KCNJ2 – Catecholaminergic Polymorphic Ventricular Tachycardia

Heterozygous missense variants in KCNJ2 have been reported in two unrelated patients presenting with exercise- or adrenergic-triggered ventricular tachycardia without classic Andersen-Tawil features. A c.679G>T (p.Val227Phe) variant was identified in a single proband and shown to confer latent, protein kinase A–dependent loss of IK1 under catecholaminergic conditions (PMID:19843922). A second variant, c.245G>A (p.Arg82Gln), was found in a 33-year-old woman with CPVT-like arrhythmia and demonstrated adrenergic-dependent rectification abnormalities with calcium sensitivity (PMID:24561538). In a cohort of 11 CPVT referrals, KCNJ2 variants were identified in four females who lacked RyR2 mutations but exhibited exercise-induced bidirectional VT, suggesting phenotypic mimicry (PMID:16818210). An Expert Panel reappraisal classified KCNJ2 as disputed for CPVT due to limited replication, absence of segregation data, and overlap with Andersen-Tawil and LQTS phenotypes (PMID:34557911).

Functional studies support a mechanism in which these Kir2.1 variants produce adrenergic-dependent channel dysfunction—PKA-stimulated reduction of outward IK1 in V227F and impaired current augmentation in R82Q—consistent with stress-induced arrhythmia phenotypes. However, only two probands have been described without familial segregation, and the gene curation framework deemed the relationship disputed. Additional case series, segregation, and replication are needed before KCNJ2 can be included reliably in CPVT diagnostic panels. Key Take-home: Although KCNJ2 variants can recapitulate CPVT-like biophysics, current evidence is insufficient for clinical CPVT gene validity.

References

• Circulation. Arrhythmia and electrophysiology | 2009 | Protein kinase A-dependent biophysical phenotype for V227F-KCNJ2 mutation in catecholaminergic polymorphic ventricular tachycardia. PMID:19843922
• Heart Rhythm | 2014 | KCNJ2 mutation causes an adrenergic-dependent rectification abnormality with calcium sensitivity and ventricular arrhythmia. PMID:24561538
• Heart Rhythm | 2006 | Genotypic heterogeneity and phenotypic mimicry among unrelated patients referred for catecholaminergic polymorphic ventricular tachycardia genetic testing. PMID:16818210
• European Heart Journal | 2022 | Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

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