Clinical and Genetic Spectrum in a Large Cohort of Hereditary Spastic Paraplegia

Abstract Background Next‐generation sequencing‐based molecular assessment has benefited the diagnosis of hereditary spastic paraplegia (HSP) subtypes. However, the clinical and genetic spectrum of HSP due to large fragment deletions/duplications has yet to be fully defined. Objective We aim to better characterize the clinical phenotypes and genetic features of HSP and to provide new thoughts on diagnosis. Methods Whole‐exome sequencing (WES) was performed in patients with clinically suspected HSP, followed by multiple ligation‐dependent probe amplification (MLPA) sequentially carried out for those with negative findings in known causative genes. Genotype–phenotype correlation analyses were conducted under specific genotypes. Results We made a genetic diagnosis in 60% (162/270) of patients, of whom 48.9% (132/270) had 24 various subtypes due to point mutations (SPG4/SPG11/SPG35/SPG7/SPG10/SPG5/SPG3A/SPG2/SPG76/SPG30/SPG6/SPG9A/SPG12/SPG15/SPG17/SPG18/SPG26/SPG49/SPG55/SPG56/SPG57/SPG62/SPG78/SPG80). Thirty patients were found to have causative rearrangements by MLPA (11.1%), among which SPG4 was the most prevalent (73.3%), followed by SPG3A (16.7%), SPG6 (3.3%), SPG7 (3.3%), and SPG11 (3.3%). Clinical analysis showed that some symptoms were often related to specific subtypes, and rearrangement‐related SPG3A patients seemingly had later onset. We observed a presumptive anticipation among SPG4 and SPG3A families due to rearrangement. Conclusions Based on the largest known Asian HSP cohort, including the largest subgroup of rearrangement‐related pedigrees, we gain a comprehensive understanding of the clinical and genetic spectrum of HSP. We propose a diagnostic flowchart to sequentially detect the causative genes in practice. Large fragment mutations account for a considerable proportion of HSP, and thus, MLPA screening acts as a beneficial supplement to routine WES. © 2024 International Parkinson and Movement Disorder Society.