Phylogenetic and physicochemical analyses enhance the classification of rare nonsynonymous single nucleotide variants in type 1 and 2 long-QT syndrome.

BACKGROUND: Hundreds of nonsynonymous single nucleotide variants (nsSNVs) have been identified in the 2 most common long-QT syndrome-susceptibility genes (KCNQ1 and KCNH2). Unfortunately, an ≈3% BACKGROUND: and KCNH2 nsSNVs amongst healthy individuals complicates the ability to distinguish rare pathogenic mutations from similarly rare yet presumably innocuous variants. METHODS AND RESULTS: In this study, 4 tools [(1) conservation across species, (2) Grantham values, (3) sorting intolerant from tolerant, and (4) polymorphism phenotyping] were used to predict pathogenic or benign status for nsSNVs identified across 388 clinically definite long-QT syndrome cases and 1344 ostensibly healthy controls. From these data, estimated predictive values were determined for each tool independently, in concert with previously published protein topology-derived estimated predictive values, and synergistically when ≥3 tools were in agreement. Overall, all 4 tools displayed a statistically significant ability to distinguish between case-derived and control-derived nsSNVs in KCNQ1, whereas each tool, except Grantham values, displayed a similar ability to differentiate KCNH2 nsSNVs. Collectively, when at least 3 of the 4 tools agreed on the pathogenic status of C-terminal nsSNVs located outside the KCNH2/Kv11.1 cyclic nucleotide-binding domain, the topology-specific estimated predictive value improved from 56% to 91%. CONCLUSIONS: Although in silico prediction tools should not be used to predict independently the pathogenicity of a novel, rare nSNV, our results support the potential clinical use of the synergistic utility of these tools to enhance the classification of nsSNVs, particularly for Kv11.1's difficult to interpret C-terminal region.

Clínica y genética en el síndrome de QT largo / Clinical and genetic characteristics of long QT syndrome

El síndrome de QT largo (SQTL) es una canalopatía arritmogénica caracterizada por una grave alteración en la repolarización ventricular, traducida electrocardiográficamente por una prolongación del intervalo QT. Predispone a muerte súbita por arritmias ventriculares malignas del tipo de torsade de pointes. A 11 años de la identificación de los principales canales afectados en esta enfermedad, se han descrito cientos de mutaciones distribuidas en hasta ahora 10 genes relacionados con el síndrome. El escrutinio genético realizado desde entonces ha mostrado que, si bien la forma grave de la enfermedad es esporádica, hay polimorfismos comunes en los genes relacionados con la enfermedad que pueden generar susceptibilidad individual al desarrollo de torsade de pointes, en particular con el uso de determinados fármacos; más aún, se han identificado polimorfismos con cualidades reguladoras que pueden exacerbar o silenciar la gravedad de una mutación. El entendimiento de los procesos moleculares de la enfermedad ha permitido optimizar el tratamiento y mejorar la supervivencia de los afectados, generando así una importante correlación genotipo-fenotipo-tratamiento. A pesar de los avances, una cuarta parte de los casos no tiene mutaciones en los genes descritos hasta el momento, por lo que el SQTL continúa siendo motivo de investigación. El presente artículo representa el análisis de los principales conceptos clínicos y genéticos desarrollados en los últimos años sobre esta singular enfermedad (AU)

Long QT syndrome (LQTS) is an arrhythmogenic ion channel disorder characterized by severely abnormal ventricular repolarization, which results in prolongation of the electrocardiographic QT interval. The condition is associated with sudden cardiac death due to malignant ventricular arrhythmias similar in form to the hallmark torsade de pointes. Eleven years after the identification of the principle cardiac channels involved in the condition, hundreds of mutations in, to date, 10 genes have been associated with the syndrome. Genetic investigations carried out up until the present have shown that, although the severe form of the disease is sporadic, there are a number of common polymorphisms in genes associated with the condition that may confer susceptibility to the development of torsade de pointes in some individuals, particularly when specific drugs are being administered. Moreover, some polymorphisms have been shown to have regulatory properties that either enhance or counteract a particular mutation's impact. Understanding of the molecular processes underlying the syndrome has enabled treatment to be optimized and has led to better survival among sufferers, thereby demonstrating a key correspondence between genotype, phenotype and therapy. Despite these developments, a quarter of patients do not have mutations in the genes identified to date. Consequently, LQTS continues to be an area of active research. This article contains a summary of the main clinical and genetic developments concerning the syndrome that have taken place during the last decade (AU)