Phenotypic heterogeneity in Andersen-Tawil syndrome: Insights from the International ATS Registry
P Bhardwaj, S B Jacobsen, B G Winkel, J Tfelt-HansenAbstract
Background
Andersen–Tawil Syndrome (ATS) is a rare channelopathy characterized by periodic paralysis, distinctive dysmorphic features, and cardiac arrhythmias. ATS is caused by mutations in the KCNJ2 gene, and it has historically been considered a subtype of long QT syndrome. Due to the rarity of ATS, most studies are based on small populations, which may result in diagnostic delays and challenges in treatment strategies. The International ATS Registry provides a large, systematically collected cohort to better characterise the disease.
Purpose
To describe the demographic, clinical, and electrocardiographic characteristics of patients with ATS enrolled in the International ATS Registry, and to illustrate the risk of life-threatening events.
Methods
We analysed data from 333 patients with a diagnosis of ATS, according to the 2022 ESC Guidelines for the management of Ventricular Arrhythmias and SCD, collected across multiple international centres. Demographic, clinical, electrocardiographic, and outcome data were extracted from standardized forms. Time-to-event analyses for life-threatening arrhythmic events (LAEs) were performed using Kaplan-Meier estimates to assess the probability of remaining event free.
Results
The cohort included 49% index patients, of whom 67% were female, with a median age at diagnosis of 25 years. Dysmorphic features were the most common manifestation (57%), followed by ventricular arrhythmias (26%) and periodic paralysis (20%) (Figure 1). The full triad was present in 4% of patients. Syncope had occurred in 27% of patients, and muscle weakness reported in 23%. Regarding therapy, 42% were treated with beta-blockers, 25% with Flecainide, and 19% received both. Electrocardiographic analysis showed a mean QTcB of 439 ± 63 ms in index patients. U-wave abnormalities were observed in 42% of index patients and 50% relatives (p = 0.20). Genetic testing was performed in 98% of patients, with 97% carrying a KCNJ2 variant. Among index patients, 8% experienced cardiac arrest (CA) and 20% had an ICD. During follow-up, 5% of patients experienced LAEs, and ICD therapy was delivered in 4%, with 93% of therapies being appropriate. Among 107 patients included in the Kaplan-Meier analysis, 15 experienced LAE (Figure 2). Cumulative LAE-free survival was 100% at age 10, 98% at age 20, and 71% at age 50, indicating that most patients remained free from LAEs through mid-adulthood, with a gradual decline in survival into later adulthood.
Conclusion
This study, representing the largest international cohort of ATS patients to date, highlights the marked clinical heterogeneity of the syndrome and underscores the potential value of standardized diagnostic criteria for risk stratification and patient management. Longitudinal follow-up suggests that most patients maintain relatively high event-free survival over time, although individual risk varies, supporting the need for careful, individualized assessment in clinical practice.Prevalence of triad features in ATSKaplan–Meier analysis of LAEs