Characterization of a Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Model for the Study of Variant Pathogenicity: Validation of a KCNJ2 Mutation

Circ Cardiovasc Genet. 2017 Oct;10(5):e001755. doi: 10.1161/CIRCGENETICS.117.001755.


Background: Long-QT syndrome is a potentially fatal condition for which 30% of patients are without a genetically confirmed diagnosis. Rapid identification of causal mutations is thus a priority to avoid at-risk situations that can lead to fatal cardiac events. Massively parallel sequencing technologies are useful for the identification of sequence variants; however, electrophysiological testing of newly identified variants is crucial to demonstrate causality. Long-QT syndrome could, therefore, benefit from having a standardized platform for functional characterization of candidate variants in the physiological context of human cardiomyocytes.

Methods and results: Using a variant in Kir2.1 (Gly52Val) revealed by whole-exome sequencing in a patient presenting with symptoms of long-QT syndrome as a proof of principle, we demonstrated that commercially available human induced pluripotent stem cell-derived cardiomyocytes are a powerful model for screening variants involved in genetic cardiac diseases. Immunohistochemistry experiments and whole-cell current recordings in human embryonic kidney cells expressing the wild-type or the mutant Kir2.1 demonstrated that Kir2.1-52V alters channel cellular trafficking and fails to form a functional channel. Using human induced pluripotent stem cell-derived cardiomyocytes, we not only confirmed these results but also further demonstrated that Kir2.1-52V is associated with a dramatic prolongation of action potential duration with evidence of arrhythmic activity, parameters which could not have been studied using human embryonic kidney cells.

Conclusions: Our study confirms the pathogenicity of Kir2.1-52V in 1 patient with long-QT syndrome and also supports the use of isogenic human induced pluripotent stem cell-derived cardiomyocytes as a physiologically relevant model for the screening of variants of unknown function.

Keywords: arrhythmias, cardiac; immunohistochemistry; induced pluripotent stem cells; long QT syndrome; mutation.

MeSH terms

  • Adult
  • Amino Acid Substitution
  • Female
  • HEK293 Cells
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Induced Pluripotent Stem Cells / pathology
  • Long QT Syndrome* / genetics
  • Long QT Syndrome* / metabolism
  • Long QT Syndrome* / pathology
  • Models, Biological*
  • Mutation, Missense*
  • Myocytes, Cardiac / metabolism*
  • Myocytes, Cardiac / pathology
  • Potassium Channels, Inwardly Rectifying* / genetics
  • Potassium Channels, Inwardly Rectifying* / metabolism


  • KCNJ2 protein, human
  • Potassium Channels, Inwardly Rectifying