Background and Aim:
Hereditary spastic paraplegia (HSPs) is a group of inherited neurodegenerative disorders characterized by progressive spasticity and weakness in lower limbs. The mode of inheritance in
HSP can be autosomal-dominant, autosomal-recessive, X-linked, or mitochondrial. There is significant genetic heterogeneity in HSP, with at least ۷۰ genes and ۸۰ loci identified thus far.
Whole exome sequencing (WES) has been used for gene discovery in
HSP since ۲۰۱۱, resulting in a marked increase in the rate of novel disease-causing genes being identified. Despite the use of WES, genetic analysis has failed in the finding of causative genes in ~۵۰% in the autosomal dominant-HSP (AD-HSP) and ~۷۰% in the autosomal recessive-HSP (AR-HSP) groups, indicating that, the majority of HSP-genes especially AR-HSPs have remained unknown.Methods: DNAs were isolated from peripheral blood leukocytes of ۴۰ Iranian families affected to HSP.
WES was done on the probands. Preliminary filtering of sequence variations was done to identify all homozygous or heterozygous changes present in the probands based on the pattern of inheritance. Subsequently, non-synonymous variations with a MAF>۰.۰۱ for AR-HSPs and MAF>۰.۰۰۱ for AD-HSPs in public databases were removed. Candidate variants were PCR amplified and sequenced subsequently checked in family members in order to co-segregation analysis. Functional studies including RNAseq for cases harboring a variation in a novel candidate gene are currently in progress.Results: This approach led us to identify the variations in ۱۶ known disease-causing genes including SPEG, ATAD۳A, SPAST (three families), ENTPD۱, SPG۷ (two families), KIF۵A, CYP۷B۱, ZFYVE۲۶, GJC۲, CAPN۱, ZFYVE۲۶, KIF۱B, SPG۱۱ (three families), ATL۱, MFN۲, C۱۹orf۱۲, and four novel candidate-HSP genes.Conclusion: Here, we could find HSP-causing genes in ۲۱ cases (۵۲.۵%). Also, we identified four novel candidate HSP-genes; one is involved in axonogenesis and
HSP is a length‐dependent, “dying back” axonopathy. The research presented the powers of
WES for facilitating gene discovery and identification of causative genes for diseases with the extensive genetic heterogeneity. The precise mechanisms underlying the
HSP are unknown. Identification of novel genes and molecular pathways will greatly enhance our knowledge of the cellular pathways that are involved in the pathogenesis of the disease.