Phenotype-Based High-Throughput Classification of Long QT Syndrome Subtypes Using Human Induced Pluripotent Stem Cells

Stem Cell Reports. 2019 Aug 13;13(2):394-404. doi: 10.1016/j.stemcr.2019.06.007. Epub 2019 Aug 1.


For long QT syndrome (LQTS), recent progress in genome-sequencing technologies enabled the identification of rare genomic variants with diagnostic, prognostic, and therapeutic implications. However, pathogenic stratification of the identified variants remains challenging, especially in variants of uncertain significance. This study aimed to propose a phenotypic cell-based diagnostic assay for identifying LQTS to recognize pathogenic variants in a high-throughput manner suitable for screening. We investigated the response of LQT2-induced pluripotent stem cell (iPSC)-derived cardiomyocytes (iPSC-CMs) following IKr blockade using a multi-electrode array, finding that the response to IKr blockade was significantly smaller than in Control-iPSC-CMs. Furthermore, we found that LQT1-iPSC-CMs and LQT3-iPSC-CMs could be distinguished from Control-iPSC-CMs by IKs blockade and INa blockade, respectively. This strategy might be helpful in compensating for the shortcomings of genetic testing of LQTS patients.

Keywords: genome editing; induced pluripotent stem cell; long QT syndrome; multi-electrode array; phenotype-based diagnosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Action Potentials / drug effects
  • Adolescent
  • Adult
  • Case-Control Studies
  • Cell Differentiation
  • Child
  • Female
  • High-Throughput Screening Assays / methods
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Long QT Syndrome / classification
  • Long QT Syndrome / diagnosis*
  • Male
  • Middle Aged
  • Myocytes, Cardiac / physiology*
  • Patch-Clamp Techniques
  • Phenotype
  • Potassium Channel Blockers / pharmacology
  • Sodium Channel Blockers / pharmacology
  • Tetrodotoxin / pharmacology
  • Young Adult


  • Potassium Channel Blockers
  • Sodium Channel Blockers
  • Tetrodotoxin