The important role of copy-number variations in hereditary spastic paraplegia

Backgrounds: Hereditary spastic paraplegia (HSP) is a genetically heterogeneousneurodegenerative disorder, characterized by progressive spasticity, and weakness. Differenttypes of mutations in more than ۷۳ genes have been identified in HSP, especially by the wholeexomesequencing (WES) method. However, WES has failed to find the causative variants in~۵۰% of HSP cases. Regarding that, typical WES analysis cannot detect copy-number variations(CNVs). CNVs have a highlighted role in HSP, as ~۲۰% of the most common type of HSP,SPG۴, is due to CNVs. Also, CNVs account for ~۱۹% of SPG۱۱ and ~۱۴% of SPG۷, the mostcommon types of autosomal recessive HSP. Nowadays, a number of tools are proposed forCNV-detection based on WES data. Therefore, we tried to analyze seven HSP-affected Iranianfamilies whose disease-causing genetic variants did not recognize by routine WES analysis.Materials and Methods: We used Germline CNV Caller to identify probably pathogenic CNVsusing WES data. Multiplex ligation-dependent probe amplification (MLPA) was used to confirmthe CNV/CNVs.Results: A large deletion of exon ۱۷ of the SPAST gene was detected in a proband (۱/۷: ~۱۴%)and confirmed by MLPA.Conclusion: This finding confirms the importance of CNVs as a cause of HSP, while typicalWES analysis will miss them. Due to the significant percentage of CNVs, especially in someHSP genes, like SPAST, SPG۱۱, and SPG۷, CNV analysis should be considered among thiscategory of neurological disorders. This analysis can be performed using tools like GermlineCNV Caller which helps to detect CNVs based on WES data.

کلیدواژه ها:

Hereditary spastic paraplegia (HSP) ، Copy-number variations (CNVs) ، whole-exome sequencing (WES) ، MLPA ، Germline CNV Caller