) that corresponded temporally with surface ECG QRS complexes, confirming ventricular electrical activity while demonstrating absent atrial signals. Further assessment involved coronary sinus electrode placement within the coronary sinus ostium (Figure 2( e )), which similarly demonstrated absence of left atrial electrical potentials, with only left ventricular electrograms (V waves) detectable (Figure 2( f )). Comprehensive pacing attempts from both the coronary sinus and right atrial positions failed to achieve atrial capture, even at maximum output parameters (20 mA), confirming the diagnosis of atrial standstill. These intraoperative findings demonstrated disease progression from the initial presentation of severe sinus bradycardia with prolonged sinus arrest in early childhood to complete bi-atrial standstill by adolescence. This aggressive pathological evolution precluded dual-chamber pacemaker implantation due to the absence of viable atrial tissue for pacing. Consequently, the therapeutic strategy was modified to single-chamber ventricular pacemaker replacement, utilising the existing ventricular pacing lead while maintaining the original pacing configuration.

Figure 2.

Intraoperative electrophysiological assessment of the proband. ( a )–( b ). CS electrode mapping demonstrated complete absence of electrical activity along the anterior right atrial wall. ( c )–( d ). Electrode was advanced across the mitral valve, revealing only ventricular electrograms that corresponded temporally with surface ECG QRS complexes, confirming ventricular electrical activity while demonstrating absent atrial signals. ( e )–( f ). CS electrode placement within the coronary sinus ostium, which similarly demonstrated absence of left atrial electrical potentials, with only left ventricular electrograms detectable.

Figure 2. Long description

The image shows an intraoperative electrophysiological assessment of the proband. The first set of images (a and b) displays CS electrode mapping, demonstrating the complete absence of electrical activity along the anterior right atrial wall. The second set (c and d) shows the electrode advanced across the mitral valve, revealing only ventricular electrograms that correspond temporally with surface ECG QRS complexes, confirming ventricular electrical activity while demonstrating absent atrial signals. The third set (e and f) illustrates the CS electrode placement within the coronary sinus ostium, which similarly demonstrates the absence of left atrial electrical potentials, with only left ventricular electrograms detectable.

To evaluate the impact of chronic right ventricular apical pacing on myocardial function, a comprehensive assessment of cardiac mechanics was performed. The ventricular demand pacing strategy with the electrode positioned at the right ventricular apex generated an electrocardiographic pattern resembling complete left bundle branch block morphology (Figure 3( a )). Left bundle branch area pacing was not feasible given the patient’s young age at initial implantation (5 years old), necessitating conventional right ventricular apical pacing with potential for electromechanical dyssynchrony and subsequent cardiac dysfunction. Myocardial strain analysis was performed to quantify regional and global left ventricular function. The assessment demonstrated the absence of significant paradoxical motion between the interventricular septum and left ventricular free wall, indicating preserved mechanical synchrony despite the non-physiological activation pattern. However, speckle-tracking echocardiography revealed mildly reduced global longitudinal strain (GLS = −7%) with particular impairment noted in the lateral myocardial segments (Figure 3( b )). This finding suggests subclinical myocardial dysfunction potentially attributable to chronic right ventricular pacing-induced electromechanical dyssynchrony, though overt mechanical dissociation was not observed.

Figure 3.

Myocardial function assessment on VVI strategy. ( a ). ECG pattern resembling CLBBB morphology. ( b ). The speckle-tracking echocardiography revealed mildly reduced global longitudinal strain (GLS = −7%) with particular impairment noted in the lateral myocardial segments.

Figure 3. Long description

The image contains two main sections. The first section (a) displays an electrocardiogram (ECG) pattern resembling complete left bundle branch block morphology. It shows multiple leads, including I, II, III, aVR, aVL, aVF, V1, V2, V3, V4, V5, and V6, each with distinct waveforms. The second section (b) presents three speckle-tracking echocardiography graphs and a polar map. These graphs illustrate the strain curves for different views: two-chamber, four-chamber, and apical long-axis. The polar map visually represents the global longitudinal strain (GLS) with values distributed across different myocardial segments. The GLS is mildly reduced at -7 percent, with notable impairment in the lateral myocardial segments. The graphs and map together provide a detailed assessment of myocardial function.

Molecular results

As an inherited cardiomyopathy had been suspected, a genetic test was involved to explore any associated variants. Whole-exon sequencing had been performed for this proband and her parents. According to the analysis result of WES, a compound heterozygous variant had been identified as c.2431C>T (p.R811C) and c.2893C>T (p.R965C) of the SCN5A gene. (Figure 4( a )) The allele c.2431C>T was maternally inherited and c.2893C>T was paternally inherited. And the variant of SCN5A c.2431C>T had never been reported once in ExAC, 1000G, and ClinVar database, which was also considered as a novel genotype. (Figure 2( b )–( d )) As there was no available full-length protein crystal structure for SCAN5A, which had been analysed by X-ray or cryo-EM, the AlphaFold3 protein structure software (https://alphafoldserver.com/) was used to predict protein crystal structure. The protein structure of SCN5A has been built and named AF-P21333-F1. ^{Reference Varadi, Anyango and Deshpande21,Reference Jumper, Evans and Pritzel22} (Figure 4( c )) Then, we performed modelling analysis using AlphaFold3 for the mutant site in wild type with the AF-Q14524-F1. Then, the molecular function of the variant site had been annotated (Figure 4( c )). This would highlight how the mutation alters the charge distribution of the protein. Changes in charge may affect protein interactions with other molecules, stability, and overall function. In accordance with the ACMG/AMP 2015 guidelines for the interpretation of sequence variants, the novel c.2431C>T (p.R811C) variant was classified as likely pathogenic. This classification is supported by the following evidence: (1) it is a de novo or compound heterozygous variant in a gene with a known recessive disease mechanism (PM2, PM3); (2) multiple lines of computational evidence, including AlphaFold3 structural modelling and charge distribution analysis, support a deleterious effect on the gene product (PP3); and (3) The patient’s phenotype of atrial standstill is highly consistent with a monogenic disorder caused by variants in the SCN5A gene, which is a known disease-causing gene for atrial standstill and cardiac arrhythmia disorders (PP4). And the c.2893C>T (p.R965C) variant, inherited from the father, is a known missense variant reported in ClinVar with conflicting interpretations of pathogenicity, but its presence in trans with a novel likely pathogenic variant supports its contribution to the compound heterozygous state. Using scRNA-seq data (GSE132658), ^{Reference Goodyer, Beyersdorf and Paik23} SCN5A were identified as highly expressed in the His bundle and Purkinje fibre across the transitional zone (Figure 4( e )). So, the loss of function of SCN5A c.2431C>T and c.2893C>T resulted in protein damage, which mainly affected the transduction manner of the His bundle and Purkinje fibre. The variants had been deposited in ClinVar (RCV006547764.1 and RCV006547587.1).

Figure 4.

The variants of SCN5A molecular features. ( a ). The proband exhibited a compound heterozygous variant of SCN5A (c.2431C>T and c.2893C>T). ( b ). The variant of SCNA5A c.2893C>T had been reported in ExAC, 1000G and ClinVar. And it has predicted protein damaging by MutationTaster. ( c ). The protein structure of SCN5A has been built and named AF-P21333-F1. ( d ). The variant of SCNA5A c.2431C>T had not been reported in ExAC, 1000G and ClinVar. And it has predicted protein damaging by MutationTaster. ( e ). Murine scRNA-seq data (GSE132658) revealed cardiac Scan5a expression is confined to the conductive bundles and fibres.

Figure 4. Long description

The illustration presents various aspects of SCN5A gene variants. Panel (a) shows a family pedigree indicating a proband with compound heterozygous variants SCN5A c.2431C>T and c.2893C>T. Panel (b) lists the known variant reports of SCN5A c.2893C>T from databases 1000G and ExAC, along with scores from MutationTester, PolyPhen-2, and SFIT indicating its damaging potential. Panel (c) displays the protein structure of SCN5A based on the AF-Q14524-F1 template, highlighting the wild-type and induced variants p.R965C and p.R811C with changes in protein features and splice sites. Panel (d) provides data on the SCN5A c.2431C>T variant, which has not been reported in major databases and is also predicted to be damaging. Panel (e) shows a violin plot of Scn5a expression in various cardiac regions based on murine scRNA-seq data, indicating confined expression in conductive bundles and fibers.

Final diagnosis and treatment

Based on comprehensive clinical evaluation, advanced cardiac imaging, and genetic analysis, the patient was diagnosed with hereditary atrial standstill characterised by aggressive disease progression, manifesting initially as severe bradycardia in early childhood with subsequent evolution to complete bi-atrial electrical silence. This rare inherited cardiomyopathy demonstrates a particularly rapid clinical course in this paediatric case. A structured long-term surveillance protocol has been established, incorporating serial monitoring of GLS as a sensitive marker of subclinical myocardial dysfunction and disease progression. Regular assessment of cardiac mechanics will facilitate early detection of pacing-induced cardiomyopathy and guide therapeutic optimisation. For future device replacement procedures, left bundle branch area pacing is under consideration as a more physiological pacing modality to minimise electromechanical dyssynchrony and preserve long-term cardiac function. This approach aims to mitigate the potential adverse effects of chronic right ventricular apical pacing while maintaining adequate cardiac support in this complex paediatric case with progressive atrial standstill. While left bundle branch area pacing represents a promising physiological pacing strategy to mitigate the deleterious effects of chronic right ventricular pacing, its application in an 11-year-old child with lifelong device dependency presents several unique technical challenges. These include (1) the smaller cardiac dimensions and thinner interventricular septum in a child, which increase the risk of septal perforation and coronary artery injury; (2) the lack of dedicated, paediatric-sized delivery sheaths and pacing leads optimised for left bundle branch area pacing; (3) the long-term uncertainty regarding the impact of a fixed pacing lead in the left bundle branch region on ventricular function and valvular competence over decades. So, a long-term surveillance protocol should be established, incorporating serial echocardiography with strain imaging to assess ventricular synchrony and function, as well as periodic device interrogation to monitor lead parameters.