Search for a genetic cause of variably protease-sensitive prionopathy

Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease currently classified as sporadic. We performed exome sequencing and targeted sequencing of PRNP non-coding regions on genomic DNA from autopsy-confirmed VPSPr patients (N = 67) in order to search for a possible genetic cause. Our search identified no potentially causal variants for VPSPr. The common polymorphism PRNP M129V was the largest genetic risk factor for VPSPr, with an odds ratio of 7.0. Other variants in and near PRNP exhibited association to VPSPr risk only in proportion to their linkage disequilibrium with M129V, and upstream expression quantitative trait loci showed no evidence of independent association to VPSPr risk. We cannot rule out the possibility of causal variants hiding in genomic regions or classes of genetic variation that our search did not canvas. Nevertheless, our data support the classification of VPSPr as a sporadic prion disease.