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: <a href="https://neurogenomics-ukdri.dsi.ic.ac.uk/">https://neurogenomics-ukdri.dsi.ic.ac.uk/</a>. R packages introduced in this study: <Emphasis FontCategory="NonProportional">KGExplorer</Emphasis> (<a href="https://github.com/neurogenomics/KGExplorer">https://github.com/neurogenomics/KGExplorer</a>), <Emphasis FontCategory="NonProportional">HPOExplorer</Emphasis> (<a href="https://github.com/neurogenomics/HPOExplorer">https://github.com/neurogenomics/HPOExplorer</a>), and <Emphasis FontCategory="NonProportional">MSTExplorer</Emphasis> (<a href="https://github.com/neurogenomics/MSTExplorer">https://github.com/neurogenomics/MSTExplorer</a>). Manuscript analyses and reproducibility code: <a href="https://github.com/neurogenomics/rare_disease_celltyping">https://github.com/neurogenomics/rare_disease_celltyping</a>.

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

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2026年6月26日

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Brian M. Schilder,
Kitty B. Murphy,
Hiranyamaya Dash,
Yichun Zhang,
Robert Gordon-Smith,
Jai Chapman,
Momoko Otani,
Nathan G. Skene

摘要

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.