Characterization of Loss-Of-Function KCNJ2 Mutations in Atypical Andersen Tawil Syndrome

Area of Science:

• Genetics
• Cardiology
• Molecular Biology

Background:

• Andersen-Tawil Syndrome (ATS) presents with cardiac arrhythmias, periodic paralysis, and dysmorphic features, typically caused by KCNJ2 mutations.
• Catecholaminergic Polymorphic Ventricular Tachycardia (CPVT), often due to RYR2 mutations, carries a high risk of sudden death and can be misdiagnosed in atypical ATS cases.
• KCNJ2 variants are rarely identified in CPVT, but their presence impacts therapeutic strategies, particularly the efficacy of beta-blockers.

Purpose of the Study:

• To investigate KCNJ2 variants in patients presenting with CPVT-like phenotypes.
• To characterize the functional consequences of novel KCNJ2 variants.
• To emphasize the importance of distinguishing atypical ATS from CPVT for optimal patient management and therapeutic decisions.

Main Methods:

• Genetic analysis of two patients with CPVT-like phenotypes.
• Identification and characterization of de novo KCNJ2 variants (p.Arg82Trp and p.Pro186Gln).
• In vitro functional studies to assess the impact of KCNJ2 variants on Kir2.1 channel activity.

Main Results:

• Two de novo KCNJ2 variants, p.Arg82Trp and p.Pro186Gln, were identified in patients with CPVT-like phenotypes.
• Both identified KCNJ2 variants resulted in dominant-negative effects, significantly reducing tetrameric channel activity.
• A novel pathogenic variant, p.Pro186Gln, in the KCNJ2 gene was characterized.

Conclusions:

• Accurate cardiologic evaluation and attention to extracardiac signs are vital for differentiating CPVT from atypical ATS.
• KCNJ2 gene analysis should be considered in the molecular investigation of CPVT to guide therapeutic choices.
• The findings highlight the importance of genetic testing in managing arrhythmias with overlapping clinical features.