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

Qiao Wei; Hai-Lin Dong; Li-Ying Pan; Cong-Xin Chen; Yang-Tian Yan; Rou-Min Wang; Hong-Fu Li; Zhi-Jun Liu; Qing-Qing Tao; Zhi-Ying Wu

doi:10.1186/s40035-019-0157-9

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

Transl Neurodegener. 2019 Jun 26:8:19. doi: 10.1186/s40035-019-0157-9. eCollection 2019.

Authors

Qiao Wei^#¹, Hai-Lin Dong^#¹, Li-Ying Pan^#², Cong-Xin Chen¹, Yang-Tian Yan¹, Rou-Min Wang¹, Hong-Fu Li¹, Zhi-Jun Liu³, Qing-Qing Tao¹, Zhi-Ying Wu^{1

4}

Affiliations

¹ 1Department 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, Hangzhou, 310009 China.
² 2Longyan First Hospital, Fujian Medical University, Longyan, China.
³ 3Department of Neurology and Institute of Neurology, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ 4Joint Institute for Genetics and Genome Medicine between Zhejiang University and University of Toronto, Zhejiang University, Hangzhou, China.

^# Contributed equally.

Abstract

Background: Although 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.

Methods: In 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.

Results: We 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.

Conclusion: Our 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.

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