KCNQ1 – Long QT Syndrome Type 1

Long QT syndrome type 1 (LQT1) is the most common subtype of congenital long QT syndrome, characterized by ventricular repolarization delay and risk of syncope and sudden cardiac death. LQT1 is caused by heterozygous mutations in the KCNQ1 gene, which encodes the Kv7.1 α-subunit of the slow delayed-rectifier potassium current (I_Ks) in the heart (PMID:37897496). The clinical presentation ranges from asymptomatic QT prolongation to life-threatening arrhythmias.

Genetic evidence supports an autosomal dominant inheritance for LQT1, with hundreds of distinct missense, nonsense, splice, frameshift, and founder variants reported in over 3 700 probands referred for clinical genetic testing (PMID:37897496). Cascade screening of 505 relatives identified 251 mutation carriers, many with QT prolongation or symptoms, confirming segregation (PMID:18752142).

The variant spectrum includes >200 unique alleles: missense substitutions in the transmembrane and pore regions, loss-of-function frameshifts and nonsense mutations, and splice-site alterations. Notable recurrent/founder variants include c.671C>T (p.Thr224Met) enriched in the Amish (1/45 carriers; n=88) (PMID:33141630) and c.1022C>T (p.Ala341Val) in a South African Xhosa founder population (PMID:25634836).

Functional studies consistently demonstrate loss of Kv7.1 channel function and dominant-negative effects. Xenopus oocyte assays showed that G325R channels abolish I_Ks and suppress wild-type current by >70% (PMID:23000022). Adenoviral expression of G306R in cardiomyocytes reduced endogenous I_Ks by >70% (PMID:11351021), and transgenic mice overexpressing a dominant-negative KvLQT1 isoform recapitulated QT prolongation, sinus node dysfunction, and AV block (PMID:11334835).

Human iPSC-derived cardiomyocyte models carrying M437V and A341V mutations display action potential prolongation and early afterdepolarizations under β-adrenergic stimulation, mirroring patient arrhythmias (PMID:31245483). Modifier loci (e.g., NOS1AP variants) and autonomic control further influence penetrance and arrhythmic risk, highlighting the importance of integrated clinical and genetic assessment.

In sum, the extensive genetic and experimental concordance establishes a definitive association between KCNQ1 and LQT1. Molecular diagnosis of KCNQ1 variants enables precise risk stratification, genotype-guided therapy (β-blockers, lifestyle modification), and family screening. Key Take-home: KCNQ1 genetic testing is essential for accurate diagnosis and management of LQT1.

References

• Europace • 2023 • Enhancing the interpretation of genetic observations in KCNQ1 in unselected populations: relevance to secondary findings PMID:37897496
• Scandinavian journal of clinical and laboratory investigation • 2008 • Molecular genetic analysis of long QT syndrome in Norway indicating a high prevalence of heterozygous mutation carriers PMID:18752142
• Circulation: Genomic and Precision Medicine • 2020 • KCNQ1 and Long QT Syndrome in 1/45 Amish: The Road From Identification to Implementation of Culturally Appropriate Precision Medicine PMID:33141630
• Journal of the American College of Cardiology • 2015 • Autonomic control of heart rate and QT interval variability influences arrhythmic risk in long QT syndrome type 1 PMID:25634836
• Gene • 2012 • Impaired ion channel function related to a common KCNQ1 mutation - implications for risk stratification in long QT syndrome 1 PMID:23000022
• The Journal of Physiology • 2001 • Functional consequences of the arrhythmogenic G306R KvLQT1 K+ channel mutant probed by viral gene transfer in cardiomyocytes PMID:11351021
• Cardiovascular Research • 2001 • Transgenic mice overexpressing human KvLQT1 dominant-negative isoform. Part I: Phenotypic characterisation PMID:11334835
• Regenerative Therapy • 2016 • Electrophysiological properties of iPS cell-derived cardiomyocytes from a patient with long QT syndrome type 1 harboring the novel mutation M437V of KCNQ1 PMID:31245483

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