Whole exome sequencing identifies a novel SPG4 mutation in a Chinese family with hereditary spastic paraplegias

Hereditary spastic paraplegias (HSPs) are a group of neurodegenerative disorders of highly clinical and genetic heterogeneity. SPG4 (SPAST) is the most common type of pure autosomal dominant hereditary spastic paraplegia (ADHSP) and its mutations account for 40% of all mutations associated with the ADHSP. The purpose of this study was to identify the causative gene mutation and explore the genotype-phenotype correlation through the investigation of a Chinese Han family with ADHSP, which could lay solid foundation for further study of the pathogenesis and provide the basis for prenatal diagnosis for this disease. Whole exome sequencing (WES) was performed on subjects with HSP from a Chinese family in Shandong Province. Systematic clinical analysis and 3.0T Magnetic resonance imaging (MRI) scans of brain and spinal cord on the affected proband were also accomplished. As a result, a novel nonsense 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 HSP patients in this pedigree. MRI revealed no significant atrophy of spinal cord and brain in the proband. In conclusion, our finding suggests that the novel nonsense mutation in SPG4 is causative to HSP and it's of great significance in supplementing the mutational spectrum of the 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.