Clinical features and genetic spectrum in Chinese patients with recessive hereditary spastic paraplegia

Translational Neurodegeneration

  ^{1    2    2    2    2    2    2    2    3    4} 

[1] 0000 0004 0619 8943, grid.11841.3d, Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China;0000 0004 1759 700X, grid.13402.34, Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China;0000 0004 1759 700X, grid.13402.34, Department of Neurology and Research Center of Neurology in Second Affiliated Hospital, and Key Laboratory of Medical Neurobiology of Zhejiang Province, Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, China;0000 0004 1759 700X, grid.13402.34, Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China;0000 0004 1797 9307, grid.256112.3, Longyan First Hospital, Fujian Medical University, Longyan, China;

关键词: Hereditary spastic paraplegia;    Autosomal recessive;    Targeted next-generation sequencing;    Chinese;    Genetic spectrum;    Phenotype;   

DOI  :  10.1186/s40035-019-0157-9

来源: publisher

【 摘 要 】

BackgroundAlthough many causative genes of hereditary spastic paraplegia (HSP) have been uncovered in recent years, there are still approximately 50% of HSP patients without genetically diagnosis, especially in autosomal recessive (AR) HSP patients. Rare studies have been performed to determine the genetic spectrum and clinical profiles of recessive HSP patients in the Chinese population.MethodsIn this study, we investigated 24 Chinese index AR/sporadic patients by targeted next-generation sequencing (NGS), Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Further functional studies were performed to identify pathogenicity of those uncertain significance variants.ResultsWe identified 11 mutations in HSP related genes including 7 novel mutations, including two (p.V1979_L1980delinsX, p.F2343 fs) in SPG11, two (p.T55 M, p.S308 T) in AP5Z1, one (p.S242 N) in ALDH18A1, one (p.D597fs) in GBA2, and one (p.Q486X) in ATP13A2 in 8 index patients and their family members. Mutations in ALDH18A1, AP5Z1, CAPN1 and ATP13A2 genes were firstly reported in the Chinese population. Furthermore, the clinical phenotypes of the patients carrying mutations were described in detail. The mutation (p.S242 N) in ALDH18A1 decreased enzyme activity of P5CS and mutations (p.T55 M, p.S308 T) in AP5Z1 induced lysosomal dysfunction.ConclusionOur results expanded the genetic spectrum and clinical profiles of AR-HSP patients and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.

【 授权许可】

CC BY