Assessing In Silico Tools for Accurate Pathogenicity Prediction in CHD Nucleosome Remodelers

Chromodomain Helicase DNA-binding (CHD) proteins compose a family of chromatin remodelers that play crucial roles in DNA repair, gene expression regulation, neural stem cell differentiation and chromatin integrity. Genetic variants in CHD chromatin remodelers are associated with neurodevelopmental disorders with features like autism spectrum disorder and intellectual disability. Consequently, the determination of variant pathogenicity in clinical genetic tests for individuals bearing CHD variants is crucial. In this study, we compared the efficiency of multiple pathogenicity prediction tools, which are valuable resources for the identification and annotation of potentially disease-causing variants, to assess the most accurate in silico tool capable of distinguishing pathogenic CHD variants from benign ones. We have focused specifically on genes that share high structural and functional similarity and are strongly linked to pathogenic mutations. Here, we evaluated a range of pathogenicity prediction tools and compared their output with pathogenicity conclusions reported in the literature and genomic databases. Our findings showed that the top performing tools were BayesDel, ClinPred, AlphaMissense, ESM-1b and SIFT. BayesDel, specifically with its addAF component, was overall the most robust tool for CHD variant pathogenicity prediction. We also suggest incorporating SnpEff's high-impact variant identification capabilities for the development of a hybrid tool that would enhance the classification of CHD variants. Our study emphasizes the need for continuous evaluation and integration of updated prediction tools, including emerging artificial intelligence (AI) approaches. This research also emphasizes the importance of gathering better clinical and mechanistic data on the deleteriousness of pathogenic variants to improve the accuracy of clinical diagnostics.