Novel Compound Missense and Intronic Splicing Mutation in Causes Autosomal Recessive Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) caused by mutations in have been reported as spastic paraplegia 9 (SPG9), with autosomal dominant and autosomal recessive transmission (SPG9A and SPG9B). SPG9 is rare and has shown phenotypic and genotypic heterogeneity in previous reports. This study screened mutations in autosomal recessive HSP patients using combined whole exome sequencing and RNA splicing analysis. We conducted investigations, co-segregation analysis, and ELISA-based analysis of P5CS (Δ1-pyrroline-5-carboxylate synthetase; encoded by ) concentration to validate the pathogenicity of the detected variants. All previously reported bi-allelic mutations and cases were reviewed to summarize the genetic and clinical features of -related HSP. A novel missense mutation c.880T>C, p.S294P and an intronic splicing mutation c.-28-13A>G were both detected in in an autosomal recessive family presenting with a complicated form HSP. ELISA assays revealed significantly decreased P5CS concentration in the proband's plasma compared with that in the healthy controls. Moreover, review of previously reported recessive cases showed that SPG9B patients in our cohort presented with milder symptoms, i.e., later age at onset and without cognitive impairment. The present study expands the genetic and clinical spectrum of SPG9B caused by mutation. Our work defines new genetic variants to facilitate future diagnoses, in addition to demonstrating the highly informative value of splicing mutation prediction in the characterization of disease-related intronic variants.