Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations
Alecu JE, Tam A, Richter S, Quiroz V, Schierbaum L, Saffari A, Ebrahimi-Fakhari D (2025)
Publication Type: Journal article
Publication year: 2025
Journal
Book Volume: 27
Article Number: 101349
Journal Issue: 3
DOI: 10.1016/j.gim.2024.101349
Abstract
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.
Involved external institutions
United States (USA) (US)
Germany (DE)How to cite
APA:
Alecu, J.E., Tam, A., Richter, S., Quiroz, V., Schierbaum, L., Saffari, A., & Ebrahimi-Fakhari, D. (2025). Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations. Genetics in Medicine, 27(3). https://doi.org/10.1016/j.gim.2024.101349
MLA:
Alecu, Julian E., et al. "Quantitative natural history modeling of HPDL-related disease based on cross-sectional data reveals genotype-phenotype correlations." Genetics in Medicine 27.3 (2025).
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