Recommendations from the Association for European Paediatric and Congenital Cardiology for training in diagnostic and interventional electrophysiology

The field of electrophysiology (EP) in paediatric cardiology patients and adults with congenital heart disease is complex and rapidly growing. The current recommendations for diagnostic and invasive electrophysiology of the working group for Cardiac Dysrhythmias and Electrophysiology of the Association for European Paediatric and Congenital Cardiology acknowledges the diveristy of European countries and centers. These training recommendations can be fulfilled in a manageable period of time, without compromising the quality of training required to become an expert in the field of paediatric and congenital EP and are for trainees undergoing or having completed accredited paediatric cardiologist fellowship. Three levels of expertise, the training for General paediatric cardiology EP, for non-invasive EP and invasive EP have been defined. This Association for European EP curriculum describes the theoretical and practicsal knowledge in clinical EP; catheter ablation, cardiac implantable electronic devices, inherited arrhythmias and arrhythmias in adults with congenital heart defects for the 3 levels of expertise.

Enhancing rare variant interpretation in inherited arrhythmias through quantitative analysis of 5182 cases from long QT syndrome and Brugada syndrome consortia cohorts and gnomAD population controls

Background/Introduction Guidelines for variant interpretation in Mendelian disease set stringent criteria to report a variant as (likely) pathogenic, prioritising control of false positive rate over test sensitivity and diagnostic yield, and require customisation for the specific genetic characteristics of gene-disease dyads. Inherited arrhythmias like long QT syndrome (LQTS) and Brugada syndrome (BrS) are genetically heterogeneous, with missense variants constituting the preponderance of disease-causing variants. Evidence from family segregation or functional assays to confirm pathogenicity are often unavailable or impractical in clinical genetic testing, leading to high rates of variants of uncertain significance and false negative test results. Methods We compared rare variant frequencies from 1847 LQTS (KCNQ1, KCNH2, SCN5A) and 3335 BrS (SCN5A) cases from the International LQTS/BrS Genetics Consortia to population-specific gnomAD data. We propose disease-specific criteria for ACMG/AMP evidence classes – rarity (PM2/BS1 rules) and enrichment of individual (PS4) and domain-specific (PM1) variants in cases over controls. Results Rare SCN5A variant prevalence differed between BrS cases with spontaneous (28.7%) versus induced (15.8%) type 1 Brugada ECG (p=1.3x10–13) and between European (20.8%) and Japanese (8.9%) patients (p=8.8x10–18). Transmembrane regions and specific N-terminus (KCNH2) and C-terminus (KCNQ1/KCNH2) domains were characterised by high enrichment of case variants and >95% probability of pathogenicity. Applying the customised rules, 17.5% of European BrS cases and 73.7% of European LQTS cases had variants classified as (likely) pathogenic, compared to estimated diagnostic yields (case excess over gnomAD) of 19.3%/82.6%. Conclusions Large case/control datasets enable quantitative implementation of ACMG/AMP guidelines and increased sensitivity for inherited arrhythmia genetic testing. Classification of Brugada/LQTS variants Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Dutch Heart Foundation, Netherlands Organisation for Scientific Research

Inherited arrhythmias and conduction disorders

Long QT syndrome is primarily a disorder of repolarization with three principal ion channel currents accounting for the condition. Management revolves around optimization of beta blockade and avoidance of triggers with implantable cardiac defibrillators (ICD) recommended in high risk cases. Brugada syndrome is thought to be caused by Na channel mutations although the aetiology is not fully established. Controversy exists regarding optimal risk stratification approaches. Catecholaminergic polymorphic ventricular tachycardia is caused by abnormalities in calcium handling leading to bidirectional ventricular tachycardia/VF and can be managed using medication –principally beta blockers and occasionally sympathectomy with ICD in cardiac arrest survivors with specific caveats. Inherited conduction disorders should always be considered in patients presenting at a younger age with conduction disease paying specific attention to lamin mutations where an ICD will need to be considered.

Evaluation of Clinical Practices Related to Variants of Uncertain Significance Results in Inherited Cardiac Arrhythmia and Inherited Cardiomyopathy Genes

Background: Increasing use of genetic tests have identified many variants of uncertain significance (VUS) in genes associated with inherited arrhythmias and cardiomyopathies. Evaluation of clinical practices, including medical management recommendations for VUS patients and their families, is important to prevent over- or under-treatment that may result in morbidity or mortality. The purpose of this study is to describe practices related to VUS results including information and medical management recommendations providers give patients and their families. Methods: An anonymous online survey was distributed to genetic counselors (GCs) and cardiologists who have seen at least one patient for inherited arrhythmias or cardiomyopathies. The survey explored providers’ confidence in counseling, explanation of VUSs, topics covered before and after genetic testing, and clinical recommendations using a hypothetical scenario maximizing uncertainty with an unclear clinical and molecular diagnosis. Descriptive statistics were calculated, and median confidence and likelihood of making various medical recommendations were compared across provider type. Results: Providers (N=102) who completed the survey included 29 cardiovascular GCs, 50 GCs from other specialties, and 23 cardiologists. GCs feel more confident than cardiologists counseling about VUS results ( P <0.001); while both cardiovascular GCs and cardiologists feel more confident than other GCs in providing input regarding medical management recommendations ( P =0.001 and P =0.01, respectively). Cardiologists were more likely than cardiac GCs to recommend clinical testing for family members even though testing in the scenario is expected to be uninformative. Conclusions: These findings illustrate how the expertise of different providers may impact decision processes, suggesting the need for interdisciplinary clinics to optimize care for challenging cases.