Allelic Complexity in Long QT Syndrome: A Family-Case Study.

Alberto Zullo,Francesco Salvatore,Angela Cordella,Emanuele Romeo,Carlos Vanoye,Raffaele Calabrò,Nicola Detta,Alfred George,Berardo Sarubbi,Giulia Frisso

doi:10.3390/ijms18081633

Abstract

Congenital long QT syndrome (LQTS) is associated with high genetic and allelic heterogeneity. In some cases, more than one genetic variant is identified in the same (compound heterozygosity) or different (digenic heterozygosity) genes, and subjects with multiple pathogenic mutations may have a more severe disease. Standard-of-care clinical genetic testing for this and other arrhythmia susceptibility syndromes improves the identification of complex genotypes. Therefore, it is important to distinguish between pathogenic mutations and benign rare variants. We identified four genetic variants (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S) in an LQTS family. On the basis of in silico analysis, clinical data from our family, and the evidence from previous studies, we analyzed two mutated channels, KCNQ1-p.R583H and KCNH2-p.C108Y, using the whole-cell patch clamp technique. We found that KCNQ1-p.R583H was not associated with a severe functional impairment, whereas KCNH2-p.C108Y, a novel variant, encoded a non-functional channel that exerts dominant-negative effects on the wild-type. Notably, the common variants KCNH2-p.K897T and KCNE1-p.G38S were previously reported to produce more severe phenotypes when combined with disease-causing alleles. Our results indicate that the novel KCNH2-C108Y variant can be a pathogenic LQTS mutation, whereas KCNQ1-p.R583H, KCNH2-p.K897T, and KCNE1-p.G38S could be LQTS modifiers.

Highlights

Long QT syndrome (LQTS) is an inherited predisposition to life-threatening ventricular arrhythmias that leads leading to sudden cardiac death in children and young adults [1], because prolongation of the QT interval is associated with delayed ventricular repolarization [2]
We identified four genetic variants in three genes (KCNQ1-p.R583H, KCNH2-p.C108Y, KCNH2-p.K897T, and KCNE1-p.G38S)
The other brother (II-3 in Figure 1A; Table 1) was screened because of the family history of long QT syndrome (LQTS) and was found to have a QTc of ~470 ms at age six years. He was treated with nadolol, but three years after beginning treatment he experienced extreme bradycardia with sinus pauses of ~4 s followed by syncope

Summary

Introduction

Long QT syndrome (LQTS) is an inherited predisposition to life-threatening ventricular arrhythmias that leads leading to sudden cardiac death in children and young adults [1], because prolongation of the QT interval is associated with delayed ventricular repolarization [2]. In most LQTS cases, causative mutations have been identified in the KCNQ1 or KCNH2 gene, which encode the pore-forming subunits of the two physiologically important potassium channels required for the slow and rapid delayed rectifier currents, IKs and IKr, respectively [7,8]. Impaired function of these important repolarizing currents is the most common defect conferred by mutations in KCNQ1 and KCNH2 [9]

Methods

Results

Conclusion