The Genetic Landscape of Hereditary Spastic Paraplegia in Greece

Hereditary spastic paraplegia (HSP) is a neurogenetic disorder characterized by progressive, length‐dependent degeneration of the upper motor neurons. We investigated 112 Greek HSP index cases collected over more than 25 years from all regions of the country, using a combination of next generation sequencing and multiplex ligation‐dependent probe amplification. In total, we identified a causative variant in 68 patients, corresponding to a diagnostic yield of 60.7%. The diagnostic yield was 62.8% in autosomal dominant HSP, 77.8% in autosomal recessive HSP and 50.0% in sporadic cases. We identified 7 novel causative variants in SPAST , SPG7 , and CYP7B1 . We found causative variants in a total of 18 different genes. The most commonly involved genes, affecting more than one family, were SPAST (25.0%), SPG11 (12.5%), CYP7B1 (3.6%), SPG7 (3.6%), KIF5A (2.7%), ABCD1 (1.8%) and PSEN1 (1.8%). Variants in ATL1 , REEP1 , BSCL2 , PLP1 , WASCHC5 , AP5Z1 , CYP27A1 , SOD1 , POLR3A, GFAP and ARG1 were identified in single families. This study presents a comprehensive overview of the phenotypic and genotypic spectrum of HSP in the Greek population, expanding previous data, and contributing to the characterisation of further pathogenic variants linked to HSP.