KCNQ1 – Long QT Syndrome Type 1

KCNQ1 encodes the α-subunit of the cardiac slow delayed rectifier K+ channel (I_Ks), and heterozygous pathogenic variants cause autosomal dominant long QT syndrome type 1 (LQT1) (MONDO:0002442). Patients present with QT prolongation on ECG, syncope, and risk of torsades de pointes and sudden cardiac death. Since its initial discovery, KCNQ1 has been implicated in both dominant Romano–Ward syndrome and recessive Jervell and Lange-Nielsen syndrome, with variable expressivity across families.

1 Assess Clinical Validity

Overall evidence supports a Definitive gene–disease association. Over 114 unrelated probands carrying KCNQ1 variants across multiple cohorts (PMID:11216980), 42 unrelated families screened in a Chinese population (PMID:12442276), and 19 founder families harboring the R518X mutation in Sweden (PMID:24552659) demonstrate consistent co-segregation. Functional studies across >20 missense, nonsense, and splice variants show concordant loss-of-function or dominant-negative effects, yielding replication over >20 years.

"gene_disease_association": {
  "value": "Definitive",
  "rationale": "Over 114 probands, 42 multiethnic families, robust segregation and functional concordance"
}

2 Summarise Genetic Evidence

Inheritance is Autosomal dominant. Segregation analysis across pedigrees identifies 86 additional affected relatives with co-segregating KCNQ1 variants. Case series include 114 probands with diverse variant classes: missense, nonsense, splice-site, frameshift, large deletions, and duplications. Variant spectrum comprises at least 45 missense, 10 nonsense, 5 splice-site, 3 frameshift, 2 large deletions, and 1 duplication alleles. Founder/recurrent variants include p.Arg518Ter and p.Gly589Ser in Swedish and Finnish populations. One representative variant: c.1552C>T (p.Arg518Ter).

"genetic_evidence": {
  "value": "Strong",
  "rationale": "114 variants in 114 probands; reached ClinGen genetic cap; multi-family segregation"
}

3 Summarise Functional / Experimental Evidence

Mechanism is loss-of-function with dominant-negative effects on I_Ks. Key assays include two-electrode voltage clamp in Xenopus oocytes and patch-clamp in mammalian cells. Mutants such as p.Gly314Arg, p.Arg243Cys, p.Trp248Arg, and p.Gly306Arg show reduced current amplitude, shifted activation voltage dependence, and impaired channel trafficking (PMID:9312006; PMID:10409658). Transgenic mice expressing dominant-negative isoforms recapitulate QT prolongation and arrhythmia susceptibility.

"functional_evidence": {
  "value": "Strong",
  "rationale": "Multiple independent electrophysiological studies demonstrate consistent loss-of-function phenotypes"
}

4 Address Conflicting Evidence

No substantive refuting studies have been reported. Mild or subclinical presentations in some heterozygotes reflect incomplete penetrance rather than alternative etiology.

5 Integrate & Conclude

KCNQ1 variants disrupt cardiac repolarization via haploinsufficiency and dominant-negative suppression of I_Ks, underpinning the clinical LQT1 phenotype. Genetic testing of KCNQ1 informs risk stratification, guides β-blocker therapy, and enables cascade screening. Additional evidence from large deletions and duplications, as well as modifier loci, further refines variant interpretation but does not alter the definitive association.

Key Take-home: KCNQ1 is definitively linked to LQT1; genetic and functional data support clinical diagnosis, family screening, and targeted management.

References

• Human mutation | 2002 | KCNQ1 and KCNH2 mutations associated with long QT syndrome in a Chinese population PMID:12442276
• EMBO J | 1997 | Properties of KvLQT1 K+ channel mutations in Romano-Ward and Jervell and Lange-Nielsen inherited cardiac arrhythmias PMID:9312006
• J Biol Chem | 1999 | Long QT syndrome-associated mutations in the S4-S5 linker of KvLQT1 potassium channels modify gating and interaction with minK subunits PMID:10409658
• Eur J Hum Genet | 1999 | Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene PMID:10482963
• BMC Cardiovasc Disord | 2014 | Phenotype, origin and estimated prevalence of a common long QT syndrome mutation: Swedish R518X/KCNQ1 families PMID:24552659

Evidence Based Scoring (AI generated)

Gene–Disease Association Definitive Over 114 probands, 42 multiethnic families, robust segregation and functional concordance Genetic Evidence Strong 114 variants in 114 probands; reached ClinGen genetic cap; multi-family segregation Functional Evidence Strong Multiple independent electrophysiological studies demonstrate consistent loss-of-function phenotypes