Bezzina, Connie R.

ABSTRACT J‐wave syndromes (JWS)—comprising Brugada syndrome (BrS) and early repolarization syndrome (ERS)—are important causes of malignant ventricular arrhythmias and sudden cardiac death in patients whose hearts appear structurally normal. Since the 2016 consensus, advances in genetics, pathophysiology, and therapy have redefined both understanding and management. BrS, once viewed as a purely electrical disorder, is now recognized along a microstructural–electrical continuum, with sodium‐channel dysfunction and subtle epicardial fibrosis of the right ventricular outflow tract as key contributors. Likewise, ERS—historically considered benign—carries significant risk when inferolateral J‐waves coexist with arrhythmic events. Genetically, SCN5A remains the sole gene with definitive disease association, while polygenic susceptibility materially modulates risk, underscoring complex inheritance. Risk stratification remains challenging: patients with prior cardiac arrest or arrhythmic syncope are highest risk, whereas asymptomatic individuals warrant multiparametric assessment integrating clinical features, ECG markers, electrophysiologic studies, and genetics. For decades, treatment centered on implantable cardioverter‐defibrillators and quinidine, both limited by availability, tolerance, and device complications. More recently, epicardial substrate ablation has emerged as a transformative therapy, with large registries and randomized trials demonstrating durable suppression of ventricular fibrillation and acceptable safety. This APHRS‐organized international consensus updates and extends the 2016 Expert Consensus and the 2022 ESC Guidelines, providing contemporary diagnostic frameworks, pragmatic risk‐stratification tools, and treatment algorithms for BrS and ERS. It emphasizes JWS as a microstructural–electrical disease spectrum and elevates substrate ablation as a major therapeutic advance, while outlining priorities for genetics, risk‐stratification and treatment algorithms.

Abstract Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%–11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research—mechanistic, translational, and clinical—is urgently needed.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is an important cause of sudden cardiac death associated with heterogeneous phenotypes, but there is no systematic framework for classifying morphology or assessing associated risks. Here, we quantitatively survey genotype-phenotype associations in HCM to derive a data-driven taxonomy of disease expression. METHODS: We enrolled 436 patients with HCM (median age, 60 years; 28.8% women) with clinical, genetic, and imaging data. An independent cohort of 60 patients with HCM from Singapore (median age, 59 years; 11% women) and a reference population from the UK Biobank (n=16 691; mean age, 55 years; 52.5% women) were also recruited. We used machine learning to analyze the 3-dimensional structure of the left ventricle from cardiac magnetic resonance imaging and build a tree-based classification of HCM phenotypes. Genotype and mortality risk distributions were projected on the tree. RESULTS: Carriers of pathogenic or likely pathogenic variants for HCM had lower left ventricular mass, but greater basal septal hypertrophy, with reduced life span (mean follow-up, 9.9 years) compared with genotype negative individuals (hazard ratio, 2.66 [95% CI, 1.42–4.96]; P <0.002). Four main phenotypic branches were identified using unsupervised learning of 3-dimensional shape: (1) nonsarcomeric hypertrophy with coexisting hypertension; (2) diffuse and basal asymmetrical hypertrophy associated with outflow tract obstruction; (3) isolated basal hypertrophy; and (4) milder nonobstructive hypertrophy enriched for familial sarcomeric HCM (odds ratio for pathogenic or likely pathogenic variants, 2.18 [95% CI, 1.93–2.28]; P =0.0001). Polygenic risk for HCM was also associated with different patterns and degrees of disease expression. The model was generalizable to an independent cohort (trustworthiness, M 1 : 0.86–0.88). CONCLUSIONS: We report a data-driven taxonomy of HCM for identifying groups of patients with similar morphology while preserving a continuum of disease severity, genetic risk, and outcomes. This approach will be of value in understanding the causes and consequences of disease diversity.

Importance Sudden infant death syndrome (SIDS) remains a leading cause of death during the first year of life. The etiology of SIDS is complex and remains largely unknown. Objective To evaluate whether siblings of children who died of SIDS have a higher risk of SIDS compared with the general pediatric population. Design, Setting, and Participants This register-based cohort study used Danish nationwide registers. Participants were all infants (&amp;lt;1 year) in Denmark between January 1, 1978, and December 31, 2016, including siblings of children who died of SIDS. Siblings were followed up from the index cases’ date of SIDS, date of birth, or immigration, whichever came first, and until age 1 year, emigration, developing SIDS, death, or study end. The median (IQR) follow-up was 1 (1-1) year. Data analysis was conducted from January 2017 to October 2022. Main Outcomes and Measures Standardized incidence ratios (SIRs) of SIDS were calculated with Poisson regression models relative to the general population. Results In a population of 2 666 834 consecutive births (1 395 199 [52%] male), 1540 infants died of SIDS (median [IQR] age at SIDS, 3 [2-4] months) during a 39-year study period. A total of 2384 younger siblings (cases) to index cases (first sibling with SIDS) were identified. A higher rate of SIDS was observed among siblings compared with the general population, with SIRs of 4.27 (95% CI, 2.13-8.53) after adjustment for sex, age, and calendar year and of 3.50 (95% CI, 1.75-7.01) after further adjustment for mother’s age (&amp;lt;29 years vs ≥29 years) and education (high school vs after high school). Conclusions and Relevance In this nationwide study, having a sibling who died of SIDS was associated with a 4-fold higher risk of SIDS compared with the general population. Shared genetic and/or environmental factors may contribute to the observed clustering of SIDS. The family history of SIDS should be considered when assessing SIDS risk in clinical settings. A multidisciplinary genetic evaluation of families with SIDS could provide additional evidence.

Background: Brugada syndrome (BrS) is characterized by the type 1 Brugada ECG pattern. Pathogenic rare variants in SCN5A (mutations) are identified in 20% of BrS families in whom incomplete penetrance and genotype-negative phenotype-positive individuals are observed. E1784K- SCN5A is the most common SCN5A mutation identified. We determined the association of a BrS genetic risk score (BrS-GRS) and SCN5A mutation type on BrS phenotype in BrS families with SCN5A mutations. Methods: Subjects with a spontaneous type 1 pattern or positive/negative drug challenge from cohorts harboring SCN5A mutations were recruited from 16 centers (n=312). Single nucleotide polymorphisms previously associated with BrS at genome-wide significance were studied in both cohorts: rs11708996, rs10428132, and rs9388451. An additive linear genetic model for the BrS-GRS was assumed (6 single nucleotide polymorphism risk alleles). Results: In the total population (n=312), BrS-GRS ≥4 risk alleles yielded an odds ratio of 4.15 for BrS phenotype ([95% CI, 1.45–11.85]; P =0.0078). Among SCN5A -positive individuals (n=258), BrS-GRS ≥4 risk alleles yielded an odds ratio of 2.35 ([95% CI, 0.89–6.22]; P =0.0846). In SCN5A -negative relatives (n=54), BrS-GRS ≥4 alleles yielded an odds ratio of 22.29 ([95% CI, 1.84–269.30]; P =0.0146). Among E1784K- SCN5A positive family members (n=79), hosting ≥4 risk alleles gave an odds ratio=5.12 ([95% CI, 1.93–13.62]; P =0.0011). Conclusions: Common genetic variation is associated with variable expressivity of BrS phenotype in SCN5A families, explaining in part incomplete penetrance and genotype-negative phenotype-positive individuals. SCN5A mutation genotype and a BrS-GRS associate with BrS phenotype, but the strength of association varies according to presence of a SCN5A mutation and severity of loss of function.

Background: Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility. Methods: We conducted genome-wide association studies followed by transethnic meta-analysis in 1656 unrelated patients with LQTS of European or Japanese ancestry and 9890 controls to identify susceptibility single nucleotide polymorphisms. We estimated the common variant heritability of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 single nucleotide polymorphisms previously associated with the QT-interval in the general population using a polygenic risk score. Results: Genome-wide association analysis identified 3 loci associated with LQTS at genome-wide statistical significance ( P <5×10 −8 ) near NOS1AP , KCNQ1 , and KLF12 , and 1 missense variant in KCNE1 (p.Asp85Asn) at the suggestive threshold ( P <10 −6 ). Heritability analyses showed that ≈15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( h2SNP 0.148; standard error 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT-interval in the general population (r g =0.40; P =3.2×10 −3 ). The polygenic risk score comprising common variants previously associated with the QT-interval in the general population was greater in LQTS cases compared with controls ( P <10−13), and it is notable that, among patients with LQTS, this polygenic risk score was greater in patients who were genotype negative compared with those who were genotype positive ( P <0.005). Conclusions: This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT-interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT-interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.

Abstract Aims Calmodulinopathies are rare life-threatening arrhythmia syndromes which affect mostly young individuals and are, caused by mutations in any of the three genes (CALM 1–3) that encode identical calmodulin proteins. We established the International Calmodulinopathy Registry (ICalmR) to understand the natural history, clinical features, and response to therapy of patients with a CALM-mediated arrhythmia syndrome. Methods and results A dedicated Case Report File was created to collect demographic, clinical, and genetic information. ICalmR has enrolled 74 subjects, with a variant in the CALM1 (n = 36), CALM2 (n = 23), or CALM3 (n = 15) genes. Sixty-four (86.5%) were symptomatic and the 10-year cumulative mortality was 27%. The two prevalent phenotypes are long QT syndrome (LQTS; CALM-LQTS, n = 36, 49%) and catecholaminergic polymorphic ventricular tachycardia (CPVT; CALM-CPVT, n = 21, 28%). CALM-LQTS patients have extremely prolonged QTc intervals (594 ± 73 ms), high prevalence (78%) of life-threatening arrhythmias with median age at onset of 1.5 years [interquartile range (IQR) 0.1–5.5 years] and poor response to therapies. Most electrocardiograms (ECGs) show late onset peaked T waves. All CALM-CPVT patients were symptomatic with median age of onset of 6.0 years (IQR 3.0–8.5 years). Basal ECG frequently shows prominent U waves. Other CALM-related phenotypes are idiopathic ventricular fibrillation (IVF, n = 7), sudden unexplained death (SUD, n = 4), overlapping features of CPVT/LQTS (n = 3), and predominant neurological phenotype (n = 1). Cardiac structural abnormalities and neurological features were present in 18 and 13 patients, respectively. Conclusion Calmodulinopathies are largely characterized by adrenergically-induced life-threatening arrhythmias. Available therapies are disquietingly insufficient, especially in CALM-LQTS. Combination therapy with drugs, sympathectomy, and devices should be considered.