Short QT Syndrome: A Comprehensive Genetic Interpretation and Clinical Translation of Rare Variants.

Campuzano O1,2,3,4, Fernandez-Falgueras A5, Lemus X5, Sarquella-Brugada G6,7, Cesar S7, Coll M5, Mates J5, Arbelo E8,9, Jordà P8,9, Perez-Serra A5, Del Olmo B5, Ferrer-Costa C5, Iglesias A5, Fiol V7, Puigmulé M5, Lopez L5, Pico F5, Brugada J8,7,9, Brugada R10,11,12,13.

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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.