PdmIRD: missense variants pathogenicity prediction for inherited retinal diseases in a disease-specific manner

• Published in: Human genetics 2024-03, Vol.143 (3), p.331-342
• Main Authors: Zeng, Bing, Liu, Dong Cheng, Huang, Jian Guo, Xia, Xiao Bo, Qin, Bo
• Format: Article
• Language: English
• Subjects: Biomedical and Life Sciences; Biomedicine; Gene Function; Genetic screening; Genomes; Human Genetics; Metabolic Diseases; Missense mutation; Molecular Medicine; Mutation; Original Investigation; Pathogenicity; Predictions; Retina
• ISSN: 0340-6717; 1432-1203
• DOI: 10.1007/s00439-024-02645-6

Accurate discrimination of pathogenic and nonpathogenic variation remains an enormous challenge in clinical genetic testing of inherited retinal diseases (IRDs) patients. Computational methods for predicting variant pathogenicity are the main solutions for this dilemma. The majority of the state-of-the-art variant pathogenicity prediction tools disregard the differences in characteristics among different genes and treat all types of mutations equally. Since missense variants are the most common type of variation in the coding region of the human genome, we developed a novel missense mutation pathogenicity prediction tool, named Prediction of Deleterious Missense Mutation for IRDs (PdmIRD) in this study. PdmIRD was tailored for IRDs-related genes and constructed with the conditional random forest model. Population frequencies and a newly available prediction tool were incorporated into PdmIRD to improve the performance of the model. The evaluation of PdmIRD demonstrated its superior performance over nonspecific tools (areas under the curves, 0.984 and 0.910) and an existing eye abnormalities-specific tool (areas under the curves, 0.975 and 0.891). We also demonstrated the submodel that used a smaller gene panel further slightly improved performance. Our study provides evidence that a disease-specific model can enhance the prediction of missense mutation pathogenicity, especially when new and important features are considered. Additionally, this study provides guidance for exploring the characteristics and functions of the mutated proteins in a greater number of Mendelian disorders.