Short Qt Syndrome 1

A number sign (#) is used with this entry because of evidence that short QT syndrome-1 (SQT1) is caused by heterozygous mutation in the KCNH2 gene (152427) on chromosome 7q36.

Description

Short QT syndrome is a cardiac channelopathy associated with a predisposition to atrial fibrillation and sudden cardiac death. Patients have a structurally normal heart, but electrocardiography (ECG) exhibits abbreviated QTc (Bazett's corrected QT) intervals of less than 360 ms (summary by Moreno et al., 2015).

Genetic Heterogeneity of Short QT Syndrome

Short QT syndrome-2 (SQT2; 609621) is caused by mutation in the KCNQ1 gene (607542). SQT3 (609622) is caused by mutation in the KCNJ2 gene (600681).

Clinical Features

Gussak et al. (2000) reported a brother, sister, and their mother who had idiopathic persistently short QT interval, which was associated in the 17-year-old sister with several episodes of paroxysmal atrial fibrillation requiring cardioversion. All 3 patients had QT intervals of less than 80% of predicted value (280 ms, 272 ms, and 260 ms in the sister, brother, and mother, respectively). Similar ECG changes (QT interval, 260 ms) in an unrelated 37-year-old female were associated with sudden cardiac death. Hong et al. (2005) reported that in the family originally studied by Gussak et al. (2000) the deceased maternal grandfather also had short QT interval and chronic atrial fibrillation. Programmed electrical stimulation in the mother and 2 sibs revealed a remarkably short atrial and ventricular refractory period and inducibility of atrial and ventricular fibrillation. All 3 affected members of the family received implantable cardioverter defibrillators, and treatment with propafenone maintained them free of atrial fibrillation.

Gaita et al. (2003) described 2 unrelated 5-generation pedigrees with a strong family history of sudden death and an idiopathic persistently and uniformly short QT interval on ECG in the absence of structural heart disease in affected individuals. Symptoms included syncope, palpitations, and cardiac arrest. Sudden death occurred in both males and females over 4 generations with father-to-son transmission in both families, suggesting an autosomal dominant mode of inheritance. Six patients underwent extensive evaluation; all exhibited a QT interval of less than 280 ms on baseline ECG and had short atrial and ventricular refractory periods; increased ventricular vulnerability to fibrillation was demonstrated in 3 of 4 patients.

Molecular Genetics

Using a candidate gene approach in 2 families with short QT syndrome, previously reported by Gaita et al. (2003), Brugada et al. (2004) directly sequenced multiple genes encoding ion channels contributing to repolarization of the ventricular action potential and identified 2 different missense mutations (152427.0017 and 152427.0018, respectively) in the KCNH2 gene, leading to the same asn588-to-lys (N588K) substitution. The mutation was present in all affected family members and in none of the unaffected individuals. The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggested the possibility of a link between KCNH2 gain-of-function mutations and sudden infant death syndrome (272120).

In a family with short QT syndrome, originally reported by Gussak et al. (2000), Hong et al. (2005) identified an N588K mutation (152427.0017) in the KCNH2 gene. They concluded that codon 588 is a hotspot for this familial form of short QT syndrome. Hong et al. (2005) noted that the disease is clinically heterogeneous, with symptoms varying from atrial to ventricular fibrillation and sudden death in the 3 families with the same mutation.

Schimpf et al. (2005) reviewed the clinical, electrophysiologic, and molecular features of 15 reported cases (Gussak et al., 2000, Gaita et al., 2003, Brugada et al., 2004, Bellocq et al., 2004, and Priori et al., 2005) and 2 unpublished cases of short QT syndrome type 1, 2, and 3.

From a cohort of 2,008 healthy individuals, Gouas et al. (2005) analyzed a group of 200 individuals with the shortest QTc intervals and a group of 198 with the longest QTc intervals, comparing the allele, genotype, and haplotype frequencies of polymorphisms in cardiac ion channel genes (10 SNPs in KCNQ1, 2 in KCNE1 (176261), 4 in SCN5A (600163), and 1 in KCNH2) between the 2 groups. Based on observed differences, Gouas et al. (2005) suggested that genetic determinants located in these genes influence QTc length in healthy individuals and may represent risk factors for arrhythmias or cardiac sudden death in patients with cardiovascular disease.