Case Report: Association of a rare single nucleotide variant in the KCNH2 gene with drug-induced QT prolongation

Background Long QT Syndrome (LQTS) is characterized by prolonged QT intervals on electrocardiogram, which may progress into life-threatening polymorphic ventricular tachycardia and sudden cardiac death. Variants in the KCNH2 gene have been associated with congenital LQTS, with thousands identified to date but very few clinically characterized. Objectives To describe the rare single nucleotide variant KCNH2 (NM_000238.4):c.1066C>T (p.Arg356Cys) associated with drug-induced QT prolongation and to assess its pathogenicity risk using in silico tools and protein structural modeling in accordance with American College of Medical Genetics and Genomics (ACMG) guidelines. Methods Next-generation sequencing was performed for a patient presenting with drug-induced QT prolongation who was found to carry the rare KCNH2 1066C>T variant. Thirteen established gene discovery computational tools were employed to analyze the variant in silico . Additionally, structural modeling of the variant’s region within the wild-type protein was performed utilizing AlphaFold. Results The clinical phenotype associated with the KCNH2 1066C>T variant has not been previously described in literature, except in combination with a variant in the KCNQ1 gene. Computational analysis with a meta-predictor, REVEL, supported variant pathogenicity, while predictive modeling and AlphaMissense illustrated the uncertainty of structural impacts in a disordered region. Risk analysis of the variant performed utilizing ACMG guidelines and ClinGen criteria-specific recommendations resulted in an overall classification of “uncertain significance”. Conclusion To our knowledge, this is the first study reporting a direct phenotype-to-genotype association between the KCNH2 1066C>T variant and drug-induced QT prolongation, supplemented by in silico analyses and ACMG-based variant risk stratification. Our study underscores the importance of recognizing genetic predisposition in drug-induced QT prolongation and motivate further investigation of KCNH2 variants within the N-linker region.