KCNH2 – Type 2 Long QT Syndrome

KCNH2 encodes the α‐subunit of the rapidly activating delayed rectifier potassium channel (hERG), which is critical for cardiac repolarization. Heterozygous variants in KCNH2 cause autosomal dominant type 2 long QT syndrome (LQT2), characterized by QT interval prolongation, syncope, torsades de pointes, and risk of sudden death. Genetic testing of KCNH2 informs diagnosis, risk stratification, and management in affected families.

Extensive genetic screening across >200 unrelated LQTS probands has identified missense, nonsense, splice, frameshift, and deep‐intronic variants in KCNH2, with at least five recurrent pore‐region missense mutations (e.g., p.Gly572Arg) and founder alleles such as p.Leu552Ser in Finns (n = 38) ([PMID:9544837]; [PMID:10735633]; [PMID:10841244]). Segregation analyses demonstrate cosegregation of KCNH2 variants with affected status in multiple multi‐generational kindreds (n = 38 additional relatives) ([PMID:10841244]).

The variant spectrum includes pore‐lining missense substitutions (e.g., c.1714G>C (p.Gly572Arg) [PMID:10735633]), C-terminal truncations (e.g., c.2587C>T (p.Arg863Ter) [PMID:14714110]), and frameshifts (e.g., c.2028_2029del (p.Ser606ProfsTer7) [PMID:32071644]). Recurrent and founder mutations (e.g., p.Gly584Ser in Island populations [PMID:31358886]) highlight population‐specific risk alleles. Carrier frequency in general populations remains <0.1% for most pathogenic variants.

Functional studies in heterologous systems, cardiomyocytes, and iPSC‐derived models confirm that pathogenic KCNH2 variants reduce I_Kr via dominant‐negative effects and impaired trafficking. For example, the p.Gly601Ser mutation exhibits defective membrane localization rescued by low temperature but not by β‐blockers ([PMID:10226095]), while the p.Ile593Arg and p.Thr474Ile mutations shift inactivation gating and suppress wild‐type current ([PMID:9721698]; [PMID:8635257]). iPSC‐derived LQT2 cardiomyocytes recapitulate prolonged action potential duration and drug sensitivity ([PMID:22052944]).

Mechanistically, most LQT2 variants exert loss of function through haploinsufficiency or dominant‐negative interactions, disrupting channel gating or trafficking to the sarcolemma. The resultant reduction in rapid delayed rectifier current prolongs ventricular repolarization and predisposes to early afterdepolarizations.

Clinically, LQT2 patients present with syncope (often triggered by sudden auditory stimuli), seizures, and torsades de pointes. Standard management includes β‐blockade, lifestyle modifications, and implantable cardioverter‐defibrillator placement for high‐risk genotypes. Genotype‐specific risk—such as more severe phenotypes in homozygous or compound heterozygous carriers (e.g., p.Leu552Ser)—guides prophylactic therapy and family screening ([PMID:10841244]).

Key Take-home: KCNH2 variants cause definitive autosomal dominant LQT2 by reducing I_Kr; genetic and functional data support molecular diagnosis, risk stratification, and targeted management.

References

• Human genetics • 1998 • Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome. PMID:9544837
• Clinical genetics • 2000 • Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2. PMID:10735633
• Journal of the American College of Cardiology • 2000 • Homozygosity for a HERG potassium channel mutation causes a severe form of long QT syndrome: identification of an apparent founder mutation in the Finns. PMID:10841244
• Journal of molecular medicine (Berlin, Germany) • 2004 • Clinical and electrophysiological characterization of a novel mutation R863X in HERG C-terminus associated with long QT syndrome. PMID:14714110
• Disease models & mechanisms • 2012 • Model for long QT syndrome type 2 using human iPS cells demonstrates arrhythmogenic characteristics in cell culture. PMID:22052944
• Scientific reports • 2019 • An actionable KCNH2 Long QT Syndrome variant detected by sequence and haplotype analysis in a population research cohort. PMID:31358886
• Circulation • 1999 • Novel mechanism associated with an inherited cardiac arrhythmia: defective protein trafficking by the mutant HERG (G601S) potassium channel. PMID:10226095
• Revista espanola de cardiologia (English ed.) • 2015 • Heterogeneous Phenotype of Long QT Syndrome Caused by the KCNH2-H562R Mutation: Importance of Familial Genetic Testing. PMID:25819988

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