Genetics Heterogeneity and Novel Genes in Hereditary Spastic Paraplegia

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 70 genes and 80 loci identified thus far. whole exome sequencing (wes) has been used for gene discovery in hsp since 2011, 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 ~50% in the autosomal dominant-hsp (ad-hsp) and ~70% 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 40 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>0.01 for ar-hsps and maf>0.001 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 16 known disease-causing genes including speg, atad3a, spast (three families), entpd1, spg7 (two families), kif5a, cyp7b1, zfyve26, gjc2, capn1, zfyve26, kif1b, spg11 (three families), atl1, mfn2, c19orf12, and four novel candidate-hsp genes.conclusion: here, we could find hsp-causing genes in 21 cases (52.5%). 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.