Identification novel LQT syndrome-associated variants in Polish population and genotype-phenotype correlations in eight families

Abstract

Congenital long QT syndrome (LQTS) is a primary cardiac channelopathy. Genetic testing has not only diagnostic but also prognostic and therapeutic implications. At present, 15 genes have been associated with the disease, with most mutations located in 3 major LQTS-susceptibility genes. During a routine genetic screening for KCNQ1, KCNH2 and SCN5A genes in index cases with LQTS, seven novel variants in KCNH2 and SCN5A genes were found. Genotypephenotype correlations were analysed in these patients and their families. An open reading frame and splice site analysis of the exons was conducted using next-generation sequencing. In novel variants, phenotypes of carriers and their affected relatives were analysed. In 39 unrelated patients, 40 pathogenic/putative pathogenic mutations were found. Thirty-three of them, predominantly missense, were reported previously: 11 were in the KCNQ, 17 in the KCNH2 and 5 in the SCN5A gene. Seven novel missense variants were found in eight families. Among them, four variants were in typical for LQTS location. Two variants in the KCNH2 gene (p.D803Y and p.D46F) and one in the SCN5A gene (G1391R) were in amino acid (AA) position which up to present has not been reported in LQTS. Phenotype analysis showed the life-threatening course of the disease in index cases with a history of sudden cardiac death in six families. Mutation carriers presented with ECG abnormalities and some of them received beta-blocker therapy. We report three novel variants (KCNQ1 p.46, KCNH2 p.D803Y, SCN5A p.G1391R) which have never been reported for this AA location in LQTS; the phenotype-genotype correlation suggests their pathogenicity. Keywords Long QT syndrome. Genetic screening. Novel variants What's new? Novel variants which have never been reported before in patients with LQT syndrome

In silico validation revealed the role of SCN5A mutations and their genotype–phenotype correlations in Brugada syndrome

“…This variant induced loss-offunction, showing a significant decrease in the current density peak than the wild-type through patch clamp (Ishikawa et al, 2021). The c.4171G>A (G1391R) variant was first reported by Szperl et al (2018) in the Polish population. Genotype and phenotype analysis showed that the carriers with G1391R variant presented a higher risk of cardiac events in females than in males (Szperl et al, 2018).…”

“…The c.4171G>A (G1391R) variant was first reported by Szperl et al (2018) in the Polish population. Genotype and phenotype analysis showed that the carriers with G1391R variant presented a higher risk of cardiac events in females than in males (Szperl et al, 2018). The minor deletion c.4850_4852delTCT (F1617del) variant was found to be associated with LQT3 syndrome, which induced the change of fast inactivation by decreasing gating charges (Chen et al, 2005).…”

Metabolic Behaviors of Aconitum Alkaloids in Different Concentrations of Aconiti Lateralis Radix Praeparata and Effects of Aconitine in Healthy Human and Long QT Syndrome Cardiomyocytes

“…The most common clinical cases are LQT1, LQT2, and LQT3, which account for about 75% of LQTS patients [24]. Researchers have found that the same dose of aconite showed a toxic effect on normal subjects and a therapeutic effect on patients with arrhythmia, and this toxic effect manifests in a variety of forms, which suggests a potential arrhythmic effect, accounting for acquired LQTS [25].…”