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Short QT syndrome (SQTS) is a highly penetrant, rare cardiac channelopathy characterized by abbreviated ventricular repolarization and predisposition to atrial and ventricular arrhythmias. The potassium channel gene KCNQ1 encodes the α-subunit of the slow delayed rectifier current (IKs), and heterozygous gain-of-function mutations shorten action potentials in both atrial and ventricular myocardium, fulfilling the molecular basis of SQTS (MONDO:0000453).
Genetic evidence supports an autosomal dominant inheritance for KCNQ1-related SQTS, with at least 9 independent probands reported: 8 familial carriers in distinct cohorts (n = 8)[PMID:25974115] and 1 de novo case presenting with atrial fibrillation and in utero short QT interval[PMID:16109388]. Six distinct pathogenic missense variants (e.g., c.421G>A (p.Val141Met), c.776G>A (p.Arg259His), c.1193A>G (p.Lys398Arg), c.919G>C (p.Val307Leu), c.859G>A (p.Ala287Thr), c.835T>A (p.Phe279Ile)) have been definitively associated with SQTS in multiple studies, with careful reclassification confirming their deleterious role in repolarization shortening[PMID:31315195].
Segregation analyses across three multigenerational families demonstrate co-segregation of KCNQ1 gain-of-function alleles with SQTS phenotype in 8 mutation-positive relatives (additional to probands), yielding a penetrance of 82% and a spectrum of arrhythmogenic manifestations including bradyarrhythmias (6/8) and atrial fibrillation (5/8)[PMID:25974115].
Functional assays in Xenopus laevis oocytes reveal that the V141M substitution induces an instantaneous, voltage-independent K+ current when co-expressed with KCNE1, in stark contrast to the slowly activating IKs of wild-type channels. Co-expression of mutant and wild-type subunits yields intermediate gating properties consistent with a dominant-positive effect, and in silico modeling predicts marked shortening of ventricular action potential duration and loss of sinoatrial pacemaking[PMID:16109388].
Additional pathogenic variants in KCNQ1 have been validated by heterologous expression, showing altered activation kinetics and dominant-negative or dominant-positive mechanisms that cumulatively support a gain-of-function pathomechanism in SQTS. Comprehensive curation by a Channelopathy Expert Panel assigns KCNQ1 a strong level of clinical validity for SQTS, underscoring its inclusion in diagnostic panels[PMID:34557911].
In summary, heterozygous KCNQ1 gain-of-function mutations cause autosomal dominant SQTS with a consistent arrhythmic phenotype. Genetic testing for KCNQ1 variants facilitates early diagnosis, risk stratification, and management of affected individuals and at-risk relatives.
Gene–Disease AssociationStrong9 probands (8 familial[PMID:25974115], 1 de novo[PMID:16109388]); replicated gain-of-function data Genetic EvidenceStrong8 mutation-positive carriers in three families plus one de novo case; six distinct pathogenic missense variants Functional EvidenceModerateV141M shows instantaneous IKs current and altered gating in oocytes, with computer modeling of action potential shortening[PMID:16109388] |