The infero-apical left ventricular aneurysm and long QT syndrome caused by mutation delKKP 1504–1506 in SCN5A gene

Abstract

Background

Long QT syndrome (LQTS) is considered a primary cardiac ion channelopathy. Several studies have shown that myocardial functional alterations may occur in patients with LQTS type 3 (LQT3). However, it is currently unclear whether there is a specific relationship between phenotype and genotype. The aim of this study is to provide additional information on the phenotype and genotype of LQT3 caused by a novel delKKP 1504–1506 mutation in a Chinese family.

Case presentation

The family came to our attention because of a sustained corrected QT interval (QTc) prolongation in a 14-year-old girl who had experienced a loss of consciousness with Mobitz type II atrioventricular block one year earlier. Three family members carrying the delKKP 1504–1506 mutation demonstrated a combination of infero-apical left ventricular aneurysms and prolonged QTc, and two members showed J-waves in the right precordial lead V2.

Conclusions

This case suggests that the delKKP 1504–1506 mutation in SCN5A may not only lead to impaired impulse propagation in the conduction system and a prolonged QTc, but may also be associated with infero-apical ventricular aneurysms and J-wave syndromes, possibly corresponding to regional myocardial fibrosis.

Supplementary Information

The online version contains supplementary material available at https://doi.org/10.1186/s12920-026-02428-0.

Introduction

Congenital long QT syndrome (LQTS) is an inherited arrhythmogenic disorder characterized by delayed ventricular repolarization, which manifests as a prolongation of the corrected QT interval (QTc) on the surface electrocardiogram (ECG), thereby increasing the risk of potentially life-threatening cardiac arrhythmias. Although LQTS is classified as a primary cardiac ion channelopathy, subclinical cardiomyopathic changes have been observed in nearly 20% of LQTS patients [1]. LQTS type 3 (LQT3) results from mutations in SCN5A, the gene encoding the α-subunit of the cardiac sodium channel responsible for the sodium current. Increasing evidence suggests that mutations in SCN5A are not only associated with LQT3 but are also linked to other arrhythmias and alterations in myocardial function, such as cardiac conduction disease, dilated cardiomyopathy (DCM), and Brugada syndrome (BrS) [2–8]. Furthermore, evidence indicates that these mutations may also be associated with cardiac fibrosis and ventricular dilatation [9, 10]. The present study identifies a novel SCN5A mutation, delKKP 1504–1506, which is associated with a combination of cardiac conduction block, infero-apical left ventricular aneurysm, prolonged QTc, and J-wave syndromes in this family.

Case presentation

Clinical features of the proband

The family came to our attention because of a sustained QTc prolongation in a 14-year-old girl who had experienced a loss of consciousness at school in the morning and had been successfully given first aid one year earlier. At the time of the event, the patient was not taking any medication, and there was no significant physical exertion and psychological stress. She was previously healthy, with no history of syncope or palpitations. During the first aid, her blood pressure was 134/96 mmHg with a heart rate of 35 bpm. The ECG showed sinus rhythm with Mobitz type II atrioventricular block. Polymorphic ventricular tachycardia or ventricular fibrillation was not observed. She gradually regained consciousness after intravenous administration of 1 mg atropine, which increased her heart rate. Upon admission, blood tests revealed a mildly elevated white blood cell count of 12.26 × 10⁹/L, a neutrophil percentage of 79.80%, N-terminal pro-B-type natriuretic peptide of 350 pg/mL, and an erythrocyte sedimentation rate of 39 mm/h. All other indicators were within normal limits, including cardiac troponin I and MB isoenzyme of creatine kinase. Holter monitoring showed QTc prolongation with a mean heart rate of 58 bpm, intermittent Mobitz type II atrioventricular block, and T-wave alternans (Fig. 1) during hospitalization. It also revealed 999 (1.2%) monomorphic frequent premature ventricular contractions (PVCs), including 13 couplets. Polymerase chain reaction assays for common viral pathogens (adenovirus, influenza A and B, respiratory syncytial virus, SARS-CoV-2, parvovirus B19, and cytomegalovirus) were negative. Coronary computed tomography angiography (CTA) showed no abnormalities. Transthoracic echocardiography demonstrated normal cardiac structure and function. The clinical diagnosis was suspected acute myocarditis, though endomyocardial biopsy was not performed. During hospitalization, appropriate doses of immunoglobulin and corticosteroids were administered.

Fig. 1.

Holter recordings of the proband during hospitalization. Continuous monitoring revealed QTc prolongation, intermittent Mobitz type II atrioventricular block, and T-wave alternans

It is worth noting that there were some inconsistencies in the proband’s first‑aid and hospitalization records. Atropine is generally ineffective and carries a significant risk of worsening or precipitating a high‑grade block in patients with Mobitz Type II atrioventricular block. Treatment with corticosteroids and intravenous immunoglobulins is not standard care for acute viral myocarditis.

Management and follow-up of the proband

After obtaining informed consent, the proband declined implantation of an implantable cardioverter-defibrillator. She exhibited no significant symptoms during more than one year of follow-up, although the ECG continued to show a prolonged QTc. Consequently, a family pedigree and genealogy survey was conducted. Lifestyle advice included avoidance of QT-prolonging drugs, restriction of competitive sports.

Family pedigree investigation

The pedigree of the family is presented in Fig. 2. Subject II-2 is the proband, a 15-year-old female. Her grandparents died several years ago from non-cardiac causes, and their medical records are unavailable. A total of four family members were investigated. Written informed consent was obtained from each family member in accordance with local institutional guidelines and the principles of the Declaration of Helsinki. Investigations included at least two 12-lead ECG recordings taken at different times. The QTc was automatically provided by advanced ECG equipment and subsequently confirmed by manual measurement. A standard echocardiographic study, including focused apical high-frequency ultrasound imaging, was performed. A 24-hour Holter ECG and CTA were performed for each affected individual.

Fig. 2.

Pedigree information for the family. A Black symbols indicate clinically affected individuals presenting with an infero-apical left ventricular aneurysm, prolonged QTc, and a positive result on SCN5A genetic screening; white symbol represents clinically unaffected individual. The arrow denotes the proband. B Sequence analysis showing a heterozygous deletion of three amino acids—Lys1504, Lys1505, and Pro1506 (KKP)—in exon 26 of SCN5A. C The corresponding control sequence contains the nine base pairs (AAGAAGCCC)

Genetic investigation

Peripheral venous blood samples from each family member were sent to the laboratory of Beijing Mygenostics Co., Ltd. for gene capture, enrichment, and Sanger sequencing. The genetic panel (WES015-1, whole-exon gene sequences, version 6, 200X coverage) covered conduction disorders, arrhythmogenic cardiomyopathy (ACM), and LQTS.

Echocardiography

All echocardiographic studies were performed using a commercially available Philips EPIQ 7 C ultrasound machine (Philips Medical Systems, Andover, MA, USA) equipped with a 1.0–5.0 MHz standard cardiac probe and a 3–12 MHz high-frequency linear transducer probe. To improve resolution, high-frequency focused apical imaging used a vascular carotid preset, as suggested in previous studies [11, 12]. All echocardiographic data were recorded and stored digitally. All measurements were performed following standard recommendations and analyzed using online software.

Results

The basic health information of the family pedigree is summarized in Table 1; Figure. 2, obtained during the family investigation. No family members exhibited significant clinical symptoms other than the proband’s event. The data for the proband (subject II-2) are detailed in the Methods section.

Table 1.

The basic health information of the family pedigree

Member	Age, year	BSA, m2	LVEDD, mm	LVEF, %	QTc, ms	J-Wave	Size of IALVA, mm	Mean HR, bpm	PVC	PSVC	SCN5A variant
I-2	52	1.48	41	61	427	No	No	−	−	−	No
I-1	53	1.56	48	58	536	Yes	26 × 16	64	27 (< 1%), including 2 couplets	67 (< 1%)	Yes
II-1	25	1.58	43	67	553	Yes	16 × 9	64	no	no	Yes
II-2	15	1.39	47	55	623	No	16 × 11	55	891 (1.2%), including 28 couplets and 2 triplets	no	Yes

The size of the infero-apical left ventricular aneurysm (IALVA) was expressed as width × depth (mm) and measured using two-dimensional echocardiography. J-waves were confined to the right precordial leads (V1–V3) on the standard surface 12-lead electrocardiogram. Body surface area (BSA) was calculated using the Mosteller formula.

Abbreviations: HR Heart rate, LVEDD Left ventricular end-diastolic diameter, LVEF Left ventricular ejection fraction, PSVC Premature supraventricular contractions, PVC Premature ventricular contractions

Electrocardiographic and holter features

Figure 3 shows the standard 12-lead ECG of each family member. The QTc were prolonged in subject I-1 (536 ms), subject II-1 (553 ms), and subject II-2 (623 ms), while subject I-2 had a normal QTc (427 ms). Overt J-waves were present in leads V2 of subjects I-1 and II-1. T-wave bidirectional or inversion in leads V1-V6 was observed in subjects I-1 and II-2, and T-wave inversion in leads V1-V6 was present in the proband. Table 1 shows Holter monitoring data from the three affected members. Holter monitoring revealed 27 (< 1%) PVCs including 2 couplets in subject I-1, and 891 (1.2%) PVCs including 28 couplets and 2 triplets in subject II-2.

Fig. 3.

The standard 12-lead electrocardiograms from each member of the family. A Standard 12-lead ECG of subject I-1 showing sinus rhythm with a prolonged QTc of 536 ms, an overt J-wave (arrow) in lead V2, and bidirectional or inverted T-waves in leads V1–V6. B ECG of subject I-2 demonstrating a normal QTc of 427 ms. C ECG of subject II-1 showing sinus rhythm with a prolonged QTc of 553 ms and a prominent J-wave (arrow) in lead V2. D ECG of the proband (subject II-2) demonstrating sinus rhythm with a prolonged QTc of 623 ms and T-wave inversion in leads V1–V6

Echocardiography and high-frequency ultrasound focused infero-apical region

The sizes of the infero-apical left ventricular aneurysms measured by two-dimensional echocardiography were 26 mm (width) × 16 mm (depth) in subject I-1 (Fig. 4, Video 1), 16 mm × 9 mm in subject II-1 (Fig. 5, Video 2), and 16 mm × 11 mm in subject II-2 (Fig. 6, Video 3). High-frequency ultrasound with a focused infero-apical view provided better visualization and measurement of the aneurysms (Figs. 4, 5 and 6, Videos 1–3). These small infero-apical left ventricular aneurysms were characterized by focal thinning, bulging, and akinesis without significant dyskinesis. The thinnest wall of the aneurysm measured approximately 1–2 mm. High-frequency ultrasound also revealed increased myocardial trabeculation in the apical left ventricular region in subjects II-1 (Fig. 5, Video 2) and II-2 (Fig. 6, Video 3).

Fig. 4.

Echocardiography of the subject Ⅰ-1 (also see Video 1). A Focused infero-apical view from the apical two-chamber projection demonstrating a left ventricular aneurysm (arrow). B Apical four-chamber view showing an approximately normal cardiac structure. C High-frequency ultrasound depicting an infero-apical ventricular aneurysm with a tiny wall measuring ~ 1 mm (arrow). D High-frequency ultrasound demonstrating an infero-apical ventricular aneurysm with an irregular protrusion (arrow). Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle

Fig. 5.

Echocardiography of the subject Ⅱ-1 (also see Video 2). A Focused infero-apical view from the apical two-chamber projection demonstrating a left ventricular aneurysm (arrow). B Apical four-chamber view showing an approximately normal cardiac structure. C High-frequency ultrasound depicting an infero-apical ventricular aneurysm with a fragile wall (arrow) and prominent myocardial trabeculation. D High-frequency apical four-chamber view showing approximately normal septo-apical myocardial thickness. With panel C, the thinnest myocardial segment of the infero-apical ventricular aneurysm is similar in thickness to the normal apical parietal pericardium (arrow). Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle

Fig. 6.

The proband’s echocardiography (also see Video 3). A Focused infero-apical view from the apical two-chamber projection showing a left ventricular aneurysm (arrow). B Apical four-chamber view demonstrating an approximately normal cardiac structure. C High-frequency ultrasound revealing an infero-apical ventricular aneurysm with a fragile wall (arrow) and marked myocardial trabeculation. D High-frequency apical four-chamber view depicting approximately normal septo-apical myocardial thickness. Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle

Genetic analysis

A heterozygous deletion of nine base pairs (AAGAAGCCC) in exon 26 of SCN5A (Fig. 2B; chr3:38597171–38597179, NM_198056.3; exon 26, c.4510_4518del, p.Lys1504_Lys1505_Pro1506del [KKP]) was identified in the proband (subject II-2), her father (subject I-1), and her brother (subject II-1) (Fig. 2C), and was excluded in her mother (I-2). No other mutations commonly associated with conduction disorders, ACM, or LQTS were found.

Discussion

Variable phenotypic expressions are observed in patients with SCN5A mutations, including cardiac conduction disease, LQTS, DCM, and BrS. Increasing evidence supports the notion that LQTS is not solely an electrical disease but rather an electro-mechanical disease, characterized by regionally heterogeneous impairment of both electrical and mechanical cardiac function [2–8]. In the present study, all three family members carrying the delKKP 1504–1506 mutation in SCN5A were found to have infero-apical left ventricular aneurysms and LQTS. However, two family members (subjects I-1 and II-1) exhibited prominent J-waves on the standard 12-lead ECG. The proband experienced a loss of consciousness with Mobitz type II atrioventricular block. While the precise mechanism underlying this phenotype remains poorly understood, the roles of gene penetrance, environmental factors, and genetic modifiers in phenotypic manifestation may have influenced the expression of the mutant gene. Further investigation is required to explain the observed variability.

Regardless of the etiology, regional ventricular aneurysms may serve as surrogate markers for myocardial fibrosis. In the present study, two family members (subjects II-1 and II-2) exhibited overt apical myocardial trabeculation. Increasing evidence supports the notion that myocardial hypertrabeculation may be an adaptive mechanism associated with other myocardial diseases and overload conditions [13, 14]. Myocardial hypertrabeculation may be an epiphenomenon of disease, associated with impaired regional function and fibrosis [15, 16].

The pathophysiology of ventricular arrhythmias is complex and multifactorial. It is generally believed to result from a complex interaction between an anatomical substrate and transient triggers, leading to electrical instability, including increased automaticity, triggered activity, and reentry. In the evolving diagnostic criteria for ACM, regional right ventricular akinesia, dyskinesia, or aneurysm, along with global right ventricular dilatation or systolic dysfunction, remain major criteria for the right ventricular phenotype, but not for the left ventricular phenotype. Left ventricular wall motion abnormalities (including regional hypokinesia, akinesia, or dyskinesia), with or without left ventricular dilatation, are classified as minor morpho-functional criteria because of their low specificity in diagnosing left-sided ACM variants; these abnormalities can also be observed in other common conditions, such as ischemic heart disease [17]. However, regional fibro-fatty myocardial scarring represents the hallmark myocardial lesion and arrhythmogenic substrate common to all phenotypic variants of ACM (scarring/ACM) [17]. Current conventional imaging techniques, including standard echocardiography, computed tomography, and cardiac magnetic resonance, may not be sensitive enough to detect early or regional arrhythmogenic substrates, as they cannot distinguish finer structural changes, such as local pericarditis [11]. High-frequency linear ultrasound, with its superior spatial and temporal resolution, can more effectively demonstrate and confirm the pathological characteristics of local ventricular aneurysms near the probe [12].

The J-wave syndromes include BrS and early repolarization syndrome. BrS is characterized by accentuated J-waves, which appear as coved-type ST-segment elevations in the right precordial leads (V1–V3) [18–20]. The mechanism underlying the typical ST-segment elevation in the right precordial leads in BrS patients has not yet been fully elucidated [21]. A combined electrophysiological, genetic, and histopathologic study provided a mechanistic basis for the association between fibrosis and BrS [9]. Growing evidence suggests that mild structural abnormalities in BrS patients, which are not detectable by conventional imaging modalities, lead to discontinuous conduction. BrS patients exhibited clear fractionated electrograms at the right ventricular outflow tract epicardium compared with controls, indicating discontinuous electrical impulse conduction that occurs when patchy fibrosis is present in the myocardium [21]. These data suggest that BrS and the susceptibility to ventricular fibrillation and sudden cardiac death may not be caused by a single mutation but rather by the inheritance of multiple BrS susceptibility variants acting in concert through one or more mechanistic pathways [22].

In this case series, two-thirds of mutation carriers exhibited a J-wave in the right-sided precordial leads. This finding offers intriguing insights into the functional effects of the SCN5A mutation on sodium channels, which are likely attributable to a gain-of-function (GoF) with late and persistent sodium current, resulting in prolonged ventricular repolarization. It is valuable to mention the pathogenic hypotheses regarding the correlation between SCN5A GoF mutations and cardiomyopathy: namely, intracellular sodium accumulation and activation of the sodium/calcium exchanger with subsequent intracellular calcium overload [2]. Conversely, the presence of J-waves (evident in the ECGs, particularly in Fig. 3A, where it is associated with a saddleback-type ST elevation of BrS) is usually correlated with loss-of-function (LoF) mutations of SCN5A [2]. The SCN5A mutation may simultaneously cause a GoF of late sodium current (prolonging QT) and a LoF of peak sodium current (reducing action potential upstroke in the right-sided precordial leads, generating J-waves/Brugada pattern). This “paradox” emphasizes that future in vitro functional studies are needed to resolve this dual effect.

Study limitations

Our study has several limitations. The genotype and phenotype were analyzed in only four family members across two generations. Due to the unavailability of medical records for other family members, the data are insufficient for statistical analysis. Although our findings are consistent with previous reports linking SCN5A mutations to cardiac conduction disease, LQTS, DCM, and BrS, detailed electrophysiological, functional, and biochemical assays were not performed. The clinical implications of our findings remain uncertain. Our study did not include cardiac magnetic resonance imaging (cMRI), which might provide better tissue characterization and arrhythmic risk stratification for carriers of the SCN5A variant. Specifically, cMRI could have detected possible septal fibrosis that might have contributed to the AV conduction disturbance and would allow better risk stratification for other family members. Furthermore, a pharmacological challenge (e.g., ajmaline test) was not performed in subjects presenting with J-waves; such a test could have provided additional diagnostic clarity and risk stratification. Given the small number of affected family members (n = 3), we cannot establish a causative relationship between the delKKP 1504–1506 mutation and left ventricular aneurysms. Larger family studies or functional studies in animal models are required to confirm causality. The management of LQTS type 3 in this case was not consistent with current practice: a severe phenotype such as ours would typically be managed with a non‑selective beta‑blocker (nadolol or propranolol) in combination with mexiletine, with pacing support. We were concerned that introducing beta‑blockers and mexiletine (which can worsen AV conduction) without a backup pacemaker/ICD was unsafe.

Conclusions

This case suggests that the delKKP 1504–1506 mutation in SCN5A may not only lead to impaired impulse propagation in the conduction system and a prolonged QTc, but may also be associated with infero-apical ventricular aneurysms and J-wave syndromes, possibly corresponding to regional myocardial fibrosis. The proband experienced a loss of consciousness with Mobitz type II atrioventricular block. While the underlying mechanism remains to be elucidated, these data may expand the spectrum of both phenotype and genotype. High-frequency linear ultrasound, with its superior spatial and temporal resolution, can more effectively demonstrate and confirm the pathological characteristics of regional ventricular aneurysms near the probe. The small, regional infero-apical left ventricular aneurysms may serve as surrogate markers for myocardial fibrosis in this family.

Abbreviations

ACM

Arrhythmogenic cardiomyopathy

BrS

Brugada syndrome

cMRI

Cardiac magnetic resonance imaging

CTA

Coronary computed tomography angiography

DCM

Dilated cardiomyopathy

ECG

The surface electrocardiogram

GoF

Gain-of-function

LoF

Loss-of-function

LQT3

LQTS type 3

LQTS

Congenital long QT syndrome

PVC

Premature ventricular contractions

QTc

The corrected QT interval

Authors’ contributions

The patient data were managed, analyzed, and interpreted by Z Lu, J Lin, Y Chen and, X Huang. All authors made significant contributions to the composition of the manuscript. The manuscript was written by Z Lu and J Lin. The treatment and follow-up of the patient were handled by X Zhou, L Lin, X Zhang, Q Wang and X Huang. The final written manuscript was reviewed and approved by all authors.

Funding

This work was supported by Dongguan Social Science and Technology Development project (grant no. 20221800906052) to J Lin and the 14th Five-Year Medical Key Specialist Construction Project of Foshan (grant no. FSZD145024) to Q Wang. There was no other form of financial support for this work.

Data availability

The novel variant has been deposited in ClinVar database. Accession numbers: SCV007517223 or https://submit.ncbi.nlm.nih.gov/api/2.0/files/lzx7myeayb0vl71h/sub16036751_100_submitter_report_b.txt/?format=attachmentThe original contributions presented in the study are included in the article/Supplementary materials, further inquiries can be directed to the corresponding authors.

Declarations

Ethics approval and consent to participate

Written informed consent to participate has been obtained from all the participants and the parents/legal guardians of minors. Written informed consent for publication of clinical details and/or clinical images has been obtained from all the participants and the parents/legal guardians of minors. This research was conducted in compliance with the Helsinki Declaration. The study protocol was reviewed and approved by Ethics Committee of Dongguan Hospital of Guangzhou University of Chinese Medicine, approval number [2025 − 0247]. And all procedures involving human participants were in accordance with local institutional guidelines.

Consent for publication

Written informed consent for publication of clinical details and/or clinical images has been obtained from all the participants and the parents/legal guardians of minors.

Competing interests

The authors declare no competing interests.