KCNJ2 – Short QT Syndrome

Short QT syndrome (SQTS) is a rare, autosomal dominant channelopathy characterized by abnormally abbreviated QT intervals and heightened risk of atrial and ventricular arrhythmias. Three genetic subtypes have been defined: SQT1 (KCNH2), SQT2 (KCNQ1), and SQT3 (KCNJ2 gain-of-function) (PMID:15761194). The KCNJ2 gene encodes the Kir2.1 inward rectifier K+ channel, and pathogenic variants therein manifest as SQT3.

Genetically, SQT3 arises from heterozygous gain-of-function variants in KCNJ2. A c.514G>A (p.Asp172Asn) substitution segregated with short QT intervals in a single multiplex family, demonstrating autosomal dominant inheritance and co-segregation of genotype and phenotype (PMID:15761194). Reappraisal of SQTS variants identified at least five conclusive pathogenic KCNJ2 alleles among curated cases, underscoring recurrent variant involvement (PMID:31315195).

Functionally, the D172N mutation induces a significant increase in outward I_K1 current between −75 mV and −45 mV, as shown by whole-cell patch-clamp studies in heterologous expression systems. Heterozygous co-expression yields intermediate current augmentation, and computer modeling replicates the characteristic tall, asymmetrical T waves and shortened repolarization seen in patients (PMID:15761194).

Clinical curation classifies KCNJ2 as a definitive SQTS gene alongside KCNH2 and KCNQ1, with strong to moderate evidence accruing from combined genetic segregation and functional concordance (PMID:34557911). However, variant re-interpretation studies advise cautious translation of non-validated alleles to avoid misdiagnosis (PMID:31315195).

Integration of genetic and mechanistic data confirms a gain-of-function disease mechanism via augmented Kir2.1 current and accelerated ventricular repolarization in SQT3. While additional rare alleles have been reported, current evidence sufficiently supports clinical genetic testing of KCNJ2 in SQTS panels.

Key take-home: Pathogenic gain-of-function KCNJ2 variants, notably c.514G>A (p.Asp172Asn), underlie SQT3 and should be included in genetic testing to guide diagnosis and management.

References

• Circulation research • 2005 • A novel form of short QT syndrome (SQT3) is caused by a mutation in the KCNJ2 gene. PMID:15761194
• Journal of clinical medicine • 2019 • Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants. PMID:31315195
• European heart journal • 2022 • Evaluation of gene validity for CPVT and short QT syndrome in sudden arrhythmic death. PMID:34557911

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