KCNH2 – Brugada syndrome

Brugada syndrome (BrS) is an autosomal dominant arrhythmia disorder characterized by right precordial ST-segment elevation and increased risk of ventricular tachyarrhythmias and sudden cardiac death. While SCN5A is the most frequently implicated gene, rare gain-of-function variants in the potassium channel gene KCNH2 (hERG) have emerged as contributors to a non-SCN5A BrS subset. Genetic screening in selected BrS cohorts has identified KCNH2 missense mutations in independent probands, supporting its role as a minor BrS gene.

Genetic evidence includes identification of 2 unrelated SCN5A-negative patients harboring KCNH2 p.Gly873Ser and p.Asn985Ser with increased I_Kr density ([PMID:16043162]), 4 gain-of-function variants (p.Thr152Ile, p.Arg164Cys, p.Trp927Gly, p.Arg1135His) in 236 BrS probands including one with ventricular fibrillation ([PMID:24400717]), and a novel c.1189C>T (p.Arg397Cys) variant in an asymptomatic male with BrS and mild QTc shortening ([PMID:38648771]). In total, 7 unrelated probands have been reported with KCNH2 gain-of-function alleles.

All reported KCNH2 variants are missense and act via gain-of-function mechanisms. The exemplar variant c.1189C>T (p.Arg397Cys) was shown to facilitate channel activation, impair inactivation, and augment window current in CHO cells, consistent with accelerated repolarization and action potential shortening ([PMID:38648771]). These functional assays recapitulate BrS ECG features and support variant pathogenicity.

Patch-clamp analyses across multiple mutations consistently demonstrate increased I_Kr current densities, hyperpolarizing shifts of activation/inactivation, and prolonged deactivation kinetics, implicating enhanced hERG channel activity in BrS pathogenesis. In silico modeling further predicts action potential abbreviation, corroborating experimental findings.

Conflicting evidence arises from a population-based study which found that many putative BrS-associated KCNH2 variants did not correlate with J-point elevation, arrhythmia susceptibility, or mortality in unselected cohorts ([PMID:27711072]). This suggests incomplete penetrance and cautions against overinterpretation of isolated variants.

In summary, KCNH2 exhibits moderate clinical validity for Brugada syndrome based on multiple unrelated probands with concordant gain-of-function functional data. While the overall contribution of KCNH2 is modest, targeted genetic testing including KCNH2 can refine molecular diagnosis in SCN5A-negative BrS cases and inform clinical management.

References

• Cardiovascular research • 2005 • Role of sequence variations in the human ether-a-go-go-related gene (HERG, KCNH2) in the Brugada syndrome. PMID:16043162
• Journal of cardiovascular electrophysiology • 2014 • Gain-of-function KCNH2 mutations in patients with Brugada syndrome. PMID:24400717
• Biochemistry. Biokhimiia • 2024 • Novel Gain-of-Function Mutation in the Kv11.1 Channel Found in the Patient with Brugada Syndrome and Mild QTc Shortening. PMID:38648771
• Genetics in medicine : official journal of the American College of Medical Genetics • 2017 • Numerous Brugada syndrome-associated genetic variants have no effect on J-point elevation, syncope susceptibility, malignant cardiac arrhythmia, and all-cause mortality. PMID:27711072

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