Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

Importance of genetic testing in unexplained cardiac arrest.

AIMS: Genetic testing is recommended in specific inherited heart diseases but its role remains unclear and it is not currently recommended in unexplained cardiac arrest (UCA). We sought to assess the yield and clinical utility of genetic testing in UCA using whole-exome sequencing (WES). METHODS AND RESULTS: Survivors of UCA requiring external defibrillation were included from the Cardiac Arrest Survivor with Preserved Ejection fraction Registry. Whole-exome sequencing was performed, followed by assessment of rare variants in previously reported cardiovascular disease genes. A total of 228 UCA survivors (mean age at arrest 39 ± 13 years) were included. The majority were males (66%) and of European ancestry (81%). Following advanced clinical testing at baseline, the likely aetiology of cardiac arrest was determined in 21/228 (9%) cases. Whole-exome sequencing identified a pathogenic or likely pathogenic (P/LP) variant in 23/228 (10%) of UCA survivors overall, increasing the proportion of 'explained' cases from 9% only following phenotyping to 18% when combining phenotyping with WES. Notably, 13 (57%) of the 23 P/LP variants identified were located in genes associated with cardiomyopathy, in the absence of a diagnosis of cardiomyopathy at the time of arrest. CONCLUSIONS: Genetic testing identifies a disease-causing variant in 10% of apparent UCA survivors. The majority of disease-causing variants was located in cardiomyopathy-associated genes, highlighting the arrhythmogenic potential of such variants in the absence of an overt cardiomyopathy diagnosis. The present study supports the use of genetic testing including assessment of arrhythmia and cardiomyopathy genes in survivors of UCA.

Arrhythmic risk prediction in arrhythmogenic right ventricular cardiomyopathy: external validation of the arrhythmogenic right ventricular cardiomyopathy risk calculator.

AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) causes ventricular arrhythmias (VAs) and sudden cardiac death (SCD). In 2019, a risk prediction model that estimates the 5-year risk of incident VAs in ARVC was developed (ARVCrisk.com). This study aimed to externally validate this prediction model in a large international multicentre cohort and to compare its performance with the risk factor approach recommended for implantable cardioverter-defibrillator (ICD) use by published guidelines and expert consensus. METHODS AND RESULTS: In a retrospective cohort of 429 individuals from 29 centres in North America and Europe, 103 (24%) experienced sustained VA during a median follow-up of 5.02 (2.05-7.90) years following diagnosis of ARVC. External validation yielded good discrimination [C-index of 0.70 (95% confidence interval-CI 0.65-0.75)] and calibration slope of 1.01 (95% CI 0.99-1.03). Compared with the three published consensus-based decision algorithms for ICD use in ARVC (Heart Rhythm Society consensus on arrhythmogenic cardiomyopathy, International Task Force consensus statement on the treatment of ARVC, and American Heart Association guidelines for VA and SCD), the risk calculator performed better with a superior net clinical benefit below risk threshold of 35%. CONCLUSION: Using a large independent cohort of patients, this study shows that the ARVC risk model provides good prognostic information and outperforms other published decision algorithms for ICD use. These findings support the use of the model to facilitate shared decision making regarding ICD implantation in the primary prevention of SCD in ARVC.

The effect of revascularization on mortality and risk of ventricular arrhythmia in patients with ischemic cardiomyopathy.

BACKGROUND: There is clear evidence that patients with prior myocardial infarction and a reduced ejection fraction benefit from implantation of a cardioverter-defibrillator (ICD). It is unclear whether this benefit is altered by whether or not revascularization is performed prior to ICD implantation. METHODS: This was a retrospective cohort study following patients who underwent ICD implantation from 2002 to 2014. Patients with ischemic cardiomyopathy and either primary or secondary prevention ICDs were selected for inclusion. Using the electronic medical record, cardiac catheterization data, revascularization status (percutaneous coronary intervention or coronary bypass surgery) were recorded. The outcomes were mortality and ventricular arrhythmia. RESULTS: There were 606 patients included in the analysis. The mean age was 66.3 ± 10.1 years, 11.9% were women, and the mean LVEF was 30.5 ± 12.0, 58.9% had a primary indication for ICD, 82.0% of the cohort had undergone coronary catheterization prior to ICD implantation. In the overall cohort, there were fewer mortality and ventricular arrhythmia events in patients who had undergone prior revascularization. In patients who had an ICD for secondary prevention, revascularization was associated with a decrease in mortality (HR 0.46, 95% CI (0.24, 0.85) p = 0.015), and a trend towards fewer ventricular arrhythmia (HR 0.62, 95% CI (0.38, 1.00) p = 0.051). There was no association between death or ventricular arrhythmia with revascularization in patients with primary prevention ICDs. CONCLUSION: Revascularization may be beneficial in preventing recurrent ventricular arrhythmia, and should be considered as adjunctive therapy to ICD implantation to improve cardiovascular outcomes.

Clinical utility of endomyocardial biopsies in the diagnosis of arrhythmogenic right ventricular cardiomyopathy in children.

BACKGROUND: Histomorphometry of endomyocardial biopsies is one component of arrhythmogenic right ventricular cardiomyopathy (ARVC) diagnosis, although there is a need for stricter diagnostic criteria for this disease in pediatrics. The clinical utility of biopsy analysis as a component of ARVC diagnosis was evaluated in pediatric patients. METHODS: Histomorphometric analysis of fibrofatty infiltrate was completed on pediatric right ventricular endomyocardial biopsy samples. Myocardial replacement by fat and fibrosis was quantified. ARVC diagnosis was established using the 2010 ARVC Task Force criteria, with the biopsy measures compared across various ARVC diagnoses (definite, borderline, possible, or no ARVC). Receiver-operating characteristic (ROC) curve analysis was also completed using biopsy measures. RESULTS: The greatest proportion of fat, fibrosis, and myocardial replacement was in the definite ARVC cohort, and was significantly larger than for the other diagnosis cohorts. ROC curve analysis (with the biopsy analysis removed from the diagnostic classification) produced cutoff values of 15 and 25% myocardial replacement, which is lower than current adult diagnosis criteria. CONCLUSION: We propose modifications in pediatric major and minor biopsy diagnosis criteria to allow for improved sensitivity. This study suggests that biopsy analysis in children is most significant for subjects with a more severe disease presentation.

2024 HRS expert consensus statement on arrhythmias in the athlete: Evaluation, treatment, and return to play.

Youth and adult participation in sports continues to increase, and athletes may be diagnosed with potentially arrhythmogenic cardiac conditions. This international multidisciplinary document is intended to guide electrophysiologists, sports cardiologists, and associated health care team members in the diagnosis, treatment, and management of arrhythmic conditions in the athlete with the goal of facilitating return to sport and avoiding the harm caused by restriction. Expert, disease-specific risk assessment in the context of athlete symptoms and diagnoses is emphasized throughout the document. After appropriate risk assessment, management of arrhythmias geared toward return to play when possible is addressed. Other topics include shared decision-making and emergency action planning. The goal of this document is to provide evidence-based recommendations impacting all areas in the care of athletes with arrhythmic conditions. Areas in need of further study are also discussed.

Personalized Care in Long QT Syndrome: Better Management, More Sports, and Fewer Devices.

Long QT Syndrome (LQTS) is a potentially life-threatening yet highly treatable inherited cardiac channelopathy. When evaluating these patients, it is important to consider patient-specific as well as genotype-specific factors in order to adequately encompass the many nuances to care that exist in its management. The tendency to follow a "one-size-fits-all" approach needs to be replaced by treatment strategies that embrace the unique considerations of the individual patient in the context of their genotype. Herein, the authors aim to review the spectrum of LQTS, including the considerations when tailoring a personalized, genotype-tailored treatment program for a patient's LQTS.

Phenotypes of Overdiagnosed Long QT Syndrome.

BACKGROUND: Long QT syndrome (LQTS) predisposes individuals to arrhythmic syncope or seizure, sudden cardiac arrest, or sudden cardiac death (SCD). Increased physician and public awareness of LQTS-associated warning signs and an increase in electrocardiographic screening programs may contribute to overdiagnosis of LQTS. OBJECTIVES: This study sought to identify the diagnostic miscues underlying the continued overdiagnosis of LQTS. METHODS: Electronic medical records were reviewed for patients who arrived with an outside diagnosis of LQTS but were dismissed as having normal findings subsequently. Data were abstracted for details on referral, clinical history, and both cardiologic and genetic test results. RESULTS: Overall, 290 of 1,841 (16%) patients with original diagnosis of LQTS (174 [60%] female; mean age at first Mayo Clinic evaluation, 22 ± 14 years; mean QTc interval, 427 ± 25 milliseconds) were dismissed as having normal findings. The main cause of LQTS misdiagnosis or overdiagnosis was a prolonged QTc interval secondary to vasovagal syncope (n = 87; 30%), followed by a seemingly positive genetic test result for a variant in 1 of the main LQTS genes (n = 68; 23%) that was ultimately deemed not to be of clinical significance. Furthermore, patients received misdiagnoses because of a positive family history of SCD that was deemed unrelated to LQTS (n = 46; 16%), isolated/transient QT prolongation (n = 44; 15%), or misinterpretation of the QTc interval as a result of inclusion of the U-wave (n = 40, 14%). CONCLUSIONS: Knowing the 5 main determinants of discordance between a previously rendered diagnosis of LQTS and full diagnostic reversal or removal (vasovagal syncope, "pseudo"-positive genetic test result in LQTS-causative genes, family history of SCD, transient QT prolongation, and misinterpretation of the QTc interval) increases awareness and provides critical guidance to reduce this burden of overdiagnosed LQTS.

Fatal Cardiac Arrhythmias During Electronic Gaming in Patients With Genetically Mediated Heart Diseases.

BACKGROUND: Recently, electronic gaming has been reported as a precipitant of life-threatening cardiac arrhythmias in susceptible individuals. However, the prevalence of cardiac events in genetic heart diseases (GHDs) in the setting of electronic gaming has not been established. OBJECTIVES: In this study, we sought to define the prevalence of cardiac events occurring in the setting of electronic gaming in GHDs. METHODS: Retrospective review of all patients evaluated and treated at Mayo Clinic's genetic heart rhythm clinic from July 2000 to November 2022 was performed to identify patients with a history of playing electronic games at the time of their cardiac event. Cardiac event was used to define events occurring before diagnosis, and breakthrough cardiac event (BCE) was used for events occurring after diagnosis. RESULTS: Of the 3,370 patients with a GHD (mean age at first evaluation 27 ± 19 years, 55% female), 1,079 (32%) had a cardiac event before diagnosis, with 5 patients (0.5%) having an electronic gaming-associated event (3 catecholaminergic polymorphic ventricular tachycardia, 1 long QT syndrome, and 1 premature ventricular contraction-triggered ventricular fibrillation). After diagnosis and treatment, 431 patients (13%) experienced ≥1 BCE during follow-up, of which 1 electronic gaming-associated BCE (0.2%) occurred in a patient with catecholamine-sensitive right outflow tract ventricular tachycardia. CONCLUSIONS: Although anecdotal cases of electronic gaming-associated life-threatening arrhythmias have been reported, in this largest single-center study to date, we show that these are extremely rare occurrences. While electronic gaming can have adverse health consequences, the threat of electronic gaming-triggered sudden death should not be used to try to curb time spent gaming.

Disparities in Referral and Utilization of Implantable Cardioverter-Defibrillators for Primary Prevention of Sudden Cardiac Death.

BACKGROUND: Implantable cardioverter-defibrillators (ICDs) reduce mortality in patients with reduced left ventricular ejection fraction (LVEF). We investigated sex disparities in a contemporary Canadian population for utilization of primary prevention ICDs. METHODS: This was a retrospective cohort study on patients with reduced LVEF admitted to hospitals from 2010 to 2020 in Nova Scotia (population = 971,935). RESULTS: There were 4406 patients eligible for ICDs: 3108 (71%) men and 1298 (29%) women. The mean follow-up time was 3.9 ± 3.0 years. Rates of coronary disease were similar between men and women (45.8% vs 44.0%; P = 0.28), but men had lower LVEF (26.6 ± 5.9% vs 27.2 ± 5.8%; P = 0.0017). The referral rate for ICD was 11% (n = 487), with 13% of men (n = 403) and 6.5% of women (n = 84) referred (P < 0.001). The ICD implantation rate in the population was 8% (n = 358), with 9.5% of men (n = 296) and 4.8% of women (n = 62) (P < 0.001) receiving the device. Men were more likely than women to receive an ICD (odds ratio 2.08, 95% confidence interval 1.61-2.70; P < 0.0001)). There was no significant difference in mortality between men and women (P = 0.2764). There was no significant difference in device therapies between men and women (43.8% vs 31.1%; P = 0.0685). CONCLUSIONS: A significant disparity exists in the utilization of primary prevention ICDs between men and women in a contemporary Canadian population.

Prevalence and management of electrical lead abnormalities in cardiac implantable electronic device leads.

Background: Electrical lead abnormalities (ELAs) can result in device malfunction, leading to significant morbidity in patients with cardiac implantable electronic devices (CIEDs). Objective: We sought to determine the prevalence and management of ELAs in patients with CIEDs. Methods: This was a retrospective cohort study of patients implanted with a CIED between 2012 and 2019 at a tertiary care center. The primary outcome was ELA defined as increased capture threshold (≥2× implantation value), decreased sensing (≤0.5 implantation value), change in impedance (>50% over 3 months), or nonphysiologic potentials. A secondary outcome of device clinic utilization was also collected. Results: There were 2996 unique patients (35% female) included with 4600 leads (57% Abbott, 43% Medtronic). ELAs were observed in 135 (3%) leads, including 124 (92%) Abbott and 10 (7%) Medtronic leads (hazard ratio 9.25, P < .001). Mean follow-up was 4.5 ± 2.2 years. ELAs were associated smaller lead French size, atrial location, and Abbott leads. Lead revision was required in 28% of cases. Patients with lead abnormalities had 38% more in-clinic visits per patient year of follow-up compared with those without (P < .001). Conclusion: ELAs were more frequent in certain models, which increased rates of revision and follow-up. Identification of factors that mitigate these abnormalities to improve lead performance are required to improve care for these devices and provide efficient healthcare.

The 2023 Canadian Cardiovascular Society Clinical Practice Update on Management of the Patient With a Prolonged QT Interval.

A prolonged QT interval on the electrocardiogram is associated with an increased risk of the torsades de pointes form of ventricular arrhythmia resulting in syncope, sudden cardiac arrest or death, or misdiagnosis as a seizure disorder. The cause of QT prolongation can be congenital and inherited as an autosomal dominant variant, or it can be transient and acquired, often because of QT-prolonging drugs or electrolyte abnormalities. Automated measurement of the QT interval can be inaccurate, especially when the baseline electrocardiogram is abnormal, and manual verification is recommended. In this clinical practice update we provide practical tips about measurement of the QT interval, diagnosis, and management of congenital long QT syndrome and acquired prolongation of the QT interval. For congenital long QT syndrome, certain ß-adrenergic-blocking drugs are highly effective, and implantable defibrillators are infrequently required. Many commonly prescribed drugs such as antidepressants and antibiotics can prolong the QT interval, and recommendations are provided on their safe use.

Cardiac fludeoxyglucose-18 positron emission tomography in genotype-positive arrhythmogenic cardiomyopathy.

BACKGROUND: Myocardial inflammation contributes to the pathogenesis of arrhythmogenic cardiomyopathy (ACM), a clinically and genetically heterogenous disorder. Due to phenotypic overlap, some patients with genetic ACM may be evaluated for an underlying inflammatory cardiomyopathy. However, the cardiac fludeoxyglucose (FDG) positron emission tomography (PET) findings in ACM patients have not been elucidated. METHODS: All genotype-positive patients in the Mayo Clinic ACM registry (n = 323) who received a cardiac FDG PET were included in this study. Pertinent data were extracted from the medical record. RESULTS: Collectively, 12/323 (4%; 67% female) genotype-positive ACM patients received a cardiac PET FDG scan as part of their clinical evaluation (median age at scan 49 ± 13 years). Amongst these patients, pathogenic/likely pathogenic variants were detected in LMNA (n = 7), DSP (n = 3), FLNC (n = 1) and PLN (n = 1). Of note, 6/12 (50%) had abnormal myocardial FDG uptake, including diffuse (entire myocardium) uptake in 2/6 (33%), focal (1-2 segments) uptake in 2/6 (33%) and patchy (3+ segments) in 2/6 (33%). Median myocardial standardized uptake value ratio was 2.1. Interestingly, LMNA-positive patients accounted for 3 out of 6 (50%) positive studies (diffuse uptake in 2 and focal uptake in 1). CONCLUSION: Abnormal myocardial FDG uptake is common in genetic ACM patients undergoing cardiac FDG PET. This study further supports the role of myocardial inflammation in ACM. Further investigation is needed to determine role of FDG PET in diagnosis and management of ACM and investigate the role of inflammation in ACM.

Perceived self-efficacy and empowerment in patients at increased risk of sudden cardiac arrest.

Background: The role of multidisciplinary clinics for psychosocial care is increasingly recognized for those living with inherited cardiac conditions (ICC). In Canada, access to healthcare providers differ between clinics. Little is known about the relationship between access to specialty care and a patient's ability to cope with, and manage their condition. Methods: We leveraged the Hearts in Rhythm Organization (HiRO) to conduct a cross-sectional, community-based survey of individuals with ICC and their family members. We aimed to describe access to services, and explore the relationships between participants' characteristics, cardiac history and self-reported health status and self-efficacy (GSE: General Self-Efficacy Scale) and empowerment (GCOS-24: Genetic Counseling Outcome Scale). Results: We collected 235 responses from Canadian participants in 10 provinces and territories. Overall, 63% of participants reported involvement of a genetic counsellor in their care. Access to genetic testing was associated with greater empowerment [mean GCOS-24: 121.14 (SD = 20.53) vs. 105.68 (SD = 21.69); p = 0.004]. Uncertain genetic test results were associated with lower perceived self-efficacy (mean GSE: uncertain = 28.85 vs. positive = 33.16, negative = 34.13; p = 0.01). Low global mental health scores correlated with both lower perceived self-efficacy and empowerment scores, with only 11% of affected participants reporting involvement of psychology services in their care. Conclusion: Differences in resource accessibility, clinical history and self-reported health status impact the perceived self-efficacy and empowerment of patients with ICC. Future research evaluating interventions to improve patient outcomes is recommended.

Persistence of left atrial thrombus in patients with hypertrophic cardiomyopathy and atrial fibrillation.

BACKGROUND: We recently demonstrated that patients with atrial fibrillation (AF) and hypertrophic cardiomyopathy (HCM) have an increased risk of left atrial (LA) thrombus. In this study, we aimed to evaluate thrombus management, thrombus persistence, and thromboembolic events for HCM and non-HCM patients with AF and LA thrombus. METHODS: From a cohort of 2,155 AF patients undergoing transesophageal echocardiography (TEE) for any indication, this study included 122 patients with LA thrombus (64 HCM patients and 58 non-HCM controls). RESULTS: There was no difference in mean CHA2DS2-VASc scores between HCM and control patients (3.9 ± 2.2 vs 3.8 ± 2.0, p = 0.88). Ten (16%) and 4 (7%) patients in the HCM and control groups, respectively, were in sinus rhythm at the time of TEE identifying the LA thrombus (p = 0.13). In all patients, the anticoagulation strategy was modified after the LA thrombus diagnosis. A total of 36 (56%) HCM patients and 34 (59%) control patients had follow-up TEE at median 90 and 62 days, respectively, after index TEE. The HCM group had significantly higher 90-day rates of persistent LA thrombus compared to the control group (88% vs 29%; p < 0.001). In adjusted models, HCM was independently associated with LA thrombus persistence. Among patients with LA thrombus, the 5-year cumulative incidence of thromboembolic events was 11% and 2% in HCM and control groups, respectively (p = 0.22). CONCLUSIONS: Among patients with AF with LA thrombus identified by TEE, those with HCM appear to have a higher risk of LA thrombus persistence than non-HCM patients despite anticoagulation.

Management of Inherited Arrhythmia Syndromes: A HiRO Consensus Handbook on Process of Care.

Inherited arrhythmia syndromes are rare genetic conditions that predispose seemingly healthy individuals to sudden cardiac arrest and death. The Hearts in Rhythm Organization is a multidisciplinary Canadian network of clinicians, researchers, patients, and families that aims to improve care for patients and families with inherited cardiac conditions, focused on those that confer predisposition to arrhythmia and sudden cardiac arrest and/or death. The field is rapidly evolving as research discoveries increase. A streamlined, practical guide for providers to diagnose and follow pediatric and adult patients with inherited cardiac conditions represents a useful tool to improve health system utilization, clinical management, and research related to these conditions. This review provides consensus care pathways for 7 conditions, including the 4 most common inherited cardiac conditions that confer predisposition to arrhythmia, with scenarios to guide investigation, diagnosis, risk stratification, and management. These conditions include Brugada syndrome, long QT syndrome, arrhythmogenic right ventricular cardiomyopathy and related arrhythmogenic cardiomyopathies, and catecholaminergic polymorphic ventricular tachycardia. In addition, an approach to investigating and managing sudden cardiac arrest, sudden unexpected death, and first-degree family members of affected individuals is provided. Referral to specialized cardiogenetic clinics should be considered in most cases. The intention of this review is to offer a framework for the process of care that is useful for both experts and nonexperts, and related allied disciplines such as hospital management, diagnostic services, coroners, and pathologists, in order to provide high-quality, multidisciplinary, standardized care.

Les syndromes d'arythmie héréditaires sont des troubles génétiques rares qui prédisposent des personnes en apparence en bonne santé à un arrêt cardiaque soudain et à la mort. L'organisation Hearts in Rhythm Organization est un réseau multidisciplinaire canadien qui regroupe des cliniciens, des chercheurs ainsi que des patients et leurs proches dans le but d'améliorer les soins prodigués aux patients atteints de maladies cardiaques héréditaires et à leur famille, en particulier dans le cas des maladies qui entraînent une prédisposition à l'arythmie et à un arrêt cardiaque soudain et/ou à la mort. Puisque ce champ de recherche évolue rapidement, la mise au point d'un guide pratique et simple à l'intention des professionnels de la santé pour le diagnostic et le suivi des patients enfants et adultes présentant une maladie cardiaque héréditaire serait donc un outil intéressant pour améliorer l'utilisation du système de santé et la prise en charge clinique de ces maladies tout en orientant la recherche à ce propos. La présente synthèse expose les trajectoires de soins faisant l'objet d'un consensus pour sept maladies, dont les quatre maladies cardiaques héréditaires les plus courantes qui prédisposent à l'arythmie. Elle présente aussi des scénarios pour orienter les examens, le diagnostic, la stratification du risque et la prise en charge des patients. Ces maladies sont le syndrome de Brugada, le syndrome du QT long, la cardiomyopathie arythmogénique du ventricule droit et les cardiomyopathies arythmogènes associées, et la tachycardie ventriculaire polymorphe catécholaminergique. En outre, une approche pour la prise en charge de l'arrêt cardiaque soudain, de mort subite inattendue et des membres de la famille immédiate de la personne touchée est proposée. L'orientation vers des cliniques spécialisées en cardiogénétique doit être envisagée dans la plupart des cas. L'objectif est d'établir un cadre de soins qui soit utile pour les experts et les non-experts ainsi que pour les professionnels des domaines connexes, par exemple le personnel de l'administration hospitalière et des services diagnostiques, les coroners et les pathologistes, en vue d'offrir des soins multidisciplinaires normalisés de grande qualité.

Identification and in-silico characterization of splice-site variants from a large cardiogenetic national registry.

Splice-site variants in cardiac genes may predispose carriers to potentially lethal arrhythmias. To investigate, we screened 1315 probands and first-degree relatives enrolled in the Canadian Hearts in Rhythm Organization (HiRO) registry. 10% (134/1315) of patients in the HiRO registry carry variants within 10 base-pairs of the intron-exon boundary with 78% (104/134) otherwise genotype negative. These 134 probands were carriers of 57 unique variants. For each variant, American College of Medical Genetics and Genomics (ACMG) classification was revisited based on consensus between nine in silico tools. Due in part to the in silico algorithms, seven variants were reclassified from the original report, with the majority (6/7) downgraded. Our analyses predicted 53% (30/57) of variants to be likely/pathogenic. For the 57 variants, an average of 9 tools were able to score variants within splice sites, while 6.5 tools responded for variants outside these sites. With likely/pathogenic classification considered a positive outcome, the ACMG classification was used to calculate sensitivity/specificity of each tool. Among these, Combined Annotation Dependent Depletion (CADD) had good sensitivity (93%) and the highest response rate (131/134, 98%), dbscSNV was also sensitive (97%), and SpliceAI was the most specific (64%) tool. Splice variants remain an important consideration in gene elusive inherited arrhythmia syndromes. Screening for intronic variants, even when restricted to the ±10 positions as performed here may improve genetic testing yield. We compare 9 freely available in silico tools and provide recommendations regarding their predictive capabilities. Moreover, we highlight several novel cardiomyopathy-associated variants which merit further study.