PRNP variants: research

What classes of variant cause genetic prion disease?

Appleby and colleagues (Frontiers in Neurology 2022) group causal variants into missense mutations, insertions or deletions in the octapeptide region of the N-terminal domain, and nonsense (stop codon) mutations. Over 60 have been described. E200K is the most common, and E200K, D178N, P102L and A117V together account for more than half of genetic prion disease. Genetic prion disease makes up 10 to 15 percent of all cases in that review.

What do population controls show about penetrance?

Minikel and colleagues (Science Translational Medicine 2016) compared 16,025 prion disease cases with 60,706 ExAC exomes and with 23andMe data. They identified 63 rare variants reported to cause prion disease. Reported pathogenic variants appeared in 52 ExAC individuals, against about 1.7 expected if all were high-penetrance, and the authors concluded that the list of reported variants likely includes false positives. They describe missense variants as occupying a risk continuum, with some likely benign and others ranging from under 0.1 percent to about 100 percent penetrance.

The V210I, V180I and M232R estimates rest on allele frequencies matched by population, and the authors call them imperfect because of population stratification. Each variant is too frequent in controls to be fully penetrant and far less frequent there than in cases. The authors state that M232R, with 4- to 6-fold enrichment in cases, could still be benign, though they judge a low-penetrance effect more likely. The estimates accord with family history rates. Baseline lifetime risk in the general population is about 1 in 5,000 in that analysis.

These are population estimates. They do not describe the risk of any individual, and interpretation for a family belongs with a genetic counsellor and the reporting laboratory.

How does position change the effect of truncating variants?

PRNP has one protein-coding exon, so a premature stop codon is expected to give a truncated polypeptide. Heterozygous C-terminal truncating variants (residue 145 or later) are known to cause prion disease, sometimes with peripheral amyloidosis. Minikel and colleagues found heterozygous N-terminal truncating variants (residue 131 or earlier) in four ExAC individuals. Three were validated, and those three were free of overt neurological disease at ages 79, 73 and 52, with no reported personal or family history of neurodegeneration or peripheral neuropathy.

Appleby and colleagues report that nonsense variants are typically associated with PrP amyloid angiopathy. Y145X, Y160X and Y226X often cause non-specific progressive cognitive impairment or Alzheimer-like dementia, while Y163X has been described with systemic PrP amyloidosis, diarrhoea and autonomic neuropathy.

What do octapeptide repeat changes do?

Appleby and colleagues report that clinicopathologic phenotype is most influenced by repeat number. One-repeat insertions are considered benign, and two-repeat insertions may minimally increase CJD risk. Penetrance generally increases with repeat number. Fewer than 8 repeats tends towards a CJD phenotype and 8 or more towards a Gerstmann-Straussler-Scheinker phenotype. Age at onset falls as repeat number rises, with considerable variability. A one-repeat deletion is considered a benign polymorphism and a two-repeat deletion a pathogenic variant, reported in only five surveillance cases, none with a family history.