KCNQ1 – Hypertrophic Cardiomyopathy

KCNQ1 encodes the alpha subunit of the cardiac slow delayed rectifier potassium channel (I_Ks), classically implicated in autosomal‐dominant long QT syndrome type 1 (LQT1). A three-generation Chinese pedigree harboring four heterozygous missense mutations, including KCNQ1:c.568C>T (p.Arg190Trp), exhibited overlapping hypertrophic cardiomyopathy (HCM) and LQT1 phenotypes; however, carriers of p.Arg190Trp uniformly showed QTc prolongation without left ventricular hypertrophy (five carriers) (PMID:25825456). Follow-up echocardiographic speckle tracking in this family confirmed that p.Arg190Trp carriers retained normal myocardial deformation parameters with only electrocardiographic abnormalities (PMID:29978770). In a separate HCM cohort enriched for unexplained QTc prolongation, two unrelated patients (8%) carried KCNQ1:c.1781G>A (p.Arg594Gln) and another variant, both associated with QTc prolongation but absent in non-HCM controls (two patients) (PMID:37089884).

No additional unrelated probands with isolated HCM have been reported for KCNQ1, and segregation of HCM features with KCNQ1 variants is lacking (affected relatives = 0). Functional assays across multiple studies demonstrate that p.Arg190Trp and other I_Ks-affecting variants induce dominant-negative suppression of repolarizing currents, yet none have been shown to drive cardiomyocyte hypertrophy or sarcomeric dysfunction directly. Thus, the evidence linking KCNQ1 to HCM is limited to oligogenic contexts where sarcomere gene mutations are primary drivers. Additional studies in independent HCM cohorts and mechanistic models are needed to clarify whether KCNQ1 variants contribute to myocardial hypertrophy. Key Take-home: Current data support a limited association of KCNQ1 variants with HCM; clinical genetic testing for KCNQ1 in HCM should be restricted to research settings or when unexplained QTc prolongation co-occurs.

References

• Europace • 2016 • Dual LQT1 and HCM phenotypes associated with tetrad heterozygous mutations in KCNQ1, MYH7, MYLK2, and TMEM70 genes in a three-generation Chinese family PMID:25825456
• Cardiology in the young • 2018 • Investigation of myocardial dysfunction using three-dimensional speckle tracking echocardiography in a genetic positive hypertrophic cardiomyopathy Chinese family PMID:29978770
• Frontiers in cardiovascular medicine • 2023 • Long QTc in hypertrophic cardiomyopathy: A consequence of structural myocardial damage or a distinct genetic disease? PMID:37089884

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