Loss-of-function Variants in CPT1C: No Support for a Causal Role in Hereditary Spastic Paraplegia

ABSTRACT Background Hereditary spastic paraplegias (HSPs) are neurodegenerative disorders characterized by lower limb spasticity. Pathogenic variants in CPT1C have been implicated in HSP. Objective To assess if CPT1C loss-of-function (LOF) variants are causally associated with HSP. Methods We analyzed whole-genome sequencing (WGS) data from UK Biobank (UKBB), whole-exome sequencing (WES) data from a Canadian cohort of HSP (Can-HSP), and genetic data from the GENESIS cohort—a large international cohort of patients with rare hereditary diseases, including HSP. Results Among >170 CPT1C LOF carriers in the UKBB (n=150,119), none exhibited HSP phenotypes. Among 585 HSP patients from Can-HSP, we did not find patients with CPT1C LOF variants. In the GENESIS cohort (n=21,217), three individuals carrying CPT1C LOF variants were also diagnosed with HSP; however, all three also carry pathogenic variants in established HSP-associated genes. Conclusion Our study does not support a causal role for CPT1C LOF variants in HSP.