Expanding the genetic and clinical landscapes of hereditary spastic paraplegia (HSP): a cohort study of 103 families

Abstract Background Hereditary spastic paraplegia (HSP) refers to a heterogeneous group of genetic disorders with more than 90 causative genes. Clinically, HSP is classified into pure and complicated forms. Pure forms are characterized primarily by lower-limb spasticity and weakness, whereas complicated forms include additional neurological or non-neurological symptoms alongside spasticity and weakness. We aimed to characterize the clinical and genetic landscapes of HSP in an Iranian cohort. Whole-exome sequencing (WES) was performed on 103 unrelated clinically suspected HSP probands. Multiple ligation-dependent probe amplification (MLPA) was performed to validate identified copy number variants (CNVs) in two probands. Results 71 pathogenic/likely pathogenic and VUS variants were identified in 81 probands; total genetically solved probands: 78.6%. Among these solved cases, 64 probands harbored variants in known HSP genes, 14 had variants in other neuromuscular/neurodegenerative-related genes, and the remaining 3 probands carried variants in four novel candidate genes including NMNAT1, SEMA3A, KCNJ14 , and EMP3 . Among all 71 identified genomic variants, two were CNVs and one was a trinucleotide repeat expansion. Taken together, these variants were located in 37 genes; 21 of these genes have been previously implicated in HSP, and four common HSP subtypes (SPG11, SPG4, SPG7, and SPG15) accounted for ~40% of our cohort. Conclusions This study demonstrates significant clinical and genetic heterogeneity of HSP within our cohort. In addition to variants in 21 known HSP-related genes, we identified variants in 14 genes related to other neurological disorders -highlighting shared biological pathways- as well as variants in four novel candidate genes. Notably, a genetic diagnosis could not be established in 22 probands, underscoring that additional, as yet unidentified genes likely contribute to HSP pathogenesis.