Variably protease-sensitive prionopathy (VPSPr) is a rare, atypical subtype of prion disease in which many patients exhibit a family history of dementia. Rare protein-coding variants in PRNP, which are causal for all known forms of genetic prion disease, have been ruled out in all VPSPr cases to date, leading to suspicion that VPSPr could be caused by variants in other genes or by non-coding variation in or near PRNP. 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 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.

EVM acknowledges speaking fees from Abbvie, Eli Lilly, and Vertex; consulting fees from Alnylam and Deerfield; research support from Eli Lilly, Gate Bio, Ionis, and Sangamo. SMV acknowledges speaking fees from Abbvie, Biogen, Eli Lilly, Illumina, and Ultragenyx; consulting fees from Alnylam and Invitae; research support from Eli Lilly, Gate Bio, Ionis, and Sangamo. BSA acknowledges research funding from CDC, NIH, CJD Foundation, and Ionis and consulting fees from Ionis, Sangamo, and Gate Bio, and royalties from Wolter Klower. AODL acknowledges consulting fees from Tome Biosciences, Ono Pharma USA, Addition Therapeutics, and Congenica; and research funding from Pacific Biosciences.

This study was funded by the National Institutes of Health (R03 NS123786). Broad CMG control cohort sequencing was funded by NIH grants UM1 HG008900 and U01 HG011755, and seqr analysis platform by R01 HG009141.

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This study was approved by the Broad Institute Office of Research Subjects Protection (NHSR-5256)

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All figures and statistics in this manuscript were generated using custom scripts in R 4.4.1. Genomic and phenotypic data for the Broad CMG cohort used for comparison is available via dbGaP accession numbers phs003047 and phs001272. Access is managed by a data access committee designated by dbGaP and is based on intended use of the requester and allowed use of the data submitter as defined by consent codes. Raw data and source code sufficient to reproduce the figures and statistics in this manuscript will be made available at https://github.com/ericminikel/vpspr

https://github.com/ericminikel/vpspr