Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project.
Identification of UBAP1 mutations in juvenile hereditary spastic paraplegia in the 100,000 Genomes Project.
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DOI：
10.1038/s41431-020-00720-w
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Tucci A
中科院分区：
文献类型：
--
作者：
Bourinaris T;Smedley D;Cipriani V;Sheikh I;Athanasiou-Fragkouli A;Chinnery P;Morris H;Real R;Harrison V;Reid E;Wood N;Genomics England Research Consortium;Vandrovcova J;Houlden H;Tucci A
遗传性痉挛性截瘫是一组以下肢痉挛为特征的异质性遗传性退行性疾病。50%的过敏性紫癜患者仍未被确诊。100，000个基因组计划（100 KGP）是一项大型的英国计划，旨在为以前未确诊的罕见疾病患者和家庭提供基因诊断。超过400个HSP家庭被招募到100 KGP。为了获得遗传诊断，使用来自基因组测序数据的Exomiser分析的候选变体，对罕见的预测致病性变体进行基于基因的负荷测试。UBAP 1和HSP存在显著的基因-疾病相关性。在来自7个家系的13例患者中鉴定出3种蛋白质截短变异。所有患者均表现为幼年型单纯HSP，发病年龄中位数10岁，表现为常染色体显性遗传或新发。其他临床特征包括帕金森综合征和学习困难，但它们与UBAP 1的相关性需要建立。
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.
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