P17 Ontological analysis of a curated dataset of genetic skin diseases reveals enrichment of key processes that are disrupted in cutaneous biology

Abstract Introduction and aims Genomic testing and precision medicine are revolutionizing dermatological practice, with the genetic basis of many inherited and mosaic skin diseases now solved. However, an unbiased, ontological analysis of these known disease-­causing genes is lacking, which could inform the understanding of cutaneous biology. To address this, we analysed the updated Genotype 2 Phenotype – SKIN (G2P-S) dataset, a comprehensive online resource that links disease-causing genes to inherited skin diseases. Methods G2P-S was curated by a team of dermatologists and geneticists. Each gene-disease association was assigned a confidence level based on the strength of evidence. Enriched gene ontology terms were retrieved covering biological processes, cellular components, molecular functions, and biological pathways annotated in the Reactome database. Biological processes were reduced and visualized using the REVIGO web tool, indicating their size and dispensability. Results We analysed 643 genes associated with skin diseases, listed in G2P-S. Gene ontology analysis revealed enrichment of genes in key clusters of biological processes, including ‘epidermal development’ (n = 25 genes), ‘intermediate filament organisation’ (n = 23) and ‘collagen fibril organisation’ (n = 16). Reactome pathway analysis revealed enrichment of genes described in processes involving primarily the developmental biology clade, including ‘formation of the cornified envelope’ (n = 35), ‘assembly of collagen fibrils and other multimeric structures’ (n = 19) and ‘regulation of MITF-M-dependent genes involved in pigmentation’ (n = 11). Bubble plot analysis additionally revealed gene enrichment for terms ‘cholesterol biosynthesis’, ‘response to UV’ and ‘positive regulation of T-cell differentiation’. Gene interaction cluster analysis visualized cluster-disease linkages (e.g. lipid metabolism genes interactions associated with ichthyosis). Conclusions G2P-S is a valuable resource, providing a curated list of known skin gene-disease associations. Gene ontology analysis highlighted enriched pathways underlying various genetic skin disorders, informing our understanding of mechanisms relevant to the development of human skin.