CDKL5 Deficiency Disorder: Revealing the Molecular Mechanism of Pathogenic Variants

This repository provides the workflow for the analysis of CDKL5 gene variants, including variant annotation, stability prediction, CDKL5 and it's substrate structural modeling, and reclassification of variants based on $\Delta\Delta G_{\text{Folding}}$ and $\Delta\Delta G_{\text{Binding}}$.

Methods:

1. Variant Curation: CDKL5 variant curation from ClinVar, gnomAD and Literatures.
2. $\Delta\Delta G_{\text{Folding}}$: Sequence-based and structure-based $\Delta\Delta G_{\text{Folding}}$ predictions using multiple methods (SAAFEC-SEQ, I-Mutant2.0, INPS, DDGun, mCSM, DDMut, DDGEmb).
3. Protein-Protein Complex: Colabfold: CDKL5-Substrate complex modeling using ColabFold.
4. Protein-Protein Docking: HADDOCK3: CDKL5-Substrate docking using HADDOCK3.
5. $\Delta\Delta G_{\text{Binding}}$: Structure-based $\Delta\Delta G_{\text{Binding}}$ analysis using follwoing tools: DDMutPPI, iSee, mCSM-PPI and SAAMBE-3D.
6. Pathogenicity prediction: CDKL5 variants pathogenicity prediction using pathogenicity predctors (PolyPhen-2, MutPred2, ESM-1v, and AlphaMissense).
7. Variant Reclassification: Reclassificaiton of CDKL5 variants based on DDG_folding, Binding and Pathogenicity.

Publication

This work is now published:

Paul, S. K.; Panday, S. K.; Boccuto, L.; Alexov, E. CDKL5 Deficiency Disorder: Revealing the Molecular Mechanism of Pathogenic Variants. Preprints 2025, 2025081241.
https://pmc.ncbi.nlm.nih.gov/articles/PMC12429097/

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