Frontiers in genetics · 2026
Case Report: Association of a rare single nucleotide variant in the KCNH2 gene with drug-induced QT prolongation.
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Wang Tianci, Norgan Radler Charlene R, Sathyamoorthy Mohanakrishnan
Аннотация
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.
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.