Genome Medicine · Published 2026-06-26 · DOI 10.1186/s13073-026-01692-0 · PMID: 42363298 · PMC
Brian M. Schilder, Kitty B. Murphy, Hiranyamaya Dash, Yichun Zhang, Robert Gordon-Smith, Jai Chapman, Momoko Otani, Nathan G. Skene
Abstract Background Rare diseases (RDs) are a highly heterogeneous and underserved group of conditions. Most RDs have a strong genetic basis but their causal pathophysiological mechanisms remain poorly understood, limiting the development of targeted therapies. Methods We systematically characterised the cell type-specific mechanisms underlying all genetically defined RD phenotypes by integrating the Human Phenotype Ontology (HPO) with whole-body single-cell transcriptomic atlases from embryonic, foetal, and adult samples. Associations were validated against orthogonal biomedical knowledge graphs and then prioritised by strength of supporting evidence, clinical severity, and gene-therapy compatibility. Results We identified significant associations between 201 cell types and 9,575/11,028 (86.7%) phenotypes across 8,628 RDs, substantially expanding knowledge of phenotype-cell type links. Prioritisation by severity (e.g. lethality, motor or mental impairment) and gene-therapy compatibility (e.g. cell type specificity, postnatal treatability) identified candidate phenotypes and cell types for therapeutic targeting. Conclusions We present a scalable, reproducible framework for phenome-wide, cell type-specific mechanism prediction in rare diseases, providing a major step toward systematic therapeutic development for patients across a broad spectrum of serious RDs. Software and data availability Interactive web portal: https://neurogenomics-ukdri.dsi.ic.ac.uk/ . R packages introduced in this study: KGExplorer ( https://github.com/neurogenomics/KGExplorer ), HPOExplorer ( https://github.com/neurogenomics/HPOExplorer ), and MSTExplorer ( https://github.com/neurogenomics/MSTExplorer ). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping .
Abstract from DOAJ. Public domain (CC0 1.0).
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Schilder, B., Murphy, K., Dash, H., et al. (2026). Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases. Genome Medicine. https://doi.org/10.1186/s13073-026-01692-0