Polygenic case of long QT syndrome confirmed through functional characterization informs the interpretation of genetic screening results

Abstract

Long QT Syndrome (LQTS) is a disorder of cardiac repolarization and is characterized by a prolonged QT interval on ECG. LQTS is usually referred to as a monogenic disorder.1 QT interval in the population is variable,2 which leads to many “borderline” cases and makes definitive diagnosis difficult.1 The utility of clinical genetic screening in congenital LQTS has been demonstrated,3 though issues remain with variants of unknown significance (VUS), false positives, and false negatives.4 The study and diagnosis of LQTS is additionally complicated by a high degree of variable penetrance, making genotyping a sub-optimal predictor of clinical outcome and complicating risk stratification.5 Genetic testing companies provide some guidance about the relevance of the mutations identified. In the genetic screening performed in this study through FAMILION, mutations are classified as Class I mutations including deleterious and probable deleterious mutants. Class II are possible deleterious mutations or mutations of unknown significance (VUS) and Class III are polymorphisms. Most reported cases of congenital LQTS have a single affected allele.3 Here, we describe a family where while only the proband presents with LQTS clinically, genetic testing revealed that all 5 family members studied carried at least one of three potential LQT mutations: two LQT2 mutations in the potassium channel hERG (Class I mutation: S654G and Class II mutation: A913V) and one LQT3 in the cardiac sodium channel SCN5A (Class I mutation: Fl596I). Our objective was to use functional characterization and computational modeling to determine the contribution to the LQT phenotype of 3 potential LQT mutations identified in a single lineage. We hypothesized this family presents a polygenic case of LQTS where an additive effect of the mutations leads to the LQT phenotype.