Inherited Arrhythmia Syndromes Research Articles

Demographics, clinical features and genetics of inherited arrhythmias in Oman

Abstract Background Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes encoding ion channels causing disruption in its structure and function and predispose affected individuals to various symptoms including sudden cardiac death (SCD). They include congenital long QT syndrome, Brugada syndrome (BrS), progressive cardiac conduction disease, short QT syndrome and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). There have been few reports of long QT syndrome from the Arabian Gulf region but this is the first comprehensive review of multiple inherited arrhythmia syndromes in the region. Objectives Our objective are to describe the demographics of children and adults with inherited arrhythmia syndromes, report the presenting clinical features, genetic mutations and management strategies. Also, to report some unique and rare genetic findings in our population. Methods This is a descriptive retrospective study that included children and adults with inherited arrhythmia syndromes diagnosed and treated at a national heart center over 16 years, between 2006 to 2022. Data collected included patient demographics, geographical distribution, clinical features, genetic reports and management strategies. Result One hundred and six patients were included in the analysis. Sixty-six (62.3%) were males, and 68 (64.2%) were adults and 38 (35.8%) were children. Three inherited arrhythmia syndromes were found in our population that included Long QT, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT), which accounted for 58 (54.7%), 39 (36.8%) and 9 (8.5%), respectively. Seventy-six (71.7%) of the patients were reported to be from consanguineous families. Most children, 31 (91.4%) had long QT, whereas most adults, 39(54.9%) had Brugada. The clinical features varied based on the type of arrhythmia. There were 28(26.4%) asymptomatic individuals who were diagnosed incidentally. Syncope was the most common presenting symptom in patients with Long QT, 24(41.4%) and Brugada syndrome, 20(51.3%). Palpitations, 4(44.4%) and bradycardia, 4(44.4%) were the predominant presenting features in patients with CPVT. The treatment modalities included beta blockers and antiarrhythmics, implantable cardioversion defibrillators(ICDs), pacemakers, and left sympathetic ganglionectomy(LSGs). We identified 36 individuals with pathogenic or likely pathogenic variants and 12 VOUS(variants of uncertain significance) in different genes of IAS. Conclusion This is the first comprehensive study on the inherited arrhythmia syndromes in Oman and the Arabian Peninsula. We provided insights about demographics, clinical, genetic profile and the treatment strategies of the most common IAS in the region. Tis study hat will help in early detection of the different types of arrhythmias and early intervention to prevent sudden cardiac death in patients and their relatives.

An inherited life-threatening arrhythmia model established by screening randomly mutagenized mice

Inherited arrhythmia syndromes (IASs) can cause life-threatening arrhythmias and are responsible for a significant proportion of sudden cardiac deaths (SCDs). Despite progress in the development of devices to prevent SCDs, the precise molecular mechanisms that induce detrimental arrhythmias remain to be fully investigated, and more effective therapies are desirable. In the present study, we screened a large-scale randomly mutagenized mouse library by electrocardiography to establish a disease model of IASs and consequently found one pedigree that exhibited spontaneous ventricular arrhythmias (VAs) followed by SCD within 1 y after birth. Genetic analysis successfully revealed a missense mutation (p.I4093V) of the ryanodine receptor 2 gene to be a cause of the arrhythmia. We found an age-related increase in arrhythmia frequency accompanied by cardiomegaly and decreased ventricular contractility in the Ryr2I4093V/+ mice. Ca2+ signaling analysis and a ryanodine binding assay indicated that the mutant ryanodine receptor 2 had a gain-of-function phenotype and enhanced Ca2+ sensitivity. Using this model, we detected the significant suppression of VA following flecainide or dantrolene treatment. Collectively, we established an inherited life-threatening arrhythmia mouse model from an electrocardiogram-based screen of randomly mutagenized mice. The present IAS model may prove feasible for use in investigating the mechanisms of SCD and assessing therapies.

Prioritize Variant Reclassification in Pediatric Long QT Syndrome-Time to Revisit.

Congenital long QT syndrome (LQTS) is an inherited arrhythmia syndrome associated with sudden cardiac death. Accurate interpretation and classification of genetic variants in LQTS patients are crucial for effective management. All patients with LQTS with a positive genetic test over the past 18years (2002-2020) in our single tertiary pediatric cardiac center were identified. Reevaluation of the reported variants in LQTS genes was conducted using the American College of Genetics and Genomics (ACMG) guideline after refinement by the US ClinGen SVI working group and guideline by Walsh et al. on genetic variant reclassification, under multidisciplinary input. Among the 59 variants identified. 18 variants (30.5%) were reclassified. A significant larger portion of variants of unknown significance (VUS) were reclassified compared to likely pathogenic (LP)/pathogenic (P) variants (57.7% vs 9.1%, p < 0.001). The rate of reclassification was significantly higher in the limited/disputed evidence group compared to the definite/moderate evidence group (p = 0.0006). All LP/P variants were downgraded in the limited/disputed evidence group (p = 0.0057). VUS upgrades are associated with VUS located in genes within the definite/moderate evidence group (p = 0.0403) and with VUS present in patients exhibiting higher corrected QT intervals (QTc) (p = 0.0445). A significant number of pediatric LQTS variants were reclassified, particularly for VUS. The strength of the gene-disease association of the genes influences the reclassification performance. The study provides important insights and guidance for pediatricians to seek for reclassification of "outdated variants" in order to facilitate contemporary precision medicine.

New Guidelines of Pediatric Cardiac Implantable Electronic Devices: What Is Changing in Clinical Practice?

Guidelines are important tools to guide the diagnosis and treatment of patients to improve the decision-making process of health professionals. They are periodically updated according to new evidence. Four new Guidelines in 2021, 2022 and 2023 referred to pediatric pacing and defibrillation. There are some relevant changes in permanent pacing. In patients with atrioventricular block, the heart rate limit in which pacemaker implantation is recommended was decreased to reduce too-early device implantation. However, it was underlined that the heart rate criterion is not absolute, as signs or symptoms of hemodynamically not tolerated bradycardia may even occur at higher rates. In sinus node dysfunction, symptomatic bradycardia is the most relevant recommendation for pacing. Physiological pacing is increasingly used and recommended when the amount of ventricular pacing is presumed to be high. New recommendations suggest that loop recorders may guide the management of inherited arrhythmia syndromes and may be useful for severe but not frequent palpitations. Regarding defibrillator implantation, the main changes are in primary prevention recommendations. In hypertrophic cardiomyopathy, pediatric risk calculators have been included in the Guidelines. In dilated cardiomyopathy, due to the rarity of sudden cardiac death in pediatric age, low ejection fraction criteria were demoted to class II. In long QT syndrome, new criteria included severely prolonged QTc with different limits according to genotype, and some specific mutations. In arrhythmogenic cardiomyopathy, hemodynamically tolerated ventricular tachycardia and arrhythmic syncope were downgraded to class II recommendation. In conclusion, these new Guidelines aim to assess all aspects of cardiac implantable electronic devices and improve treatment strategies.

Insights into adherence to medication and lifestyle recommendations in an international cohort of patients with catecholaminergic polymorphic ventricular tachycardia.

In patients with catecholaminergic polymorphic ventricular tachycardia (CPVT), a rare inherited arrhythmia syndrome, arrhythmic events can be prevented by medication and lifestyle recommendations. In patients who experience breakthrough arrhythmic events, non-adherence plays an essential role. We aimed to investigate the incidence and potential reasons for non-adherence to medication and lifestyle recommendations in a large, international cohort of patients with CPVT. An online multilingual survey was shared with CPVT patients worldwide by their cardiologists, through peer-recruitment, and on social media from November 2022 until July 2023. Self-reported non-adherence was measured using the validated Medication Adherence Rating Scale (MARS) and a newly developed questionnaire about lifestyle. Additionally, validated questionnaires were used to assess potential reasons for medication non-adherence. Two-hundred-and-eighteen patients completed the survey, of whom 200 (92%) were prescribed medication [122 (61%) female; median age 33.5 years (interquartile range: 22-50)]. One-hundred-and-three (52%) were prescribed beta-blocker and flecainide, 85 (43%) beta-blocker, and 11 (6%) flecainide. Thirty-four (17%) patients experienced a syncope, aborted cardiac arrest or appropriate implantable cardioverter defibrillator shock after diagnosis. Nineteen (13.4%) patients were exercising more than recommended. Thirty (15%) patients were non-adherent to medication. Female sex [odds ratio (OR) 3.7, 95% confidence interval (CI) 1.3-12.0, P = 0.019], flecainide monotherapy compared to combination therapy (OR 6.8, 95% CI 1.6-31.0, P = 0.010), and a higher agreement with statements regarding concerns about CPVT medication (OR 1.2, 95% CI 1.1-1.3, P < 0.001) were independently associated with non-adherence. The significant rate of non-adherence associated with concerns regarding CPVT-related medication, emphasizes the potential for improving therapy adherence by targeted patient education.

Cascade genetic counseling and testing in hereditary syndromes: inherited cardiovascular disease as a model: a narrative review.

Inherited cardiovascular diseases cover the inherited cardiovascular disease familial hypercholesterolemia and inherited cardiac diseases, like inherited cardiomyopathies and inherited arrhythmia syndromes. Cascade genetic counseling and testing in inherited cardiovascular diseases have had three decades of academic attention. Inherited cardiovascular diseases affect around 1-2% of the population worldwide and cascade genetic counseling and testing are considered valuable since preventive measures and/or treatments are available. Cascade genetic counseling via a family-mediated approach leads to an uptake of genetic counseling and testing among at-risk relatives of around 40% one year after identification of the causal variant in the proband, with uptake remaining far from complete on the long-term. These findings align with uptake rates among relatives at-risk for other late onset medically actionable hereditary diseases, like hereditary cancer syndromes. Previous interventions to increase uptake have focused on optimizing the process of informing relatives through the proband and on contacting relatives directly. However, despite successful information dissemination to at-risk relatives, these approaches had little or no effect on uptake. The limited research into the barriers that impede at-risk relatives from seeking counseling has revealed knowledge, attitudinal, social and practical barriers but it remains unknown how these factors contribute to the decision-making process for seeking counseling in at-risk relatives. A significant effect on uptake of genetic testing has only been reached in the setting of familial hypercholesterolemia, where active information provision was accompanied by a reduction of health-system-related barriers. We propose that more research is needed on barriers -including health-system-related barriers- and how they hinder counseling and testing in at-risk relatives, so that uptake can be optimized by (adjusted) interventions.

Development of automated patch clamp assays to overcome the burden of variants of uncertain significance in inheritable arrhythmia syndromes

Advances in next-generation sequencing have been exceptionally valuable for identifying variants in medically actionable genes. However, for most missense variants there is insufficient evidence to permit definitive classification of variants as benign or pathogenic. To overcome the deluge of Variants of Uncertain Significance, there is an urgent need for high throughput functional assays to assist with the classification of variants. Advances in parallel planar patch clamp technologies has enabled the development of automated high throughput platforms capable of increasing throughput 10- to 100-fold compared to manual patch clamp methods. Automated patch clamp electrophysiology is poised to revolutionize the field of functional genomics for inheritable cardiac ion channelopathies. In this review, we outline i) the evolution of patch clamping, ii) the development of high-throughput automated patch clamp assays to assess cardiac ion channel variants, iii) clinical application of these assays and iv) where the field is heading.

Catecholaminergic polymorphic ventricular tachycardia (and seizure) caused by a novel homozygous likely pathogenic variant in CASQ2 gene

BackgroundAlthough structural heart disease is frequently present among patients who experience sudden cardiac death (SCD), inherited arrhythmia syndromes can also play an important role in the occurrence of SCD. CPVT2, which is the second-most prevalent form of CPVT, arises from an abnormality in the CASQ2 gene. ObjectiveWe represent a novel CASQ2 variant that causes CPVT2 and conduct a comprehensive review on this topic. MethodsThe proband underwent Whole-exome sequencing (WES) in order to ascertain the etiology of CPVT. Subsequently, the process of segregating the available family members was carried out through the utilization of PCR and Sanger Sequencing. We searched the google scholar and PubMed/Medline for studies reporting CASQ2 variants, published up to May 10,2023. We used the following mesh term “Calsequestrin” and using free-text method with terms including “CASQ2”,”CASQ2 variants”, and “CASQ2 mutation”. ResultsThe CASQ2 gene was found to contain an autosomal recessive nonsense variant c.268_269insTA:p.Gly90ValfsTer4, which was identified by WES. This variant was determined to be the most probable cause of CPVT in the pedigree under investigation. ConclusionCASQ2 variants play an important role in pathogenesis of CPVT2. Notabely, based on results of our study and other findings in the literature the variant in this gene may cause an neurological signs in the patients with CPVT2. Further studies are needed for more details about the role of this gene in CPVT evaluation, diagnosis, and gene therapy.

Implantable loop recorder monitoring in inherited cardiomyopathies: yield of clinically relevant arrhythmias

Abstract Background Implantable loop recorders (ILRs) are a minimally invasive tool for the diagnosis of arrhythmias in patients with unexplained syncope or asymptomatic arrhythmias. Their use in patients with inherited arrhythmia syndromes has been recommended in the recent 2022 ESC Guidelines (1). However, the clinical utility of ILRs in patients with inherited cardiomyopathies remains unexplored. Purpose The purpose of this study was to evaluate the yield of ILR monitoring in detecting clinically relevant events in a single cohort of patients with inherited cardiomyopathies. Methods We prospectively collected demographic, clinical, and follow-up data from patients with inherited cardiomyopathies (Arrhythmogenic Cardiomyopathy, ACM; Hypertrophic Cardiomyopathy, HCM; Dilated Cardiomyopathy, DCM; Left Ventricular Non-Compaction, LVNC) who were implanted with an ILR and were followed with telemedicine. The primary endpoint was a clinically significant event recorded with the ILR that required an update to an implantable cardioverter defibrillator (ICD). Results The study cohort included 53 consecutive patients (55% males; mean age at ILR implantation 35±14 years) with inherited cardiomyopathies: 33/53 (62%) with ACM, 9/53 (17%) with HCM, 7/53 (13%) LVNC, 4/33 (8%) DCM. None of the patients implanted had previously experienced life-threatening arrhythmias. During a median follow-up of 2.6 years (IQR 1.4-3.7 years) after ILR implantation, clinically relevant arrhythmic events were documented in 9/53 (17%) of patients. Specifically, sustained or non-sustained ventricular tachycardia episodes were detected in 8 patients (5 with ACM, 2 with LVNC, 1 with LMNA-related DCM), whereas one patient with HCM showed symptomatic pauses &amp;gt; 3 seconds due to sick sinus syndrome. In all cases, the detection of such episodes led to the upgrade to ICD implantation. Conclusions ILR monitoring of patients with inherited cardiomyopathies identified clinically relevant events in almost one-fifth of patients, suggesting that the use of ILR may substantially improve the management of these patients. Figure 1. Representative example of clinically actionable event detected by implantable loop recorder (ILR) in a patient with inherited cardiomyopathy. The patient, a 19-year-old male with a definitive diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) and a pathogenic PKP2 truncating variant, presented with palpitations and vertigo during physical exertion one year after the implantation of an ILR. ILR monitoring documented a rapid tachycardia with a mean frequency of 250 bpm lasting 3 minutes, prompting an indication for an implantable cardioverter defibrillator (ICD).Figure 1.

Identification of concealed cardiomyopathy using next-generation sequencing-based genetic testing in Korean patients initially diagnosed with idiopathic ventricular fibrillation.

Idiopathic ventricular fibrillation (IVF) is a disease in which the cause of ventricular fibrillation cannot be identified despite comprehensive clinical evaluation. This study aimed to investigate the clinical yield and implications of genetic testing for IVF. This study was based on the multi-centre inherited arrhythmia syndrome registry in South Korea from 2014 to 2017. Next-generation sequencing-based genetic testing was performed that included 174 genes previously linked to cardiovascular disease. A total of 96 patients were clinically diagnosed with IVF. The mean age of the onset was 41.2 ± 12.7 years, and 79 patients were males (82.3%). Of these, 74 underwent genetic testing and four (5.4%) of the IVF probands had pathogenic or likely pathogenic variants (each having one of MYBPC3, MYH7, DSP, and TNNI3). All pathogenic or likely pathogenic variants were located in genes with definite evidence of a cardiomyopathy phenotype, either hypertrophic cardiomyopathy or arrhythmogenic right ventricular cardiomyopathy. Next-generation sequencing-based genetic testing identified pathogenic or likely pathogenic variants in 5.4% of patients initially diagnosed with IVF, suggesting that genetic testing with definite evidence genes of cardiomyopathy may enable molecular diagnosis in a minority of patients with IVF. Further clinical evaluation and follow-up of patients with IVF with positive genotypes are needed to unveil concealed phenotypes, such as the pre-clinical phase of cardiomyopathy.

From Death to Life/Back to the Future: Detailed Premorbid Clinical and Family History Can Save Lives and Address the Final Diagnosis in Sudden Unexplained Deaths With Negative Autopsy.

Sudden cardiac death is a sudden, unexpected death developed by one of the many different causes of cardiac arrest that occur within 1 hour of the onset of new symptoms. Sudden unexplained death (SUD) comprises a normal heart at postmortem examination and negative toxicological analysis. SUD often arises from cardiac genetic disease, particularly channelopathies. Channelopathies, or inherited arrhythmia syndromes, are a group of disorders characterized by an increased risk of sudden cardiac death, abnormal cardiac electrical function, and, typically, a structurally normal heart. They share an underlying genetic etiology where disease-causing genetic variants may lead to the absence or dysfunction of proteins involved in the generation and propagation of the cardiac action potential. Our study aimed to evaluate the importance of next-generation sequencing in the postmortem investigations of SUD cases. In this study, 5 forensic SUD cases were investigated for inherited cardiac disorders. We screened a total of 68 cardiac genes for the sibling of case 1, as well as case 2, and 51 genes for cases 3, 4, and 5. Of the 12 variants identified, 2 likely pathogenic variants (16.7%) were the TMEM43 _ c.1000+2T>C splice site mutation and the SCN5A _ p.W703X nonsense mutation. The remaining 10 variants of uncertain significance were detected in the TRPM4 , RANGRF , A KAP9 , KCND3 , KCNE1 , DSG2 , CASQ1 , and SNTA1 genes. Irrespective of genetic testing, all SUD families require detailed clinical testing to identify relatives who may be at risk. Molecular autopsy and detailed premorbid clinical and family histories can survive family members of SUD cases.

Novelties in Brugada Syndrome: Complex Genetics, Risk Stratification, and Catheter Ablation.

Brugada syndrome (BrS) is an inherited arrhythmia syndrome with distinctive electrocardiographic abnormalities in the right precordial leads and predisposes to ventricular arrhythmias and sudden cardiac death in otherwise healthy patients. Its complex genetic architecture and pathophysiological mechanism are not yet completely understood, and risk stratification remains challenging, particularly in patients at intermediate risk of arrhythmic events. Further understanding of its complex genetic architecture may help improving future risk stratification, and advances in management may contribute to alternatives to implantable cardioverter-defibrillators. Here, the authors review the latest insights and developments in BrS.

Catecholaminergic Polymorphic Ventricular Tachycardia: A Review of Therapeutic Strategies.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by bidirectional or polymorphic ventricular arrhythmia provoked by exercise or emotion. Most cases are caused by pathogenic variants in the gene encoding the cardiac ryanodine receptor (RYR2). The options for treating patients with CPVT have increased during the years, and evidence suggests that these have led to lower arrhythmic event rates. In addition, numerous potential new therapies are being investigated. In this review, we summarize the state of knowledge on both established and potential future treatment strategies for patients with CPVT and describe our approach to their management.

Abstract P3135: In Vivo Dissection Of CaMKII-Mediated Arrhythmias In CPVT

Background: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome of the structurally intact heart manifesting life-threatening bursts of ventricular tachycardias due to dominant gain-of-function mutations in the ryanodine receptor type 2 (RyR2) and β-adrenergic (β-AR) stimulation. Both protein kinase A (PKA) and Ca 2+ - calmodulin-dependent protein kinase II (CaMKII) can phosphorylate RyR2 channels, but only the latter can initiate the arrhythmogenic phenotype in CPVT. Whether through L-type Ca 2+ channel (LTCC)-mediated Ca 2+ increase or the Epac2-nitric oxide pathway, the exact mechanism by which β-AR-mediated CaMKII activation unmasks lethal arrhythmias in CPVT remains unresolved. Aim: To gain mechanistic insight and ablate ventricular arrhythmias in a mouse model of CPVT by selectively disrupting integral components of β-AR signaling. Methods: By utilizing either direct adeno-associated virus (AAV) delivery or the CRISPR/Cas9-AAV-based somatic mutagenesis (CASAAV) system, we selectively expressed a mutant LTCC β 2 -subunit, ablated the small GTPase Rad, or disrupted other components of the β-AR pathway in the hearts of mice with the pathogenic RyR2 mutation R4650I as a model of CPVT. The effects of disruption of LTCC regulation were determined by high-speed Ca 2+ imaging of isolated ventricular cardiomyocytes or whole animal electrophysiological (EP) testing for ventricular arrhythmia incidence in vivo . Results &amp; Conclusions: Our data demonstrate that abnormal RyR2-mediated calcium release events are induced by hyperactivated LTCCs in vitro , even in the absence of adrenergic stimulation, with increased arrhythmia incidence in vivo . These results suggest that β-AR stimulation leads to pathogenic RyR2 Ca 2+ leak through LTCC-mediated contribution to CaMKII hyperactivity. Alternative mechanisms of CaMKII activation that mediate arrhythmia induction in CPVT require additional future investigation.

Insights on the mechanism of flecainide in catecholaminergic polymorphic ventricular tachycardia.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmia syndrome characterized by defective cardiac ryanodine receptor (RyR2) calcium release during times of adrenergic stimulation, resulting in bidirectional or polymorphic ventricular tachycardia. Flecainide is a class 1c anti-arrhythmic drug that has demonstrated therapeutic efficacy in treating CPVT. However, its mechanism of action remains disputed. One group proposes a direct effect of flecainide on RyR2-mediated calcium release, while another proposes an indirect effect via sodium channel blockade and modulation of intracellular calcium dynamics. In light of recent studies, this commentary aims to explore and discuss the evidence base for these potential mechanisms.

Current gaps in knowledge in inherited arrhythmia syndromes.

The 3most common inherited arrhythmia syndromes-Brugada syndrome, congenital long QT syndrome and catecholaminergic polymorphic ventricular tachycardia-were initially described in the previous century. Since then, research has evolved, which has enabled us to identify patients prior to the onset of potentially life-threatening symptoms. However, there are significant gaps in knowledge that complicate clinical management of these patients today. With this review paper, we aim to highlight the most important knowledge gaps in clinical research of these inherited arrhythmia syndromes.

Value of next-generation sequencing in inherited arrhythmia syndromes

BackgroundGenetic studies are clinically recommended in some cases of inherited arrhythmia syndromes. Next-generation sequencing (NGS) would be helpful because of its high analytical throughput and relative speed. This study aimed to assess the mutation-detection yield obtained by NGS compared with conventional Sanger sequencing method.MethodsPatients with aborted sudden cardiac death and their families who underwent gene sequencing tests for inherited arrhythmia syndromes were retrospectively and enrolled in this study from 2017 to 2022 at Chonnam National University Hospital. We evaluated NGS study results of 17 patients (NGS group) and Sanger study results of 19 patients (Sanger group).Results64.7% of NGS and 94.7% of Sanger group were probands. Type 1 Brugada pattern ECG was more frequent in NGS group (64.7% vs. 21.1%; p = 0.007). BrS was the most common disorder in NGS group (76.5%), and idiopathic ventricular fibrillation was the most common one in Sanger group (63.2%). Mutations with uncertain significance were the most common ones in NGS group (89.5%), and pathogenic or likely pathogenic mutations were the most common ones in Sanger group (45.7%). When positive yield was defined as the ratio of pathogenic or likely pathogenic mutations that were detected by sequencing, the yields were 10.5% and 45.7% in NGS and Sanger groups, respectively. The NGS arrhythmia panel did not cover two inherited arrhythmia-related mutations (RYR1, APOA5) that were detected by the Sanger method. The extended NGS arrhythmia panel was able to detect 84.8% of inherited arrhythmia-related mutations that were detected in Sanger group.ConclusionsNGS study has some limitations in obtaining the full genetic data of probands. Well-designed NGS panels are needed to increase the efficiency of the NGS study. With the well-designed panels, large-scale gene sequencing can efficiently and rapidly be applied in real clinical practices, especially in inherited fatal arrhythmia syndromes that have a high detection yield in genetic analyses.

Fetal Heart Rate < 3rd Percentile for Gestational Age Can Be a Marker of Inherited Arrhythmia Syndromes.

Repeated fetal heart rates (FHR) < 3rd percentile for gestational age (GA) with 1:1 atrioventricular conduction (sinus bradycardia) can be a marker for long QT syndrome. We hypothesized that other inherited arrhythmia syndromes might present with fetal sinus bradycardia. We reviewed pregnancies referred with sinus bradycardia to the Colorado Fetal Care Center between 2013 and 2023. FHR/GA data, family history, medication exposure, normalized isovolumic contraction times (n-IVRT), postnatal genetic testing, and ECGs at 4-6 weeks after birth were reviewed. Twenty-nine bradycardic subjects were evaluated by fetal echocardiography. Five were lost to follow-up, one refused genetic testing, and one had negative genetic testing for any inherited arrhythmia. Six had non-genetic causes of fetal bradycardia with normal prenatal n-IVRT and postnatal QTc. Thirteen carried pathogenic variants in RYR2 (n = 2), HCN4 (n = 2), KCNQ1 (6), and other LQTS genes (n = 4). The postnatal QTc was <470 ms in subjects with RYR2, HCN4, and two of those with KCNQ1 mutations, and >470 ms in subjects with CALM 2, KCNH2, SCN5A, and four of those with KCNQ1 mutations. LQTS and RYR2 mutations were associated with prolonged n-IVRT, but HCN4 was not. Two fetuses died in utero with variants of uncertain significance (CACNA1 and KCNE1). Cascade testing uncovered six affected but undiagnosed parents and confirmed familial inheritance in five. In addition to heralding LQTS, repeated FHR < 3rd percentile for GA is a risk factor for other inherited arrhythmia syndromes. These findings suggest that genetic testing should be offered to infants with a history of FHR < 3rd percentile for GA even if the postnatal ECG demonstrates a normal QTc interval.

RYR2-ryanodinopathies: from calcium overload to calcium deficiency.

The sarcoplasmatic reticulum (SR) cardiac ryanodine receptor/calcium release channel RyR2 is an essential regulator of cardiac excitation-contraction coupling and intracellular calcium homeostasis. Mutations of the RYR2 are the cause of rare, potentially lethal inherited arrhythmia disorders. Catecholaminergic polymorphic ventricular tachycardia (CPVT) was first described more than 20 years ago and is the most common and most extensively studied cardiac ryanodinopathy. Over time, other distinct inherited arrhythmia syndromes have been related to abnormal RyR2 function. In addition to CPVT, there are at least two other distinct RYR2-ryanodinopathies that differ mechanistically and phenotypically from CPVT: RYR2 exon-3 deletion syndrome and the recently identified calcium release deficiency syndrome (CRDS). The pathophysiology of the different cardiac ryanodinopathies is characterized by complex mechanisms resulting in excessive spontaneous SR calcium release or SR calcium release deficiency. While the vast majority of CPVT cases are related to gain-of-function variants of the RyR2 protein, the recently identified CRDS is linked to RyR2 loss-of-function variants. The increasing number of these cardiac 'ryanodinopathies' reflects the complexity of RYR2-related cardiogenetic disorders and represents an ongoing challenge for clinicians. This state-of-the-art review summarizes our contemporary understanding of RYR2-related inherited arrhythmia disorders and provides a systematic and comprehensive description of the distinct cardiac ryanodinopathies discussing clinical aspects and molecular insights. Accurate identification of the underlying type of cardiac ryanodinopathy is essential for the clinical management of affected patients and their families.

Genome Editing and Cardiac Arrhythmias

This article reviews progress in the field of cardiac genome editing, in particular, its potential utility in treating cardiac arrhythmias. First, we discuss genome editing methods by which DNA can be disrupted, inserted, deleted, or corrected in cardiomyocytes. Second, we provide an overview of in vivo genome editing in preclinical models of heritable and acquired arrhythmias. Third, we discuss recent advancements in cardiac gene transfer, including delivery methods, gene expression optimization, and potential adverse effects associated with therapeutic somatic genome editing. While genome editing for cardiac arrhythmias is still in its infancy, this approach holds great promise, especially for inherited arrhythmia syndromes with a defined genetic defect.