Document Detail

An In Vivo Cardiac Assay to Determine the Functional Consequences of Putative Long QT Syndrome Mutations.
MedLine Citation:
PMID:  23303164     Owner:  NLM     Status:  Publisher    
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.
Chuanchau J Jou; Spencer M Barnett; Jian-Tao Bian; H Cindy Weng; Xiaoming Sheng; Martin Tristani-Firouzi
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-9
Journal Detail:
Title:  Circulation research     Volume:  -     ISSN:  1524-4571     ISO Abbreviation:  Circ. Res.     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-10     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0047103     Medline TA:  Circ Res     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
1Dept of Pediatrics, University of Utah, Ion Channel Lab, 95 South 2000 East, Building 500 Room 160, Salt Lake City, Utah, 84112, UNITED STATES.
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