Long QT Syndrome

Timothy syndrome (TS) is a severe, multisystem disorder characterized by autism, epilepsy, long-QT syndrome and other neuropsychiatric conditions1. TS type 1 (TS1) is caused by a gain-of-function variant in the alternatively spliced and developmentally enriched CACNA1C exon 8A, as opposed to its counterpart exon 8. We previously uncovered several phenotypes in neurons derived from patients with TS1, including delayed channel inactivation, prolonged depolarization-induced calcium rise, impaired interneuron migration, activity-dependent dendrite retraction and an unanticipated persistent expression of exon 8A2-6. We reasoned that switching CACNA1C exon utilization from 8A to 8 would represent a potential therapeutic strategy. Here we developed antisense oligonucleotides (ASOs) to effectively decrease the inclusion of exon 8A in human cells both in vitro and, following transplantation, in vivo. We discovered that the ASO-mediated switch from exon 8A to 8 robustly rescued defects in patient-derived cortical organoids and migration in forebrain assembloids. Leveraging a transplantation platform previously developed7, we found that a single intrathecal ASO administration rescued calcium changes and in vivo dendrite retraction of patient neurons, suggesting that suppression of CACNA1C exon 8A expression is a potential treatment for TS1. Broadly, these experiments illustrate how a multilevel, in vivo and in vitro stem cell model-based approach can identify strategies to reverse disease-relevant neural pathophysiology.

Pediatric cardiomyopathies (CMs) and electrical diseases constitute a heterogeneous spectrum of disorders distinguished by structural and electrical abnormalities in the heart muscle, attributed to a genetic variant. They rank among the main causes of morbidity and mortality in the pediatric population, with an annual incidence of 1.1-1.5 per 100,000 in children under the age of 18. The most common conditions are dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM). Despite great enthusiasm for research in this field, studies in this population are still limited, and the management and treatment often follow adult recommendations, which have significantly more data on treatment benefits. Although adult and pediatric cardiac diseases share similar morphological and clinical manifestations, their outcomes significantly differ. This review summarizes the latest evidence on genetics, clinical characteristics, management, and updated outcomes of primary pediatric CMs and electrical diseases, including DCM, HCM, arrhythmogenic right ventricular cardiomyopathy (ARVC), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), long QT syndrome (LQTS), and short QT syndrome (SQTS).

Primary electrical heart diseases, often considered channelopathies, are inherited genetic abnormalities of cardiomyocyte electrical behavior carrying the risk of malignant arrhythmias leading to sudden cardiac death (SCD). Approximately 54% of sudden, unexpected deaths in individuals under the age of 35 do not exhibit signs of structural heart disease during autopsy, suggesting the potential significance of channelopathies in this group of age. Channelopathies constitute a highly heterogenous group comprising various diseases such as long QT syndrome (LQTS), short QT syndrome (SQTS), idiopathic ventricular fibrillation (IVF), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), and early repolarization syndromes (ERS). Although new advances in the diagnostic process of channelopathies have been made, the link between a disease and sudden cardiac death remains not fully explained. Evolving data in electrophysiology and genetic testing suggest previously described diseases as complex with multiple underlying genes and a high variety of factors associated with SCD in channelopathies. This review summarizes available, well-established information about channelopathy pathogenesis, genetic basics, and molecular aspects relative to principles of the pathophysiology of arrhythmia. In addition, general information about diagnostic approaches and management is presented. Analyzing principles of channelopathies and their underlying causes improves the understanding of genetic and molecular basics that may assist general research and improve SCD prevention.

BackgroundBepridil is an antiarrhythmic drug used to treat paroxysmal atrial fibrillation; however, its use is limited by corrected QT interval (QTc) prolongation and the risk of ventricular arrhythmias. This study aimed to identify genetic variants associated with bepridil-associated QTc prolongation after catheter ablation for paroxysmal atrial fibrillation.MethodsA total of 523 patients who initiated bepridil therapy after catheter ablation at Hiroshima University between November 2013 and March 2023 were enrolled. Of these, 445 patients were included in a genome-wide association study, and 78 were used as an independent replication cohort. QTc was measured 1 month after treatment initiation, with QTc prolongation defined as ≥450 ms in men and ≥460 ms in women. Logistic regression analyses were conducted using additive, dominant, and recessive genetic models. Variants showing suggestive associations in the genome-wide association study (P-6) were evaluated in the replication cohort, followed by random-effects meta-analyses, with genome-wide significance defined as P-8. Linear regression analyses were conducted for QTc prolongation.ResultsAfter quality control, 443 patients were analyzed in the genome-wide association study. Of these, 122 (28%) exhibited QTc prolongation. Under the recessive model, rs12622919, an intronic variant in the FSHR (follicle-stimulating hormone receptor) gene, showed a suggestive association. In the random-effects meta-analysis combining the discovery and replication cohorts, rs12622919 reached genome-wide significance. Exploratory sex-stratified analyses suggested a potential association in women (P=0.026), although no statistically significant genotype-by-sex interaction was observed. Inclusion of rs12622919 improved discrimination for QTc prolongation (area under the curve, 0.77 [95% CI, 0.70-0.84]; Welch's t test, PP=0.0078).ConclusionThe FSHR variant rs12622919 is associated with bepridil-associated QTc prolongation and may serve as a genetic biomarker for individual risk assessment. Because the findings are based on meta-analysis, independent validation is required.