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

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. Genotype-phenotype 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.