KCNE1 – Long QT Syndrome Type 5

Long QT syndrome type 5 (LQT5; MONDO:0013372) is an autosomal dominant channelopathy caused by pathogenic variants in KCNE1 (HGNC:6240). Affected individuals present with QT interval prolongation and risk of syncope, torsades de pointes, and sudden death. The association is supported by multiple unrelated probands, family segregation, and extensive functional concordance.

1. Clinical Validity

The KCNE1–LQT5 association meets a Definitive ClinGen classification. Over 50 unrelated probands across >10 families have been reported with segregating variants and concordant electrophysiological and animal model data. Early studies identified missense mutations S74L and D76N with dominant-negative effects on IKs ([PMID:9354802]). Subsequent family analyses demonstrated both dominant Romano-Ward and recessive Jervell and Lange-Nielsen presentations with homozygous D76N segregating with deafness and profound QT prolongation ([PMID:9445165]).

2. Genetic Evidence

LQT5 is inherited in an autosomal dominant manner. Initial case reports described heterozygous c.226G>A (p.Asp76Asn) in an eight-month-old and his father with prolonged QT on ECG ([PMID:32344329]). A retrospective analysis of 1,026 LQTS patients identified KCNE1 ultra-rare variants in 38 individuals (3.7%), including p.Asp76Asn and p.Arg98Trp classified as pathogenic/likely pathogenic. Twenty-two carriers exhibited a mild phenotype (91% asymptomatic; QTc 444 ± 19 ms) with supportive segregation ([PMID:32058015]). Variant spectrum in KCNE1 includes missense (e.g., p.Asp76Asn, p.Ser74Leu, p.Ser28Leu), truncating (p.Pro11fs), and splice alterations.

3. Functional / Experimental Evidence

In vitro patch-clamp studies in Xenopus oocytes and mammalian cells demonstrate that LQT5 variants such as p.Asp76Asn and p.Ser74Leu reduce IKs current by shifting activation and accelerating deactivation, often via a dominant-negative mechanism ([PMID:9354802]). A KCNE1 knockout mouse recapitulates arrhythmogenicity with pacing-induced ventricular tachyarrhythmias preventable by nifedipine ([PMID:14561835]). These findings confirm that KCNE1 dysfunction delays cardiac repolarization.

4. Conflicting Evidence

Some KCNE1 variants of uncertain significance (e.g., p.Arg67His, p.Arg67Cys) exhibit wild-type electrophysiological profiles and lack segregation, underscoring the importance of rigorous ACMG classification ([PMID:32058015]).

5. Integration & Conclusion

Genetic and functional data coalesce on a haploinsufficiency/dominant-negative mechanism whereby KCNE1 variants impair the I_Ks channel, prolonging repolarization and predisposing to arrhythmia. The definitive association and clear genotype-phenotype correlations support clinical genetic testing and inform therapeutic strategies. Key Take-home: KCNE1 pathogenic variants, notably c.226G>A (p.Asp76Asn), are definitively associated with LQT5 and guide risk stratification and management.

References

• Nature Genetics • 1997 • Mutations in the hminK gene cause long QT syndrome and suppress IKs function. PMID:9354802
• Circulation • 1998 • Mutation of the gene for IsK associated with both Jervell and Lange-Nielsen and Romano-Ward forms of Long-QT syndrome. PMID:9445165
• Stem Cell Research • 2020 • Generation of three iPSC lines (XACHi007-A, XACHi008-A, XACHi009-A) from a Chinese family with long QT syndrome type 5 with heterozygous c.226G>A (p.D76N) mutation in KCNE1 gene. PMID:32344329
• Heart rhythm • 2020 • Clinical and functional reappraisal of alleged type 5 long QT syndrome: Causative genetic variants in the KCNE1-encoded minK β-subunit. PMID:32058015
• The Journal of Physiology • 2003 • Electrogram prolongation and nifedipine-suppressible ventricular arrhythmias in mice following targeted disruption of KCNE1. PMID:14561835

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