Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations
Purpose - Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and ph...
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| Hauptverfasser: | , , , , , , |
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| Dokumenttyp: | Article (Journal) |
| Sprache: | Englisch |
| Veröffentlicht: |
25 December 2024
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| In: |
Genetics in medicine
Year: 2025, Jahrgang: 27, Heft: 3, Pages: 1-12 |
| ISSN: | 1530-0366 |
| DOI: | 10.1016/j.gim.2024.101349 |
| Online-Zugang: | Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.gim.2024.101349 Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1098360024002831 
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| Verfasserangaben: | Julian E. Alecu, Amy Tam, Silja Richter, Vicente Quiroz, Luca Schierbaum, Afshin Saffari, Darius Ebrahimi-Fakhari |
| Zusammenfassung: | Purpose - Biallelic HPDL variants have been identified as the cause of a progressive childhood-onset movement disorder, with a broad clinical spectrum from severe neurodevelopmental disorder to juvenile-onset pure hereditary spastic paraplegia type 83. This study aims at delineating the geno- and phenotypic spectra of patients with HPDL-related disease, quantitatively modeling the natural history, and uncovering genotype-phenotype associations. - Methods - A cross-sectional analysis of 90 published and 1 novel case was performed, using a Human-Phenotype-Ontology-based approach. Unsupervised phenotypic clustering was used alongside in silico analyses to identify distinct patient subgroups. - Results - The study models the natural history of the HPDL-related disease in a global cohort, clarifying the molecular and phenotypic spectrum and identifying 3 distinct subgroups characterized by differences in onset, clinical trajectories, and survival. It establishes genotype-phenotype associations, showing that the presence of moderately pathogenic missense variants in 1 allele leads to a milder, spastic paraplegic phenotype with later disease onset, whereas biallelic, highly pathogenic missense or truncating variants are associated with a more severe phenotype and reduced life span. - Conclusion - Quantitative and unbiased natural history modeling in HPDL-related disease reveals significant genotype-phenotype associations, providing a foundation for variant interpretation, anticipatory guidance, and choice of outcome measures in future prospective and functional studies. |
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| Beschreibung: | Gesehen am 22.09.2025 |
| Beschreibung: | Online Resource |
| ISSN: | 1530-0366 |
| DOI: | 10.1016/j.gim.2024.101349 |