Alecu Julian E, Tam Amy, Richter Silja, Quiroz Vicente, Schierbaum Luca, Saffari Afshin, Ebrahimi-Fakhari Darius
Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA; Medical Faculty of the Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany.
Movement Disorders Program, Department of Neurology and F.M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA.
Genet Med. 2025 Mar;27(3):101349. doi: 10.1016/j.gim.2024.101349. Epub 2024 Dec 25.
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.
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.
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.
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.
双等位基因HPDL变异已被确定为一种进行性儿童期起病的运动障碍的病因，其临床谱广泛，从严重的神经发育障碍到青少年期起病的83型单纯遗传性痉挛性截瘫。本研究旨在描绘HPDL相关疾病患者的基因和表型谱，对其自然史进行定量建模，并揭示基因型-表型关联。
采用基于人类表型本体论的方法，对90例已发表病例和1例新病例进行横断面分析。无监督表型聚类与计算机分析一起用于识别不同的患者亚组。
该研究对全球队列中HPDL相关疾病的自然史进行了建模，阐明了分子和表型谱，并确定了3个不同的亚组，其特征在于发病、临床病程和生存方面的差异。它建立了基因型-表型关联，表明1个等位基因中存在中度致病性错义变异会导致较轻的痉挛性截瘫表型，疾病发病较晚，而双等位基因、高度致病性错义或截短变异与更严重的表型和缩短的寿命相关。
HPDL相关疾病的定量和无偏自然史建模揭示了显著的基因型-表型关联，为未来前瞻性和功能研究中的变异解释、预期指导和结局指标选择提供了基础。
