Genetic Spectrum And Clinical Features In Patients With Recessive Hereditary Spastic Paraplegia

Background:Hereditary spastic paraplegia(HSP)is a heterogeneous group of inherited neurodegenerative disorders which is classified into pure and complex forms.Although many causative genes 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 features of recessive HSP patients in the Chinese population.Aim:To depict the genetic spectrum and clinical phenotype of AR/sporadic 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.F2343fs)in SPG11,two(p.T55M,p.S308T)in AP5Z1,one(p.S242N)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,CAPN 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.S242N)in ALDH18A1 decreased enzyme activity of P5CS and mutations(p.T55M,p.S308T)in AP5Z1 induced lysosomal dysfunction.Conclusion:Our results expanded the genetic spectrum and clinical phenotype of AR-HSP patients in the Chinese population,and further demonstrated the efficiency and reliability of targeted NGS diagnosing suspected HSP patients.