Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project

Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis t...

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Bibliographic Details
Published in:European journal of human genetics : EJHG 2020-12, Vol.28 (12), p.1763-1768
Main Authors: Bourinaris, Thomas, Smedley, Damian, Cipriani, Valentina, Sheikh, Isabella, Athanasiou-Fragkouli, Alkyoni, Chinnery, Patrick, Morris, Huw, Real, Raquel, Harrison, Victoria, Reid, Evan, Wood, Nicholas, Vandrovcova, Jana, Houlden, Henry, Tucci, Arianna
Format: Article
Language:English
Subjects:
Autosomal dominant inheritance
Basal ganglia
Brief Communication
Central nervous system diseases
Genetic screening
Genomes
Hereditary spastic paraplegia
Heredity
Movement disorders
Paralysis
Spasticity
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Summary:Hereditary spastic paraplegia (HSP) is a group of heterogeneous inherited degenerative disorders characterized by lower limb spasticity. Fifty percent of HSP patients remain yet genetically undiagnosed. The 100,000 Genomes Project (100KGP) is a large UK-wide initiative to provide genetic diagnosis to previously undiagnosed patients and families with rare conditions. Over 400 HSP families were recruited to the 100KGP. In order to obtain genetic diagnoses, gene-based burden testing was carried out for rare, predicted pathogenic variants using candidate variants from the Exomiser analysis of the genome sequencing data. A significant gene-disease association was identified for UBAP1 and HSP. Three protein truncating variants were identified in 13 patients from 7 families. All patients presented with juvenile form of pure HSP, with median age at onset 10 years, showing autosomal dominant inheritance or de novo occurrence. Additional clinical features included parkinsonism and learning difficulties, but their association with UBAP1 needs to be established.
ISSN:1018-4813
1476-5438
DOI:10.1038/s41431-020-00720-w