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Published on: April 4, 2018
Predicting the pathogenicity of RPE65 mutations
1Department of Ophthalmology and Visual Sciences, University of Iowa Hospitals and Clinics, Iowa City, Iowa.
Human Mutation
|May 12, 2009
Summary
An objective algorithm, the estimate of pathogenic probability (EPP), accurately distinguishes disease-causing mutations from benign variants. This tool shows high concordance with functional assays for RPE65 gene variations linked to Leber congenital amaurosis.
Area of Science:
- Genetics
- Molecular Biology
- Ophthalmology
Background:
- Distinguishing pathogenic mutations from nonpathogenic polymorphisms is crucial for genetic diagnosis.
- Leber congenital amaurosis (LCA) is a severe inherited retinal disease often caused by mutations in the RPE65 gene.
Purpose of the Study:
- To develop and validate an objective algorithm, the estimate of pathogenic probability (EPP), for assessing the pathogenicity of missense variations.
- To evaluate the EPP algorithm's accuracy using RPE65 gene variations in LCA patients.
Main Methods:
- Developed an EPP algorithm incorporating variation prevalence, family segregation, and predicted protein structure effects.
- Assessed eleven missense variations in the RPE65 gene using the EPP algorithm.
- Validated EPP predictions through a cell-culture assay measuring RPE65-isomerase activity.
Main Results:
- The EPP algorithm correctly identified eight disease-causing RPE65 variants with <6% wild-type isomerase activity.
- The algorithm also identified three non-disease-causing variants with isomerase activities ranging from 68% to 127% of wild-type.
- Complete concordance was observed between EPP predictions and functional assay results.
Conclusions:
- The EPP algorithm accurately predicts the pathogenicity of missense variations in the RPE65 gene.
- This objective algorithm shows potential utility for evaluating missense variations in other disease genes, especially when functional assays are unavailable.
