Is it time to develop a 'pathogenicity' score to distinguish long QT syndrome causing mutations from 'background' genetic noise?

摘要

The congenital long QT syndromes (LQTSs) are a group of genetic disorders that affect cardiac ion channels, are characterized by prolongation of the QT interval, and carry a risk for the life-threatening ventricular tachycardia tor-sades de pointes. Shortly after Jervell and Lange-Nielsen described the autosomal recessive syndrome of congenital deafness, prolongation of the QT interval, and sudden cardiac death in 1957, Romano and Ward each independently described an "autosomal dominant" form without congenital deafness. In the late 1990s, the first five LQTS genes were identified, all of which encode ion channel subunits that underlie the cardiac action potential. The most commonly affected genes, KCNQ1 and KCNH2 (underlying LQT1 and LQT2, respectively), encode proteins that form the alpha subunits of two major repolarizing potassium currents, IKs and I_(kr).