Phenotype variability in patients carrying KCNJ2 mutations.

Area of Science:

• Cardiovascular Genetics
• Channelopathies
• Molecular Cardiology

Background:

• Andersen-Tawil syndrome (ATS) is caused by KCNJ2 gene mutations, affecting the Kir2.1 potassium channel.
• ATS typically presents with ventricular arrhythmia, periodic paralysis, and dysmorphic features.
• Some KCNJ2 mutation carriers exhibit phenotypes overlapping with catecholaminergic polymorphic ventricular tachycardia (CPVT) or present with only one ATS feature.

Purpose of the Study:

• To investigate the clinical and biophysical characteristics of KCNJ2 mutation carriers with atypical Andersen-Tawil syndrome (ATS).
• To determine the diagnostic yield of KCNJ2 gene screening in patients with atypical ATS phenotypes, including CPVT and single ATS features.

Main Methods:

• Mutational analysis of the KCNJ2 gene in 57 unrelated probands with typical or atypical ATS.
• Clinical phenotyping and electrophysiological assessments (QUc interval, U-wave amplitude) of identified mutation carriers.
• Functional characterization of novel KCNJ2 mutations using electrophysiological assays.

Main Results:

• KCNJ2 mutations were identified in 75% of typical ATS and 71% of cardiac phenotype-only cases, but only 7% of CPVT cases.
• Of 45 carriers, 53% exhibited atypical phenotypes, while 47% had typical ATS.
• Atypical phenotypes showed shorter QUc intervals and lower U-wave amplitudes compared to typical ATS. Functional studies revealed significant dominant-negative effects for mutations R82Q, R82W, and G144D, and moderate suppression for T305S.

Conclusions:

• KCNJ2 gene screening is clinically important for atypical ATS phenotypes, as over half of mutation carriers present with non-classical symptoms.
• The study underscores the genetic heterogeneity and variable expressivity of KCNJ2-related disorders.
• Broader genetic testing criteria may be necessary to diagnose all individuals affected by KCNJ2 channelopathies.