KCNJ2 – Long QT Syndrome

KCNJ2 encodes the inward rectifier potassium channel Kir2.1, which contributes to cardiac action potential repolarization. Although primarily implicated in Andersen–Tawil syndrome, rare KCNJ2 variants have been reported in long QT syndrome (LQTS) cohorts. Three unrelated LQTS probands harboring heterozygous KCNJ2 missense changes and one proband with a 542 kb heterozygous deletion of the entire gene have been described, with limited familial segregation and no multisite replication ([PMID:24133349]; [PMID:24395924]; [PMID:21875779]). Replication in larger LQTS registries remains lacking.

Genetic Evidence

Inheritance is autosomal dominant. In total, four unrelated LQTS probands have been reported with KCNJ2 variants: three missense and one whole-gene deletion. Segregation was documented in a single family, where the deletion co-segregated with electrocardiographic abnormalities in a parent ([PMID:24395924]). Variant classes include missense substitutions and copy-number loss. Only one variant, c.1199C>T (p.Thr400Met), has been described in an LQTS-specific presentation with ventricular fibrillation after exercise and adrenergic provocation ([PMID:21875779]).

Functional Evidence

Functional assays of various Kir2.1 mutants demonstrate a loss-of-function dominant-negative mechanism resulting in reduced I_K1 and prolonged repolarization. Xenopus oocyte and mammalian cell studies of Kir2.1 mutants show absent or diminished currents and dominant-negative suppression of wild-type channels ([PMID:11371347]; [PMID:15276028]). In silico and multiscale cardiac modeling of loss-of-function Kir2.1 reproduces QT prolongation and T-wave alterations, consistent with LQTS phenotypes ([PMID:16936001]).

Conflicting Evidence

A recent evidence-based reappraisal classified KCNJ2 as a gene with limited or disputed evidence for causation of typical LQTS, citing only sparse case data and insufficient segregation ([PMID:31983240]). Most functional work addresses Andersen–Tawil syndrome rather than classical LQTS.

Integration and Clinical Perspective

Overall, KCNJ2 variants are a rare and incompletely validated cause of LQTS. Genetic findings lack robust segregation, and functional data largely derive from Andersen–Tawil syndrome contexts. At present, KCNJ2 variant detection in LQTS should be interpreted cautiously, with reliance on additional genetic and clinical evidence before informing management.

Key Take-home: KCNJ2 variants exhibit limited clinical validity for LQTS and should not alone guide diagnosis or therapy without further corroborative evidence.

References

• The Canadian journal of cardiology • 2011 • KCNJ2 variant of unknown significance reclassified as long QT syndrome causing ventricular fibrillation. PMID:21875779
• Circulation. Cardiovascular genetics • 2014 • Array comparative genomic hybridization identifies a heterozygous deletion of the entire KCNJ2 gene as a cause of sudden cardiac death. PMID:24395924
• Journal of Korean medical science • 2013 • Long QT syndrome: a Korean single center study. PMID:24133349
• Cell • 2001 • Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. PMID:11371347
• Journal of molecular and cellular cardiology • 2004 • Loss-of-function mutations of the K(+) channel gene KCNJ2 constitute a rare cause of long QT syndrome. PMID:15276028
• American journal of physiology. Heart and circulatory physiology • 2007 • Modeling of IK1 mutations in human left ventricular myocytes and tissue. PMID:16936001
• Circulation • 2020 • An International, Multicentered, Evidence-Based Reappraisal of Genes Reported to Cause Congenital Long QT Syndrome. PMID:31983240

Evidence Based Scoring (AI generated)