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