Abstract
Short QT syndrome, one of the most lethal entities associated with sudden cardiac death, is a rare genetic disease characterized by short QT intervals detected by electrocardiogram. Several genetic variants are causally linked to the disease, but there has yet to be a comprehensive analysis of variants among patients with short QT syndrome. To fill this gap, we performed an exhaustive study of variants currently catalogued as deleterious in short QT syndrome according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Analysis of the 32 variants described in the literature determined that only nine (28.12%) have a conclusive pathogenic role. All definitively pathogenic variants are located in KCNQ1, KCNH2, or KCNJ2; three genes encoding potassium channels. Other variants located in genes encoding calcium or sodium channels are associated with electrical alterations concomitant with shortened QT intervals but do not guarantee a diagnosis of short QT syndrome. We recommend caution regarding previously reported variants classified as pathogenic. An exhaustive re-analysis is necessary to clarify the role of each variant before routinely translating genetic findings to the clinical setting.
Highlights
In 2000, Gussak et al described short QT syndrome (SQTS) as a new clinical entity
Published data concerning SQTS show 15 variants reported as disease mutations (DM): two in KCNQ1, eight in KCNH2, three in KCNJ2, and one variant in SLC4A3
17 variants have been classified as having ambiguous significance due to a lack of conclusive data and conflicting clinical phenotypes. These rare variants have been identified in five genes: KCNQ1, KCNJ2, CACNA1C, CACNB2, and SCN5A
Summary
In 2000, Gussak et al described short QT syndrome (SQTS) as a new clinical entity. It was described as inherited condition because four individuals from the same family presented with idiopathic and persistent short QT intervals via electrocardiogram (ECG) [1]. In 2011, Gollob et al proposed a SQTS diagnostic criteria based on four components including ECG, clinical history, family history, and genotype [2]. Clinical diagnosis of SQTS is characterized by a shortened QT interval (QTc < 340 ms), tall and peaked T waves, and poor rate adaptation of the QT interval, all without structural heart abnormalities [4]. SQTS can be diagnosed with a QTc interval of
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