Short QT Research Articles

Ivabradine - Evolving Role as an Anti-arrhythmic Agent.

Ivabradine - Evolving Role as an Anti-arrhythmic Agent.

Demographics, Clinical Features and Genetics of Common Inherited Arrhythmias in Oman.

Inherited arrhythmia syndromes (IAS) are a group of rare disorders that result from genetic mutations in several genes including congenital long QT syndrome, Brugada syndrome (BrS), short QT syndrome, and Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT). Affected individuals may have various symptoms including sudden cardiac death (SCD). Few reports have highlighted long QT syndrome from the Arbian Gulf region. The current study aims to describe demographics of children and adults with inherited arrhythmia syndromes; report the presenting clinical features, genetic mutations and management strategies. This is a descriptive retrospective study that included Omani children and adults with inherited arrhythmia syndromes who were diagnosed and treated at the National Heart Centre (NHC) of the Royal Hospital, between 2006 and 2022. Data collected include patient demographics, geographical distribution, clinical features, genetic reports and management strategies. A total of one hundred and six Omani patients were included. Sixty-six (62.3 %) were males, and 71 (67 %) were adults at diagnosis and 35 (33 %) were children. Three inherited arrhythmia syndromes were found including Long QT, Brugada and catecholaminergic polymorphic ventricular tachycardia (CPVT) and these accounted for 58 (54.7 %), 39 (36.8 %) and 9 (8.5 %), respectively. Seventy-six (71.7 %) of the patients were from consanguineous families. The clinical features varied based on the type of arrhythmia. The treatment modalities constituted of beta blockers and antiarrhythmics, implantable cardioverter defibrillators (ICDs), pacemakers, and left sympathetic ganglionectomy (LSGs). Seventy-one individuals (66.9 %) underwent genetic testing. It is important to highlight that 36 (50.7 %) individuals were with pathogenic or likely pathogenic variants and 13 (18.3 %) individuals were with variants of uncertain significance (VUS) in different IAS related genes. The current study is the first comprehensive study on the inherited arrhythmia syndromes in Oman and the Arabian Gulf countries. It provides insight about the demographic, clinical and genetic profile of the most common IAS in the region, hence helping in early detection of different types of IAS types and prevention of sudden cardiac death in patients and their relatives. Continuous research efforts in the genetic and cellular mechanisms underlying these disorders will help to identify potential targets for improved disease-specific treatments.

Sudden cardiac death. Review. Part I. Risk assessment, primary and secondary prevention in various clinical conditions

One of the most acute problems of modern cardiology is the problem of sudden cardiac death. This review provides a definition of sudden cardiac death, considers the pathogenetic mechanisms of its development, and presents the frequency of sudden cardiac death in different age groups and in different nosological conditions. Particular attention is paid to the problem of stratification of the risk of sudden cardiac death, as well as the issues of primary and secondary prevention of ventricular arrhythmias. It is shown that ventricular arrhythmias are among the main and most common causes of sudden cardiac death in various clinical conditions. The review provides detailed data on the etiological factors of sudden cardiac mortality, which can be divided into two groups. The first group of etiological factors of sudden cardiac death consists of diseases characterized by the presence of specific structural changes in the heart — ischemic heart disease, idiopathic ventricular extrasystole/ventricular tachycardia, cardiomyopathies, including those caused by ventricular extrasystole, inflammatory heart diseases and heart defects. The second group consists of diseases related to primary electrical heart disease, namely idiopathic ventricular fibrillation, long QT syndrome (including acquired long QT syndrome), Andersen‑Tavil syndrome type 1, Brugada syndrome, early repolarization syndrome, catecholaminergic polymorphic ventricular tachycardia and short QT syndrome. Part I of this review discusses in detail the etiological factors of sudden cardiac death, which belong to the first group. At the same time, it is shown that the most common cause of sudden cardiac death is ischemic heart disease. Also, this part of the review presents the most informative methods for assessing the risk of sudden cardiac death and measures for primary and secondary prevention of this terminal condition in patients with various structural heart diseases.

Analysis of Electrocardiogram Changes in in COPD Patients and Controls in the Shahrekord City: A Cohort Study Population in 2020

<i>Background:</i> Chronic Obstructive Pulmonary Disease (COPD) is one of the most prevalent and rapidly growing health problems worldwide. It is a progressive disease characterized by limited or obstructed airflow that is irreversible. "COPD is primarily caused by an excessive inflammatory response to inhaled pollutants and irritants, and is often characterized by a chronic cough, with or without mucus production. Chronic bronchitis and emphysema are the two conditions that comprise COPD, and they are not always precisely distinguishable. Due to the high prevalence of COPD among the elderly population, extensive studies have reported various electrocardiogram (ECG) changes in these patients. Examples include alterations in the axis and height of the P wave and a decrease in the height of the QRS complex in limb and precordial leads. Although not all COPD patients undergo routine ECG evaluations, the occurrence of various arrhythmias remains one of the significant and preventable causes of death in this population. Multiple factors, such as impaired autonomic control of cardiac and pulmonary function, may contribute to the development of arrhythmias in COPD patients. <i>Method:</i> A total of 86 individuals diagnosed with COPD were selected through census sampling and considered the case group. For the control group, twice the number of participants (individuals without any obstructive pulmonary disease) were selected from the cohort population. Information on COPD patients were confirmed via spirometry, and their ECGs were analyzed for arrhythmias and abnormal changes.". These included alterations in wave axes, lengthening or shortening of waves, changes in the R wave, and other deviations from the normal ECG pattern. The collected data were then analyzed and compared using statistical tests.<i> Findings:</i> This study included 85 COPD patients and 168 healthy individuals as the control group, comprising a total of 253 participants. The mean age of the study population was 50.8 years, with 54% of the participants being female and 45% of the COPD patients being male. Significant ECG changes observed in COPD patients compared to the control group included weak progression of the R wave, atrial abnormalities (right atrial enlargement [RAE] and left atrial enlargement [LAE]), right ventricular hypertrophy (RVH), decreased QRS duration, and a short QT interval (<i>P-value < 0.05</i>). <i>Conclusion:</i> The observed ECG changes, such as weak R wave progression and atrial abnormalities, emphasize the importance of ECG as a non-invasive diagnostic tool for identifying cardiovascular complications in COPD patients. This highlights the need for regular cardiac monitoring in these individuals. Since certain cardiac complications in COPD patients are preventable or manageable, regular examinations such as ECG and echocardiography are recommended.

Autoimmune cardiac channelopathies and heart rhythm disorders: A contemporary review.

Cardiac arrhythmias still represent a major health problem worldwide, at least in part because the fundamental pathogenic mechanisms are not fully understood, thus affecting the efficacy of therapeutic measures. In fact, whereas cardiac arrhythmias are in most cases due to structural heart diseases, the underlying cause remains elusive in a significant number of patients despite intensive investigations even including postmortem examination and molecular autopsy. A large body of data progressively accumulated during the last decade provides strong evidence that autoimmune mechanisms may be involved in a significant number of such unexplained or poorly explained cardiac arrhythmias. Several proarrhythmic anti-cardiac ion channel autoantibodies have been discovered, in all cases able to directly interfere with the electrophysiologic properties of the heart but leading to different arrhythmic phenotypes, including long QT syndrome, short QT syndrome, and atrioventricular block. These autoantibodies, which may develop independent of a history of autoimmune diseases, could help explain a percentage of arrhythmic events of unknown origin, thereby opening new frontiers for diagnosis and treatment of heart rhythm disorders. Based on this evidence, the novel term autoimmune cardiac channelopathies was coined in 2017. Since then, the interest in the field of cardioimmunology has shown a tumultuous growth, so much so that the number of arrhythmogenic anti-ion channel autoantibodies reported has significantly increased, also in association with not previously described arrhythmic phenotypes, such as atrial fibrillation, Brugada syndrome, and ventricular fibrillation/cardiac arrest. Thus, an updated reassessment of this topic, also highlighting perspectives and unmet needs, has become necessary and represents the main objective of this review.

Characterization of static and dynamic depolarization and repolarization characteristics in the short-QT syndrome

Characterization of static and dynamic depolarization and repolarization characteristics in the short-QT syndrome

ATrial arrhythmias in inhEriTed aRrhythmIa Syndromes: results from the TETRIS study

aTrial arrhythmias in inhEriTed aRrhythmIa Syndromes: results from the TETRIS study

Genetic mapping of electrocardiographic parameters in BXD strains reveals Chromosome 3 loci to be associated with cardiac repolarization abnormalities.

Risk factors for cardiac arrhythmias that can cause sudden death and heart failure include genetics, age, lifestyle, and other environmental factors. The study assessed electrocardiography (ECG) traits in BXD mice and explored associated quantitative trait loci (QTLs). Five-minute electrocardiograms were recorded in 44 BXD strains at 4-5 mo of age (n ≥ 5 mice/sex/strain). ECG and arrhythmia traits were associated with echocardiography, blood pressure, genome, and heart transcriptome data followed by expression QTL mapping. A significant variability in ECG parameters and arrhythmias was recorded among BXDs. Among male BXDs, QRS duration was significantly associated with increased left ventricular internal diameter (LVID) and reduced ejection fraction and fractional shortening, whereas premature ventricular contractions (PVCs) were correlated with LVID, left ventricular (LV) volumes, and pulmonary vein peak pressure. In female BXDs, PVCs and premature atrial contractions (PACs) were significantly related with right ventricular ID and cardiac output. One significant QTL associated with QTc and JT durations was identified on Chromosome (Chr) 3 in male BXDs, whereas Chr 9 locus was suggestive for association with QTc and QT intervals in female mice. Gon4l was predicted as a strong candidate gene associated with repolarization abnormalities including short or long QT syndromes in humans. Study results suggested an influence of genetic background on expression of ECG parameters and arrhythmias based on significant variations of those traits between mouse strains of the BXD family. We conclude that murine BXD family can serve as a valuable reference for systems biology and comparative predictions of arrhythmia disorders.NEW & NOTEWORTHY Our study identified significant variances in ECG phenotypes and arrhythmias segregation in BXD mice. A significant quantitative trait locus (QTL) on Chromosome (Chr) 3 in the mouse genome was associated with increased QTc and JT intervals in male BXD mice. A suggestive QTL on Chr 9 associated with QT and QTc intervals was determined in female BXD mice. We identified a strong candidate gene, Gon4l, that may underlie cardiac repolarization abnormalities such as long and short QT syndromes.

Congenital Short QT Syndrome - Review Focused on KCNQ1 p.Val141Met Variant.

Short QT syndrome (SQTS) is a very rare inherited arrhythmia characterized by extremely short QT intervals on electrocardiograms and sudden cardiac death in young patients. Among the genotypes of SQTS, gain-of-function variants in the potassium voltage-gated channel subfamily Q member 1 (KCNQ1) gene are accountable for SQTS type 2 (SQT2). Pathogenic variants for SQT2 are rare and, among them, the p.Val141Met is relatively prevalent. This review summarizes findings for 5 SQTS patients harboring p.Val141Met we recently encountered and compares them to another 14 patients reported in the literature.

Short QT Syndrome and Drug Treatment: A systematic Literature Review and PRISMA Analysis

Short QT Syndrome (SQTS) is a rare inherited myocardial ion channel disease characterized by abbreviated cardiac repolarization and shortened QT interval in ECGs, resulting to a high incidence of sudden death and malignant arrhythmias. While various gene mutations that encode subunits of K+, Ca2+, and Na+ channels, as well as the SLC4A3 gene mutation associated with plasma membrane anion exchange, have been implicated, targeted gene screening remains relatively low. In this review, we searched multiple databases, such as PubMed, ScienceDirect, Embase, Web of Science, and Medline, and followed the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) to conduct a systematic review of literatures in SQTS. We first used VOSviewer to analyze the co-authorship, co-occurrence of countries, organizations, authors, and keywords in the published literatures of SQTs, and then surveyed evidences regarding the impact of single or polygenic gene mutations identified is SQT patients on the electrophysiological properties of IKr, IKs, IK1, ICa-L, INa, and the anion exchanger AE3. Additionally, this review also surveyed current progress in the understandings of potential mechanisms underlying arrhythmogenesis of the SQT gene mutations, and possible drug therapy, unraveled by both experimental and simulation studies.

Genetic mapping of electrocardiographic values in a genetic reference population of BXD mice uncovers distinct loci regulating cardiac repolarization in males and females

Introduction: Heart rhythm disorders or cardiac arrhythmias can cause sudden death and heart failure. Risk factors for cardiac arrhythmias include genetics, sex, age, environment, diet, and other factors. Objectives: To determine the underlying sex and genetic background relations in expression of cardiac rhythm phenotypes, we assessed electrocardiography (ECG) traits in the BXD family of recombinant inbred (RI) mice and explored a quantitative genetic architecture of those traits. Methods: The results of five-minute surface ECG recording in 44 BXD strains (N>5 mice/sex/strain/4-5-month-old) were associated with blood pressure (BP), echocardiography (ECHO), genome and heart transcriptome values followed by quantitative trait loci (QTLs) mapping. Results: Significant variabilities in heart rate (HR), ECG, BP and ECHO parameters were recorded among male and female BXD strains. Correlation analysis identified a significantassociation between QRS duration and increased left ventricular internal diameter (LVID), reduced ejection fraction (EF%) and fractional shortening (FS%). Varied arrhythmias [bradycardia, atrioventricular block, premature atrial/ventricular complexes (PAC/PVC), ventricular tachycardia and sick sinus syndrome] were recorded among BXDs. Both PACs and PVCs were significantly associated with cardiac function and BP burden. While systolic BP values were significantly correlated with the frequency of PVCs in both male and female mice, the correlation was opposite with a negative association in female mice, while male mice showed positive association. Frequent PVCs and PACs were significantly correlated with right ventricular internal diameter (RVID) and cardiac output in female mice. Among male BXDs, frequency of PVCs was significantly (p<0.05) correlated with LVID, LV volumes, pulmonary vein peak pressure, and prolonged QT, QTc and JT intervals. A high variability in QTc and JT intervals were genetically regulated (P≤0.03) among male and female mice, while no underlying sex basis was determined. Further genetic mapping identified a significant QTL on murine Chromosome (Chr) 3 associated with QTc and JT durations in male BXDs, while the Chr 9 locus was suggestive for association with QTc and QT durations in females. A candidate gene, Gon4l, was predicted to be associated with repolarization abnormalities such as long or short QT syndromes in males. Conclusions: The study identified varied associations of ECG, BP, and ECHO traits between BXD strains and sexes. Significant differences in arrhythmia-induced phenotype burden between female and male mice from the same BXD strain indicates the sex-dependent outcomes of rhythm disturbances on expression of BP, cardiac morphology (LVID, RVID, and volumes) and function (EF% and FS%) phenotypes. We conclude that the BXD family of RI mice can serve as an invaluable preclinical tool for comparative prediction and systems genetics studies for cardiac rhythm and repolarization disorders in humans. R01 HL128350 (LL) R01 HL151438 (JAT, LL, EP) This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

A Gain-of -Function SLC4A3 Mutation Causes Short-QT Syndrome: From Molecular Analysis to Novel Diagnostic Testing.

A Gain-of -Function SLC4A3 Mutation Causes Short-QT Syndrome: From Molecular Analysis to Novel Diagnostic Testing.

Atomic-level investigation of KCNJ2 mutations associated with ventricular arrhythmic syndrome phenotypes

KCNJ2 encodes the inward rectifying potassium channel (Kir2.1) that underlies IK1 which maintains the cardiac resting membrane potential and regulates excitability. Mutations in KCNJ2 have been linked to several clinical phenotypes associated with life-threatening ventricular arrhythmia and sudden death including Andersen-Tawil syndrome (ATS) from loss of function mutations, and Short QT Syndrome 3 from gain of function mutations. Detailed structural-functional relationships to explain the arrhythmia phenotypes are understudied and limit the capacity to provide precision medicine. Here, we combine in-depth and complementary computational molecular modeling techniques with functional analysis from three patients with ATS that harbor KCNJ2 mutations R67Q, R218L, and G300D. Whole-cell patch-clamp experiments revealed loss of function in homomeric mutant channels. Full-length Kir2.1 models were developed for structure-based investigation, and mutations were introduced in both open and closed conformations. Site-directed mutagenesis identified altered interaction profiles contributing to structural perturbations. Molecular dynamics simulations assessed the impact of each mutation on overall channel conformation and stability. Principal component analysis and normal mode analysis revealed mutation-specific structural perturbations. The findings afford atomic mechanistic underpinnings of mutation-specific perturbations. Our multifaceted approach provides first atomic-level insights into the molecular mechanisms underlying ATS, paving the way for structure-guided targeted therapeutic strategies for ATS and related channelopathies.

A novel <i>SCN5A </i>variant causing Brugada syndrome: a case of Slovenian family

Brugada syndrome is an inherited cardiac channelopathy with pathognomonic early repolarization alteration (Brugada sign) and is associated with a high risk for sudden death from ventricular fibrillation (VF). Documented ventricular arrhythmic events, sudden unexpected death in family members, accurate evaluation of Brugada signs and arrhythmic syncope, and genotyping of SCN5A for cardiac fast sodium channel Nav1.5, are the most important steps in diagnostic and prognostic evaluation. Treatment with quinidine and the recently introduced catheter ablation procedure are important methods for reducing the high burden of ventricular arrhythmias. However, the decision of whether to implant a cardioverter defibrillator to prevent sudden cardiac death is essential.We present a case of a patient and his family with a novel heterozygotic variant in exon 15 of the gene SCN5A(NM_000335.5):c.2271del, p.(Ile759PhefsTer6), associated with cardiac arrest because of VF during intensive physical effort, with mild structural heart disease, and a short QT. We discuss current guidelines for optimal management of patients with suspected Brugada syndrome.

PO-05-104 A TMEM175 VARIANT CAUSING IKATP ACTIVATION BY DISRUPTING LYSOSOMAL-TO-MITOCHONDRIAL INTERACTION IS A NOVEL GENETIC CAUSE OF SHORT QT SYNDROME

PO-05-104 A TMEM175 VARIANT CAUSING IKATP ACTIVATION BY DISRUPTING LYSOSOMAL-TO-MITOCHONDRIAL INTERACTION IS A NOVEL GENETIC CAUSE OF SHORT QT SYNDROME

BS-495073-003 KCNH2 SUPPRESSION-REPLACEMENT GENE THERAPY FOR TYPE 1 SHORT QT SYNDROME (SQT1): A PROOF-OF-CONCEPT EFFICACY TRIAL IN RABBITS WITH SQT1

BS-495073-003 KCNH2 SUPPRESSION-REPLACEMENT GENE THERAPY FOR TYPE 1 SHORT QT SYNDROME (SQT1): A PROOF-OF-CONCEPT EFFICACY TRIAL IN RABBITS WITH SQT1

Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval.

Generation of human induced pluripotent stem cell (hiPSC) lines from patients with extreme high and low polygenic scores for QT interval.

The Uncommon Phenomenon of Short QT Syndrome: A Scoping Review of the Literature.

Background: Short QT syndrome (SQTS) is a rare inheritable channelopathy characterized by a shortened corrected QT interval on an electrocardiogram and a significant risk of atrial and ventricular arrhythmias, potentially leading to sudden cardiac death. Despite advancements in our understanding of SQTS, knowledge gaps persist due to its extreme rarity. This scoping review aims to summarize the available knowledge on its clinical presentations, genetic mutations, and management strategies, while identifying areas for further investigation. Methods: This scoping review was conducted across the PubMed, Scopus, and Cochrane databases and identified relevant case reports, case series, and available studies on SQTS. We focused on articles that reported clinical outcomes, genetic mutations, diagnostic criteria, and management strategies, while excluding studies on the secondary causes of short QT intervals. Results: SQTS is present across a wide age range, from asymptomatic individuals to those experiencing syncope, palpitations, or sudden cardiac arrest. Common genetic mutations include KCNQ1, KCNH2, and KCNJ2. Management strategies vary, with some patients receiving implantable cardioverter defibrillators for secondary prevention and others treated pharmacologically, primarily with hydroquinidine. Our findings highlight the rarity and clinical variability of SQTS, underscoring the need for optimized diagnostic criteria and individualized management strategies. Conclusions: This review emphasizes the need for continued research to better understand the genetic basis of SQTS, optimize diagnostic tools, and improve treatment approaches. Large-scale studies and the integration of genetic and clinical data are critical to addressing the gaps in SQTS management and improving outcomes for patients with this potentially life-threatening arrhythmic disorder.

Clinical heterogeneity in a family with pathogenic variant in the KCNQ1 gene: Dilated cardiomyopathy and Long QT Syndrome

IntroductionDilated cardiomyopathy (DCM) is mainly associated with pathogenic variants in genes encoding sarcomeric proteins, Z-disk/cytoskeleton proteins, or intercalated disk proteins. In a few cases, mutations in the SCN5A gene are involved (MIM# 601154). KCNQ1 gene (MIM* 607542) encodes a potassium channel and is not a gene classically associated with forms of DCM. Heterozygous pathogenic variants in this gene, at cardiac level, are mainly responsible for Long QT Syndrome type 1 (LQTS1, MIM# 192500), but are also associated with Short QT Syndrome (SQT2, MIM# 609621) and Atrial Fibrillation Family 3 (ATFB3, MIM# 607554).In this study, we report a family with a heterozygous pathogenic variant NM_000218.3:c.1637C>T;(p.Ser546Leu) in the KCNQ1 gene and a different phenotypic expression in three generations (Figure 1). At the age of 73, the proband presents a diagnosis of dilated cardiomyopathy, with ICD implantation in secondary prevention, diagnosed with Echocardiogram and cardiac MRI (Figure 2). The daughter is clinically healthy, and the daughter's son has Long QT Syndrome diagnosed after birth and detection of the pathogenic variant.MethodsGenomic DNA of the proband was extracted from peripheral blood using EZ1 Advanced XL (Qiagen), according to the manufacturer's instructions. After Qubit 2.0 quantification, Next Generation Sequencing was performed (Ion Torrent S5 and Ion Chef System) analyzying a panel of genes associated with dilated and arrhythmogenic cardiomyopathy designed by Ion Ampliseq Designer (Thermo Fisher Scientific). Results were analyzed with Ion reporter and Integrated Genome Viewer (IGV).ResultsThe genetic test did not detect the presence of pathogenic variants in causative genes associated with dilated/arrhythmogenic cardiomyopathy, however it did detect incidentally the heterozygous presence of the familial missense variant in the KCNQ1 gene: NM_000218.3:c.1637C>T;(p.Ser546Leu).ConclusionIn literature, a case with a loss of function in the KCNQ1 gene and an overlapping phenotype of DCM, ventricular tachycardia and QT interval prolongation has been reported (1). The phenotypic spectrum of KCNQ1 mutations appears to expand beyond the arrhythmia syndromes known to date. Another study also disclosed a KCNQ1 variant in a 5-year-old girl with cardiac arrest, left ventricular non-compaction syndrome, cardiac hypertrophy and myocardial fibrosis (2).Clinical impactOur work aims to focus more attention on the pathogenic variants in the KCNQ1 gene and the possible association with dilated cardiomyopathy to collect more case studies and study whether some forms of DCM can be associated with pathogenic variants in the KCNQ1 gene.Figure 1To the left: CMR of the proband, on the post contrast image (short axis view, at basal level) the area of LGE is found with a transmural pattern in the anterior septal segment. CMR, cardiac magnetic resonance; DCM, dilated cardiomyopathy; LGE, late gadolinium enhancement. To the right: in this short axis view, at medial level, the area of LGE is present in the mid-wall layer of the anterior and inferior septal segments. Courtesy of Medical Genetic Unit Policlinico Tor Vergata.Figure 2The family tree of our proband. DCM, dilatative cardiomyopathy. Courtesy of Prof. Calò, Policlinico Casilino.1) Xiong Q, Cao Q, Zhou Q, Xie J, Shen Y, Wan R, Yu J, Yan S, Marian AJ, Hong K. Arrhythmogenic cardiomyopathy in a patient with a rare loss-of-function KCNQ1 mutation. J Am Heart Assoc. 2015 Jan 23;4(1):e001526. doi: 10.1161/JAHA.114.001526. PMID: 256169762) Nakashima L. et al. A left ventricular noncompaction in a patient with long QT syndrome caused by a KCNQ1 mutation: A case report. 2013. doi: 10.1007/s00380-012-0235-8

Genetic Background and Clinical Phenotype in an Italian Cohort with Inherited Arrhythmia Syndromes and Arrhythmogenic Cardiomyopathy (ACM): A Whole-Exome Sequencing Study.

Inherited arrhythmia syndromes include several different diseases, as well as Brugada syndrome (BrS), long QT syndrome (LQTS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and short QT syndrome (SQTS). They represent, together with arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C), an important cause of sudden cardiac death in the young. Most arrhythmia syndromes are inherited in an autosomal dominant manner, and genetic studies are suggested.: to report the spectrum of genetic variations and clinical phenotype in an Italian cohort with confirmed inherited arrhythmia syndromes and arrhythmogenic cardiomyopathy using whole-exome sequencing (WES). Patients with confirmed inherited arrhythmia syndromes and hereditary cardiomyopathy were recruited at the Cardiology Unit, University Polyclinic Hospital of Foggia, Italy and were included in this study. Genomic DNA samples were extracted from peripheral blood and conducted for WES. The variants were annotated using BaseSpace Variant Interpreter Annotation Engine 3.15.0.0 (Illumina). Reported variants were investigated using ClinVar, VarSome Franklin and a literature review. They were categorised agreeing to the criteria of the American College of Medical Genetics and Genomics. Overall, 62 patients were enrolled. Most of them had a clinical diagnosis of BrS (n 48, 77%). The remaining patients included in the present study had diagnosis of confirmed LQT (n 7, 11%), AR-DCM (n 4, 6.5%), ARVD (n 2, 3%), and SQT (n 1, 1.6%). Using the WES technique, 22 variants in 15 genes associated with Brugada syndrome were identified in 21 patients (34%). Among these, the SCN5A gene had the highest number of variants (6 variants, 27%), followed by KCNJ5 and CASQ2 (2 variants). Only one variant was identified in the remaining genes. In 27 patients with a clinical diagnosis of BrS, no gene variant was detected. In patients with confirmed LQT, SQT, 10 variants in 9 genes were identified. Among patients with ARVD and AR-DCM, 6 variants in 5 genes were found. Variants found in our cohort were classified as pathogenic (6), likely pathogenic (3), of uncertain significance (26), and benign (1). Two additional gene variants were classified as risk factors. In this study, 13 novel genetic variations were recognized to be associated with inherited arrhythmogenic cardiomyopathies. Our understanding of inherited arrhythmia syndromes continues to progress. The era of next-generation sequencing has advanced quickly, given new genetic evidence including pathogenicity, background genetic noise, and increased discovery of variants of uncertain significance. Although NGS study has some limits in finding the full genetic data of probands, large-scale gene sequencing can promptly be applied in real clinical practices, especially in inherited and possibly fatal arrhythmia syndromes.