Genetic variability in Andersen-Tawil syndrome: insights from the international ATS Registry

Introduction

Andersen-Tawil Syndrome (ATS) is a rare autosomal dominant channelopathy caused by variants in KCNJ2, which encodes the Kir2.1 channel. Clinical presentation ranges from minor dysmorphic features to periodic paralysis and life-threatening ventricular arrhythmias. Due to its rarity, most studies are limited to small cohorts, restricting the analysis of genotype-phenotype correlation.

Purpose

This study aims to characterise the genetic landscape of ATS using data from the International ATS Registry. We aim to describe the distribution of KCNJ2 variants and assess genotype-phenotype correlations.

Methods

The International ATS Registry is an international, multicentre registry collecting clinical and genetic data from ATS patients worldwide. Inclusion followed the diagnostic criteria outlined in the "2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death". At the time of analysis, a total of 327 ATS patients from 23 countries were enrolled. Clinical data included phenotypic characteristics, such as cardiac manifestations, muscular weakness/paralysis, and the presence of dysmorphic features. KCNJ2 variants were assessed, and Kir2.1 protein domains were defined according to the RCSB Protein Data Bank. Kruskal-Wallis and Fisher’s exact tests were used to assess differences in phenotypic presentation among patients with variants in different Kir2.1 domains.

Results

Among 327 ATS patients, genetic testing was performed in 98%, identifying KCNJ2 variants in 97% of those tested. A total of 69 unique KCNJ2 variants were identified: 16 in the N-terminal, 21 in the transmembrane domain, and 31 in the C-terminal of the Kir2.1 channel (Fig. 1). One deletion spanned both exons of the KCNJ2 gene. Missense substitutions accounted for 89.9% of all variants. While the cohort size limited the identification of statistically significant genotype-phenotype correlations, a trend was observed as patients with N-terminal variants more frequently exhibited dysmorphic features and less frequently experienced cardiac arrhythmias compared to patients with variants in the other domains (Fig. 2).

Three mutational hotspots were identified at residues 67, 82, and 218, with 37, 62, and 71 patients, respectively, carrying a variant at these positions. Analysis of phenotypes in families with variants within these hotspots revealed considerable heterogeneity among individuals with the same variant.

Conclusion

The International ATS Registry provides the largest cohort of ATS patients to date. This study includes the most comprehensive characterisation of KCNJ2 variants in ATS patients, highlighting mutational hotspots and domain-specific trends in phenotypic presentation. The marked phenotypic variability among patients with identical variants underscores the complexity of ATS and the importance of international collaboration to further elucidate its genetic landscape.Fig 1:Variants in Kir2.1 domainsFig 2:Phenotypic characteristics