ZFIN ID: ZDB-PUB-130124-3
An In Vivo Cardiac Assay to Determine the Functional Consequences of Putative Long QT Syndrome Mutations
Jou, C.J., Barnett, S.M., Bian, J.T., Weng, H.C., Sheng, X., and Tristani-Firouzi, M.
Date: 2013
Source: Circulation research   112(5): 826-830 (Journal)
Registered Authors: Sheng, Xiaoming
Keywords: model organism, sudden death, arrhythmia, genetic testing, channelopathy, long QT syndrome, gene mutation, genetic polymorphism, genomics-physiological
MeSH Terms:
  • Algorithms
  • Animals
  • Disease Models, Animal
  • Ether-A-Go-Go Potassium Channels/genetics
  • Gene Knockdown Techniques
  • Genetic Predisposition to Disease/genetics
  • Genetic Testing
  • Heart/physiopathology*
  • High-Throughput Screening Assays/methods*
  • Long QT Syndrome/genetics*
  • Long QT Syndrome/physiopathology*
  • Mutation/genetics*
  • Polymorphism, Genetic/genetics
  • Predictive Value of Tests
  • Zebrafish/embryology
  • Zebrafish/genetics*
  • Zebrafish Proteins/genetics
PubMed: 23303164 Full text @ Circ. Res.

Rationale: Genetic testing for Long QT Syndrome (LQTS) is now a standard and integral component of clinical cardiology. A major obstacle to the interpretation of genetic findings is the lack of robust functional assays to determine the pathogenicity of identified gene variants in a high throughput manner.

Objective: The goal of this study was to design and test a high throughput in vivo cardiac assay to distinguish between disease-causing and benign KCNH2 (hERG1) variants, using the zebrafish as a model organism.

Methods and Results: We tested the ability of previously characterized LQTS hERG1 mutations and polymorphisms to restore normal repolarization in the kcnh2-knockdown embryonic zebrafish. The cardiac assay correctly identified a benign variant in 9 of 10 cases (negative predictive value 90%) while correctly identifying a disease-causing variant in 39/39 cases (positive predictive value 100%).

Conclusions: The in vivo zebrafish cardiac assay approaches the accuracy of the current benchmark in vitro assay for the detection of disease-causing mutations and is far superior in terms of throughput rate. Together with emerging algorithms for interpreting a positive LQTS genetic test, the zebrafish cardiac assay provides an additional tool for the final determination of pathogenicity of gene variants identified in LQTS genetic screening.