Table of Contents
Year : 2021  |  Volume : 6  |  Issue : 2  |  Page : 132-140

Differential diagnosis of PRKAG2 Cardiac syndrome in hypertrophic cardiomyopathy patients of han nationality

1 Department of Echocardiography; Department of Cardiology, Zhongshan Hospital, Fudan University; Departments of Cardiology, Shanghai Institute of Cardiovascular Diseases, Shanghai, China
2 Department of Echocardiography; Department of Cardiology, Zhongshan Hospital, Fudan University; Departments of Cardiology, Shanghai Institute of Cardiovascular Diseases; Departments of Echocardiography, Shanghai Institute of Medical Imaging, Shanghai, China
3 Department of Echocardiography, Zhongshan Hospital, Fudan University; Departments of Cardiology, Shanghai Institute of Cardiovascular Diseases; Departments of Echocardiography, Shanghai Institute of Medical Imaging, Shanghai, China

Date of Submission02-Feb-2021
Date of Acceptance11-May-2021
Date of Web Publication30-Jun-2021

Correspondence Address:
Xian-Hong Shu
Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/2470-7511.320319

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Objectives: This study aimed to diversify the spectrum of PRKAG2 variants and explore its clinical features in a Chinese Han population with hypertrophic cardiomyopathy (HCM). Methods: Whole-exome sequencing was performed on 200 patients diagnosed with HCM, and four causative PRKAG2 variants were identified in the probands and their relatives using Sanger sequencing. Their clinical manifestations, laboratory examinations, therapeutic methods, and outcomes were documented and analyzed. Results: Four variants were identified in six probands and seven of their relatives. Left ventricular hypertrophy was present in all probands. Five probands had sinus bradycardia, three had implanted pacemakers (PM), one developed heart failure, two had ventricular preexcitation, and one had atrial fibrillation. Conclusions: PRKAG2 cardiac syndrome (PCS) is a rare autosomal dominant disease characterized by ventricular hypertrophy, preexcitation, and progressive conduction defects, resulting in a high incidence of PM implantation. Genetic testing provides robust information for distinguishing PCS from sarcomeric HCM, which will be beneficial in guiding therapy and improving prognosis.

Keywords: Hypertrophic cardiomyopathy; PRKAG2 protein; Whole-exome sequencing

How to cite this article:
Li XJ, Zhou NW, Xie HL, Liu W, Pan CZ, Shu XH. Differential diagnosis of PRKAG2 Cardiac syndrome in hypertrophic cardiomyopathy patients of han nationality. Cardiol Plus 2021;6:132-40

How to cite this URL:
Li XJ, Zhou NW, Xie HL, Liu W, Pan CZ, Shu XH. Differential diagnosis of PRKAG2 Cardiac syndrome in hypertrophic cardiomyopathy patients of han nationality. Cardiol Plus [serial online] 2021 [cited 2021 Oct 25];6:132-40. Available from:

  Introduction Top

Conventionally, the clinical diagnosis of hypertrophic cardiomyopathy (HCM) based on morphology has tended to be inaccurate. The clinical manifestations, treatment, and prognosis of myocardial hypertrophy caused by sarcomeric gene mutations and other metabolic or neuromuscular diseases are heterogeneous.[1],[2],[3] which emphasizes the importance of differential diagnosis of HCM. PRKAG2 cardiac syndrome (PCS) is a rare inherited disease caused by PRKAG2 mutations, which was previously considered to be HCM. This study aims to distinguish PCS patients from HCM populations and to provide a fundamental understanding of its genotype–phenotype correlations.

  Materials and Methods Top


Two hundred unrelated Chinese Han patients clinically diagnosed with HCM were prospectively enrolled from 2017 to 2019. The clinical diagnosis of HCM was confirmed by transthoracic echocardiography (TTE) with a maximum end-diastolic left ventricular wall thickness ≥15 mm in the absence of secondary causes, or ≥13 mm when there was a family history of HCM. The patients with PRKAG2 variants and their relatives were enrolled. Their clinical data were collected, including age of onset, clinical manifestations, family history, laboratory examinations, methods of treatment, and clinical outcomes. This study was approved by the Medical Ethics Committee of Zhongshan Hospital, Fudan University (Approval No. B2016-016(2)R), and all participants or their guardians provided written informed consent.

Whole-exome sequencing and annotation

Genomic DNA was isolated from peripheral blood using TruSeq DNA Sample Preparation Kit. Whole-exome capture was performed using TruSeq Exome Enrichment Kit, and the HiSeq 2500 platform (Illumina Inc., San Diego, CA, USA) was used for sequencing. The raw data generated from sequencing were quality controlled with Cutadapt and FastQC. Subsequently, clean reads were aligned to the human reference genome (GRCh37/hg19) using BWA software. After mapping, the Genome Analysis Toolkit was used for variant calling, single-nucleotide variants, and insertions and deletions were annotated using ANNOtate VARiation and filtered using multiple databases, including Genome Aggregation Database (gnomAD), 1000Genome, Exome Aggregation Consortium, and dbNSFP based on the frequency and types of variants.

Identification and validation of variants

In silico prediction tools including PolyPhen-2, SIFT, MutationTaster, PROVEAN, I-Mutant2.0,[4] and MUpro[5] were used to predict the possible impact of variants on protein function and stability. According to the ACMG/AMP standards and guidelines,[6] variants are classified into five groups: pathogenic (P), likely pathogenic (LP), variant of uncertain significance (VUS), likely benign (LB), and benign (B). We selected those variants that were interpreted as P/LP/VUS and designed specific primers for each variant. Sanger sequencing was performed to validate these variants in the probands and their relatives.

  Results Top

Variant results and clinical features

Four PRKAG2 variants (A44T, R302Q, F407L, and H530R) were detected in six probands (numbered 1–6) and seven relatives, and none carried sarcomere mutations. Detailed information and in silico prediction results are summarized in [Table 1]. The clinical data of the probands are shown in [Table 2]. Some of the relatives who had been clinically diagnosed with HCM refused to undergo genetic testing or had succumbed to HCM. The clinical characteristics of these untested relatives and all mutation carriers are presented in [Figure 1]. Five probands (three females) presented with typical exertional chest pain and syncope, and one male proband was asymptomatic. Electrocardiograph (ECG) abnormalities included sinus bradycardia (four probands and three relatives), cardiac conduction block (three probands and one relative), and ventricular preexcitation (three probands and two relatives). All probands and all affected relatives exhibited left ventricular hypertrophy (LVH) without left ventricular outflow tract obstruction (LVOTO). The pedigree charts, characteristic ECG, and TTE images of the affected families are illustrated in [Figure 2], [Figure 3],[Figure 4],[Figure 5], [Figure 6], [Figure 7.
Table 1: Characteristics and functional prediction of of PRKAG2 variants

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Table 2: Clinical characteristics and electrocardiograph and transthoracic echocardiography findings of the probands

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Figure 1: Clinical characteristics of mutation carriers and relatives.
A, Clinical characteristics of all carriers of PRKAG2 variants (including probands and their relatives). B, Clinical characteristics of untested relatives who were clinically diagnosed with HCM.
Implantable cardioverter-defibrillator, VT: Ventricular tachycardia, AF: Atrial fibrillation, LVH: Left ventricular hypertrophy, HCM: Hypertrophic cardiomyopathy, SCD: Sudden cardiac death, PM: Pacemakers

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Figure 2: Pedigree chart, electrocardiograph, and clinical imaging data of proband 1.
The squares and circles in the family pedigree chart represent males and females, respectively. Partially black symbols indicate variant carriers of autosomal dominant heterozygous variations. The black symbol indicates a family member who was clinically diagnosed with HCM but was not genetically tested. The symbol marked with a slash indicates deceased status. The arrow indicates the proband. II-1 carried the same variant as his son. TTE images of the proband (left) and his father (right) revealed septum and left ventricular anterior wall hypertrophy resembling HCM. ECG of the proband (left) and his father (right) both revealed sinus bradycardia and left ventricular high voltage, and the father also exhibited a shortened PR interval.
HCM: Hypertrophic cardiomyopathy, TTE: Transthoracic echocardiography, ECG: Electrocardiograph

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Figure 3: Pedigree chart, electrocardiograph, and clinical imaging data of proband 2.
III-1, 3 and IV-1, 2, 3 underwent Sanger sequencing, and causative mutations were identified in III-1, 3. II-1, 2, 3, 4 and III-3, 4, 5, 6, 7 were clinically diagnosed with HCM and did not undergo genetic testing; II-2,3,4 had preexisting bradycardia and preexcitation before decease; III-2 had died of SCD at 33 years old; III-4,5,6,7 all received PM implantation due to bradycardia. TTE of the proband revealed marked hypertrophy of the septum and LV inferior wall. ECG of the proband (left) failed to reveal intermittent ventricular preexcitation; ECG of her cousin (III-3) (right) indicated bradycardia.
HCM: Hypertrophic cardiomyopathy, SCD: Sudden cardiac death, TTE: Transthoracic echocardiography, LV: Left ventricular, ECG: Electrocardiograph

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Figure 4: Pedigree chart, electrocardiograph, and clinical imaging data of proband 3.
II-1 and his son (III-1) had succumbed to HCM at ages 60 and 41, respectively. II-2 had PM implantation at age 67 years; her son also had HCM and had succumbed to SCD at age 42. The proband`s mother (II-3) and her sibling (III-4) are carriers who exhibited characteristic symptoms and ECG findings consistent with PCS. TTE of the proband revealed severe hypertrophy of the LV and RV walls. ECG of the proband (left) failed to reveal intermittent ventricular preexcitation. TTE of her brother (middle) also revealed multi-segmental hypertrophy, and his ECG (right) revealed sinus bradycardia and RBBB. HCM: Hypertrophic cardiomyopathy, SCD: Sudden cardiac death, PM: Pacemakers, ECG: Electrocardiograph, PCS: PRKAG2 cardiac syndrome, LV: Left ventricular, RV: Right ventricle, TTE: Transthoracic echocardiography, RBBB: Right bundle branch block

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Figure 5: Pedigree chart, electrocardiograph, and clinical imaging data of proband 4.
II-1 had died by accident, and his brother II-2 had died from myocardial infarction. Only III-1 and her son had undergone genetic screening. The ECG of III-1 revealed a pacemaker-generated rhythm with advanced AVB. Her TTE revealed posterior septum and RV free wall hypertrophy. ECG: Electrocardiograph, AVB: Atrioventricular block, TTE: Transthoracic echocardiography

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Figure 6: Pedigree chart, electrocardiograph, and clinical imaging data of proband 5.
The proband's son (III-2), one daughter (III-1), and one grandchild (IV-5) are carriers. ECG of III-1 revealed LV hyper-voltage (A) and a small ventricular septal defect was detected by TTE (not shown). ECG of his granddaughter (B) revealed a shortened PR interval and signs of LVH. TTE of the proband indicated a noticeable LVH (upper); ECG of the proband before PM implantation (C) revealed no signs of conduction defects and preexcitation. TTE of his son (middle) also revealed multi-segmental LVH, and his ECG (D) revealed signs of LVH.

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Figure 7: Pedigree chart, electrocardiograph, and clinical imaging data of proband 6.
The proband`s cousin (III-1) had died of SCD in his 20s. The proband`s son (IV-5) had received gene screening and carried the mutation. ECG showed RBBB without other arrhythmia. TTE of the proband revealed significant LVH
SCD: Sudden cardiac death, ECG: Electrocardiograph, TTE: Transthoracic echocardiography, LVH: Left ventricular hypertrophy

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The previously-reported pathological variants, R302Q and H530R, were identified in three families and in one family. A44T was also a previously reported variant, which had conflicting interpretations in ClinVar. A44T is located at the N-terminal domain of PRKAG2 (noncystathionine β-synthase [CBS] domain). The prediction of pathogenicity of A44T led to conflicting conclusions, but it was predicted to decrease the protein stability of PRKAG2. Given the relatively high conservation of the original sequence, the changes of amino acid polarity, as well as its co-segregation with LVH or ECG changes in the family, it was categorized as a VUS. We also discovered one novel variant, a C to A transition at nucleotide 1221 that leads to the substitution of leucine for phenylalanine at 407. F407 L, like most reported variants, is located at the CBS domain. F407 L was absent from the public database gnomAD and the disease-related databases ClinVar and dbSNP. It was predicted to be deleterious and to decrease protein stability; it was therefore categorized as a likely pathological variant.

Pedigree study

Proband 1

A 15-year-old man underwent a medical examination at our hospital because his father had been diagnosed with HCM in 2017. His TTE revealed a left ventricular wall thickness of 13–15 mm and his ECG indicated sinus bradycardia (heart rate [HR]: 50 bpm) with no signs of preexcitation and cardiac block. His father exhibited the typical symptom of exertional dyspnea but did not receive beta-blockers due to bradycardia. The father's ECG indicated sinus bradycardia (HR: 47 bpm), shortened PR interval, and left bundle branch block. Their family pedigree chart and clinical imaging data are depicted in [Figure 2].

Proband 2

A 47-year-old woman had chest tightness for 28 years with two episodes of syncope. Twenty-five years prior, she had lost consciousness for about 30 s after running and experienced several similar attacks in the following years but had not sought treatment. Due to her sister's diagnosis of HCM, she underwent a cardiac evaluation in 2010. Her ECG revealed sinus bradycardia and intermittent preexcitation; 24-h ambulatory Holter monitoring recorded an average HR of 48 bpm with a minimal HR of 35 bpm. She was referred to our hospital and underwent implantable cardioverter-defibrillator (ICD) placement in November 2017. After surgery, she was routinely managed on diltiazem hydrochloride and cardiac symptoms did not recur during follow-up management.

Her mother, younger sister, and aunt were all diagnosed with HCM but could not receive medications due to bradycardia. Her mother had died during sleep at the age of 69 years, and her sister had died from sudden cardiac death (SCD) at the age of 33 years. Her pedigree chart [Figure 3] shows the family members who had been initially diagnosed with HCM and those who were re-diagnosed with PCS after genetic testing.

Proband 3

A 36-year-old woman had experienced progressive exertional chest distress and dizziness in August 2018. She had been diagnosed with HCM 12 years prior and could not receive medical treatment due to sinus bradycardia. TTE demonstrated pronounced LVH along with right ventricular (RV) free wall hypertrophy; the maximum wall thickness of the left ventricle (LV) and RV was 29 and 10 mm, respectively. Her ECG revealed severe sinus bradycardia (HR: 43 bpm) and intraventricular block. She was administered trimetazidine and coenzyme Q, and her symptoms subsided.

Her mother had been suffering from chest distress in recent decades, and her ECG indicated sinus bradycardia with shortened PR interval, LV high voltage, and intraventricular conduction block. Her younger brother complained of intermittent dizziness for 5 years and palpitations for 1 year, and his ECG revealed right bundle branch block (RBBB) and LV high voltage.

Proband 4

A 38-year-old woman presented with recurrent syncope and loss of consciousness for about 10 s on the same day without precipitating cause 13 years ago. On examination, TTE revealed marked hypertrophy of the LV posterior wall, septum, and RV free wall and the ECG revealed a third-degree atrioventricular block (AVB). Temporary cardiac pacing was used, while electrocardiogram monitoring documented recurrent episodes of nonsustained ventricular tachycardia (VT) with ventricular preexcitation and prolonged RR interval (10 s) during hospitalization. Electrophysiologic study (EPS) revealed a right anterior free wall accessory pathway without HV conduction. Eventually, she underwent ICD implantation in June 2010, received beta-blocker treatment, and was in stable condition at the regular follow-ups. The proband and her son underwent genetic testing, and her son did not possess the PRKAG2 variant [Figure 5].

Proband 5

A 67-year-old man suffered from chest tightness and palpitations without obvious inducement for 12 years. He was diagnosed with HCM and was managed with beta-blockers. For the first 6 years, no ventricular preexcitation, sinus arrest, or AVB was identified. Four years prior, he had developed persistent atrial fibrillation (AF) with slow ventricular rate (mean HR: 55 bpm) and intermittent advanced AVB, the number of ventricular pauses >2 s was 2498, with the longest ventricular pause persisting for 5.16 s. He did not exhibit bradycardia. He discontinued metoprolol and subsequently received permanent cardiac pacemaker (PM) implantation (VVI mode) in 2018. He experienced a sudden onset of VT (HR: 191 bpm) in June 2020. After antiarrhythmic drug treatment, the VVI PM was replaced with an ICD.

His son, one of his daughters, and his granddaughter are carriers [Figure 6]. His son was diagnosed with HCM at 23 years of age, due to an abnormal ECG, and was treated with beta-blockers. His daughter exhibited no clinical symptoms. Her ECG revealed high voltage, and TTE detected a small ventricular septal defect. His 7-year-old granddaughter exhibited no clinical symptoms, but her ECG indicated a shortened PR interval and signs of LVH.

Proband 6

A 57-year-old man experienced chest tightness for 14 years. He was diagnosed with HCM and treated with beta-blockers; he underwent regular Holter monitoring. The symptoms persisted and progressed to exertional dyspnea, paroxysmal nocturnal dyspnea, and cough and sputum. He was admitted to our hospital in January 2019. ECG revealed complete RBBB without other arrhythmias, TTE revealed LVH of 15–28 mm and left atrium enlargement, and chest CT findings suggested pulmonary infection. He was diagnosed with pulmonary infection-induced acute left heart failure (HF) and was prescribed diuretics and antimicrobial therapy. His symptoms subsided. He was continued on beta-blockers and other standard treatment modalities for HF.

His mother had been clinically diagnosed with HCM and had died of pulmonary infection and HF at the age of 60 years. One of his cousins had also been diagnosed with HCM and had succumbed to SCD in his 20s [Figure 7].

  Discussion Top

Research status of PRKAG2 cardiac syndrome

In 2001, Gollob et al.[7] identified a missense mutation c.995C>A (p.R302Q) within PRKAG2 in two families with ventricular preexcitation, conduction defect, and LVH, and for the first time, defined this autosomal dominant disease with the causative gene PRKAG2. Several mutations were identified in subsequent studies, which were mainly missense substitutions.[8],[9] Adenosine monophosphate-activated protein kinase (AMPK) is the sensor and regulator of cell energy metabolism, and as its γ subunit, PRKAG2 mediates the binding of AMP/ADP and regulates the inhibition or activation of AMPK.[10] PRKAG2 has four tandem CBS motifs, forming two highly conserved Bateman domains. AMP binds to Bateman directly, inducing the rapid activation of AMPK, thereby maintaining energy homeostasis.[11],[12]

For a considerable time, PCS was considered an etiology of HCM, but according to the AHA/ACC guidelines, with the exception of sarcomeric HCM, other cardiac or systemic diseases that similarly present with LVH should not be classified as HCM.[13] Owing to the high rate of misdiagnosis, the prevalence and pathophysiological features of PCS are still poorly understood.

Porto et al.[14] retrospectively analyzed 193 patients with PCS in 23 studies, in which 68% of the patients had ventricular preexcitation, 53% had LVH, ~50% had PM or ICD implantation due to advanced AVB or sinus node lesion, and 8.7% experienced SCD. Lopez-Sainz et al.[15] evaluated 64 PCS patients and reported that the average age of diagnosis for the two most common mutations was 19 (N488I) and 36 years (R302Q); ~one-third of the patients had ventricular preexcitation; ~10% of patients experienced SCD, which was usually caused by supraventricular arrhythmia (such as AF) combined with accessory pathway conduction in younger patients (<30 years old) and by sudden advanced AVB in older patients. Over 30% of patients needed a permanent PM (average age: 37 years).

Several studies on transgenic mice demonstrated that glycogen accumulation occurs in parallel with ventricular preexcitation[16],[17],[18],[19] and is partly related to LVH but unrelated to conduction system disorders.[20],[21] Other glycogen accumulation-independent mechanisms, such as mechanistic target of rapamycin activation and voltage-gated sodium channel changes, are also involved in LVH and conducting system damage.[21]

Clinical phenotypes of PRKAG2 cardiac syndrome

PCS patients exhibit similar but heterogeneous phenotypes, and the severity varies considerably, ranging from death in infancy to mild symptoms in adulthood. The genotype-phenotype correlation and underlying molecular mechanisms have not yet been fully elucidated. Among the reported variants, R531Q and R384T produce extremely severe phenotypes of biventricular hypertrophy, fetal bradycardia, and neonatal death. R531 and R384 are located at CBS4 and CBS2, respectively, and the side-chains of the residues directly interact with the phosphate group of AMP, thereby significantly weakening the binding capacity between AMP and Bateman. Mutations within the non-CBS region appear to have weaker biological consequences, as they may indirectly impair the binding ability between the CBS region and AMP.

New findings

Our study revealed that, compared to HCM patients, PCS patients mainly manifest concentric hypertrophy without LVOTO. We identified a novel F407 L mutation within the CBS region. Carriers of mutations within the CBS region presented with characteristic ECG findings of bradycardia, preexcitation, conduction defects, and VT. Two probands with R302Q exhibited juvenile-onset sinus node lesions with a family history of SCD and PM implantation. The other proband possessing R302Q developed VT and underwent ICD implantation. The proband with F407 L did not display typical ECG features initially but progressed to AF with intermittent AVB and VT. The proband with A44T manifested only RBBB and developed HF in his late 50s, reflecting the relatively milder phenotype of the non-CBS domain variant.

Differential diagnosis and therapy for PRKAG2 cardiac syndrome and hypertrophic cardiomyopathy

The actual incidence of PCS remains unknown, but it is relatively lower than that of HCM (~0.6%). A newly published study reported that the penetrance of PCS is 100%,[22] whereas that of HCM is ~46%, with variable expressivity.[23]

There are obvious pathological distinctions between HCM and PCS. HCM is characterized by hypertrophic cardiomyocyte disarray with myocardial interstitial fibrosis, whereas PCS presents with the cytoplasmic vacuolation of hypertrophic cardiomyocytes without interstitial fibrosis. Most patients with PCS progress to conduction defects and ventricular preexcitation, as a result of annulus fibrosus disruption and glycogen deposition. However, HCM patients rarely develop advanced AVB or ventricular preexcitation.

The clinical manifestations of PCS and HCM partially overlap but also vary considerably. PCS patients often present from progressive sinus bradycardia, chronotropic incompetence, a higher incidence of SCD, and are more likely to develop systolic HF.[14] The hypertrophy in HCM patients may involve all segments of the LV, and the distinctive manifestation is asymmetric septum hypertrophy. Approximately 70% of HCM patients exhibit LVOTO after resting or after exercise. Late gadolinium enhancement by CMR is also a characteristic feature of HCM. The thickness and location of myocardial hypertrophy in PCS patients were not specific, showing symmetrical hypertrophy in each segment. Thus far, no single segment phenotype was involved in LVH in PCS patients, and there was also no CMR-specific manifestation. LVOTO incidence in PCS patients was very low in previous reports, and none of the carriers in the present study exhibited LVOTO. HCM patients do not display clinical findings beyond cardiac phenotype, but thus far, there have been some reports of noncardiac phenotypes caused by PCS, including musculoskeletal diseases, dyslipidemia, overweight, and kidney failure. In this study, the proband with F407 L had primary hypertension, and the proband with A44T had dyslipidemia and type 2 diabetes, whereas these phenotypes were not observed in the other probands and affected relatives. Although the direct correlation between PCS and these phenotypes has not been confirmed, it is speculated that the dysregulation of AMPK signaling may have potential effects on vascular endothelial cells, smooth muscle cells, and the kidney.

Given the high incidence and sudden effect of advanced AVB, timely PM implantation is critical. Unlike HCM, therapeutic strategies for PCS now aim to prevent arrhythmia and SCD. Most R302Q mutation carriers have a fasciculoventricular pathway confirmed by cardiac EPS, which is a rare preexcitation syndrome (Mahaim syndrome).[24] Radiofrequency ablation of this accessory pathway may cause iatrogenic AVB; therefore, it is critical to distinguish PCS and identify this kind of accessory pathway. Genome editing and molecular therapies for PCS have also been investigated.[25],[26]

A limitation of this study lies in the regional constraints of the patients, and the regional and ethnic differences of the variant spectrum may appear. Further studies involving more patients with more extended follow-up are imperative for risk classification and timing of invasive intervention, such as PM or ICD implantation.

  Conclusions Top

We explored the genetic and clinical manifestations of PCS in HCM patients of the Han ethnicity. One novel PRKAG2 variant was identified, and the phenotypes were preliminarily discussed. The molecular mechanism of the newly found variant requires further investigation.

Modalities of genetic testing including whole-exome sequencing have revolutionized the differentiation of LVH. Early differential diagnosis of PCS from HCM is of great significance for genetic consultation, drug selection, SCD prevention, and accurate prediction of prognosis. Multiple segmental LVH with short PR interval and/or conduction defect is highly indicative of PCS. Genetic testing is strongly recommended for patients suspected of PCS, and mutation screening of the relatives of a confirmed proband should be conducted without delay. With the growing recognition of PCS and the popularity and standardization of genetic testing, more patients could benefit from earlier definitive diagnoses, which would facilitate appropriate clinical decision-making.

Financial support and sponsorship

This research was supported by the National Natural Science Foundation of China (No. 82071933); Shanghai Science and Technology Commission(No. 20JC1418400).

Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7]

  [Table 1], [Table 2]


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