CRONDEX: a web-based platform for exploring links between chromatin-related genes and neurodevelopmental disorders

Chromatin regulatory genes are essential for orchestrating neurodevelopment by controlling DNA accessibility and the expression of genes required for neuronal differentiation and maturation. Mutations affecting these regulators-including histone modifiers, chromatin remodelers, and chromatin-binding factors-are a major cause of neurodevelopmental disorders (NDDs), many of which display overlapping yet mechanistically heterogeneous clinical features. As the catalogue of chromatin-related NDD genes has expanded, so too has the availability of phenotypic, functional, and pathway annotations. However, these data remain dispersed across multiple resources, making it difficult to integrate them in order to systematically compare genes or explore shared mechanisms. Existing platforms such as the Human Phenotype Ontology and the Monarch Initiative offer powerful phenotype-gene mapping tools, but they operate across the full genomic space and do not provide the focused framework needed to examine chromatin-related NDD genes as a coherent group.

We present CRONDEX (ChROmatin and NeuroDevelopmental disorder-related genes EXploratory platform), a user-friendly web resource developed to meet this need by supporting integrative exploration of relationships among chromatin-related genes implicated in NDDs. The database was constructed by intersecting curated chromatin (EpiFactors) and neurodevelopmental (SysNDD+Orphanet+SFARI+NDD-GeneHub) gene sets while excluding transcription factors, and enriched with annotations from Gene Ontology, KEGG, and the Human Phenotype Ontology. CRONDEX provides two complementary query modes: (i) a Gene-Based Query, which identifies genes with phenotypic profiles similar to a user-defined target using Jaccard similarity metrics; and (ii) a Criteria-Based Query, which retrieves genes matching specific phenotypic, functional, or pathway filters. Through representative examples, we show how the Gene-Based Query recovers biologically coherent relationships-from paralogous pairs such as CREBBP-EP300 to functionally convergent modules like the BAFopathies-while the Criteria-Based Query enables hypothesis-driven exploration, exemplified by the intersection of thermogenesis and chromatin-related NDDs, and by chromatin-binding genes linked to status epilepticus. By enabling rapid, integrative, and hypothesis-oriented analyses, CRONDEX facilitates the discovery of shared mechanisms across chromatin-related NDDs and supports both basic and translational research. The platform is freely accessible at https://jgf-bioinfo.shinyapps.io/CRONDEX/ .

CRONDEX provides a domain-focused platform that enables phenotype-guided exploration of chromatin-related genes, supporting mechanistic hypothesis generation in NDDs.