KCNH2 – Long QT Syndrome Type 2

Long QT syndrome type 2 (LQT2) is an autosomal dominant cardiac channelopathy caused by pathogenic variants in KCNH2, which encodes the α-subunit of the rapid delayed rectifier potassium current (IKr) channel ([HGNC:6251])(https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:6251)–[KCNH2]. The disease is cataloged as MONDO:0013367–Long QT syndrome 2, reflecting prolonged ventricular repolarization and risk of life-threatening arrhythmias.

Genetic evidence supports a Definitive gene–disease association. Over 429 unrelated LQT2 probands have been reported with rare KCNH2 variants, including 234 probands in a recent cohort study (PMID:36861347). Familial studies document multi-generation segregation of missense, nonsense, frameshift, and splice variants with disease status, as seen in consanguineous pedigrees with biallelic loss-of-function alleles (PMID:10491368).

Inheritance is autosomal dominant with variable penetrance. Segregation analyses across multiple families have identified at least 19 affected relatives carrying heterozygous KCNH2 variants, confirming co-segregation with prolonged QT and syncope phenotypes. Founder and recurrent alleles, such as the c.3099_3112del (p.Ser606ProfsTer7) variant in diverse populations, underscore population-specific risks.

The variant spectrum includes over 900 distinct changes: ~70% missense, ~15% frameshift or nonsense introducing premature termination codons, splice-site alterations, and deep-intronic mutations. A representative frameshift, c.3370dup (p.Ala1124fs), causes a 74% reduction in IKr density without dominant-negative effects (PMID:15572050).

Functional assays reveal a predominant loss-of-function mechanism mediated by defective protein trafficking, accelerated inactivation, or altered gating. The PAS-domain missense variant c.232G>A (p.Ala78Thr) yields immature, ubiquitinated protein retained intracellularly with absent current in HEK293 cells; stability is partially restored by heat-shock factor 1 (PMID:27761169).

Patient-derived iPSC cardiomyocytes harboring KCNH2 variants recapitulate prolonged action potentials and arrhythmic phenotypes, confirming clinical relevance. Pharmacological and temperature rescue of trafficking-deficient mutants further demonstrate that stabilizing channel conformation can restore surface expression and current amplitude (PMID:15572050).

Collectively, robust genetic segregation, extensive variant characterization, and convergent functional data establish KCNH2 as definitively causal for LQT2. Genetic testing for KCNH2 variants informs risk stratification and guides therapeutic interventions, including β-blocker therapy and device implantation. Key Take-home: Definitive evidence supports autosomal dominant KCNH2 loss-of-function as the molecular basis of LQT2, with direct implications for diagnosis, management, and targeted therapies.

References

• Journal of molecular and cellular cardiology • 2004 • Novel C-terminus frameshift mutation, 1122fs/147, of HERG in LQT2: additional amino acids generated by frameshift cause accelerated inactivation. PMID:15572050
• Journal of arrhythmia • 2016 • Characterization of the novel mutant A78T-HERG from a long QT syndrome type 2 patient: Instability of the mutant protein and stabilization by heat shock factor 1. PMID:27761169
• Europace • 2023 • Non-missense variants of KCNH2 show better outcomes in type 2 long QT syndrome. PMID:36861347
• Circulation • 1999 • Homozygous premature truncation of the HERG protein : the human HERG knockout. PMID:10491368

Evidence Based Scoring (AI generated)