Cell type-specific contextualisation of the human phenome: towards the systematic treatment of all rare diseases

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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: ( https://github.com/neurogenomics/KGExplorer ), ( https://github.com/neurogenomics/HPOExplorer ), and ( https://github.com/neurogenomics/MSTExplorer ). Manuscript analyses and reproducibility code: https://github.com/neurogenomics/rare_disease_celltyping .
Funding Information
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)
  • UK Dementia Research Institute (UK DRI) Future Leaders Fellowship (MR/T04327X/1)

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