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High-Depth PRNP Sequencing in Brains With Sporadic Creutzfeldt-Jakob Disease.

Accepted version
Peer-reviewed

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Authors

Murley, Alexander G  ORCID logo  https://orcid.org/0000-0003-0813-0670
Nie, Yu 
Golder, Zoe 
Keogh, Michael John 
Smith, Colin 

Abstract

BACKGROUND AND OBJECTIVES: Sporadic Creutzfeldt-Jakob disease (sCJD) has established genetic risk factors, but, in contrast to genetic and acquired CJD, the initial trigger for misfolded prion aggregation and spread is not known. In this study, we tested the hypotheses that pathologic somatic variants in the prion gene PRNP are increased in sCJD, potentially leading to the seeding of misfolded prion protein. METHODS: High-depth amplicon-based short read sequencing of the PRNP coding region was performed on postmortem brain tissue from patients with a clinical and neuropathologic diagnosis of sCJD (n = 142), Alzheimer disease (AD) (n = 51) and controls with no clinical or neuropathologic diagnosis of a neurodegenerative disease (n = 71). Each DNA sample was sequenced twice, including independent PCR amplification, library preparation, and sequencing. We used RePlow to call somatic variants with high sensitivity and specificity and optimal sequence kernel association test to compare variant burden between groups. RESULTS: Two sCJD cases had somatic (variant allele frequency 0.5-1%) PRNP variants not previously identified, but with high in silico predicated pathogenicity. However, the pathogenicity of these variants is uncertain, as both located in the octapeptide repeat region where no point variations have previously been associated with sCJD. There was no overall difference in burden somatic PRNP in sCJD compared with controls and a lower burden compared with Alzheimer disease. DISCUSSION: Somatic variants in PRNP are unlikely to play a major role in sCJD but may contribute to the disease mechanism in a minority of cases.

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Keywords

Journal Title

Neurol Genet

Conference Name

Journal ISSN

2376-7839
2376-7839

Volume Title

Publisher

Ovid Technologies (Wolters Kluwer Health)
Sponsorship
MRC (via University of Edinburgh) (162126)
Wellcome Trust (212219/Z/18/Z)