Whole Exome Sequencing Identifies The Causative Gene Mutation In A Chinese Family With Hereditary Spastic Paraplegias

Objective Hereditary spastic paraplegias(HSPs)are a group of neurodegenerative disorders with clinical and genetic heterogeneity characterized by progressive muscular tension of bilateral lower limbs,muscle weakness and spasticity.The purpose of this study was to identify the causative gene mutation for a Chinese Han family with HSP,which could provide the basis for diagnosis and prenatal diagnosis for this disease and lay solid foundation for further study of the pathogenesis.Methods We collected a five-generation pedigree including 32 members and the proband was diagnosed with HSP.Systematic clinical analysis and 3.0T Magnetic resonance imaging(MRI)scans of brain and spinal cord of proband(?11),her elder affected sister(?8)and a normal individual(?9)were also accomplished.Whole exome sequencing(WES)was performed on ?11??8 and ?9 and bioinformatics software was used to identify the causative mutation.The suspicious variant was validated using PCR and Sanger sequencing in 19 members in this affected pedigree and 50 control individuals.Results ?11 and ?8 were diagnosed with pure HSP without cognitive impairment and other psychological symptoms,MRI revealed no significant atrophy of spinal cord and brain.A novel nonsense SPAST(SPG4)mutation,a single-nucleotide change from C to T which caused a substitution from glutamine to an immature stop codon at codon 536(c.1606C>T,p.Gln536X),was identified.This mutation co-segregates with the HSPs patients in this pedigree and never been found in the control individuals.According to the HSPs mutation database,the mutation(c.1606C>T)has never been previously demonstrated.Conclusion Our finding suggests that the novel nonsense mutation in SPAST(SPG4)is causative to HSPs and it's of great significance in supplementing the mutational spectrum of SPAST(SPG4)and explaining the mechanism of HSPs.Our study also indicates that WES can be an efficient and rapid diagnostic tool for some complex and genetically heterogeneous diseases.