Rare novel CYP2U1 and ZFYVE26 variants identified in two Pakistani families with spastic paraplegia

Bakground: Hereditary Spastic paraplegias (HSPs) are a clinically and genetically heterogeneous group of degenerative disorders characterized by progressive spasticity and weakness of the lower limbs. This study aimed to identify causative gene variants in two unrelated consanguineous Pakistani families presented with 2 different forms of HSP. Methods: Whole exome sequencing (WES) was performed in the two families and variants were validated by Sanger sequencing and segregation analysis. Analysis: In family A, a homozygous pathogenic variant in ZFYVE26 was identified in one family. While in family B, a frameshift variant in CYP2U1 was identified in 4 affected individuals presented with clinical features of SPG56. Our study is the first report of ZFYVE26 mutations causing HSP in the Pakistani population and the second report of CYP2U1 in a Pakistani family. Conclusions: Our findings enhance the clinical and genetic variability associated with two rare autosomal recessive HSP genes, highlighting the complexity of HSPs. These findings further emphasize the usefulness of WES as a powerful diagnostic tool.