Minikel EV et al. 2016, Quantifying prion disease penetrance using large population control cohorts (Sci Transl Med 8(322):322ra9, PMID 26791950, doi 10.1126/scitranslmed.aad5169)

This 2016 Science Translational Medicine paper, led by Eric Vallabh Minikel and Sonia M. Vallabh with Daniel G. MacArthur as senior author and the Exome Aggregation Consortium as a collaborator, compared PRNP variants seen in prion disease cases with those seen in very large control datasets. It combined 16,025 cases, 60,706 control exomes and 531,575 people genotyped by a consumer genetics company, and concluded that many variants listed as pathogenic are far too common in the general population to cause fully penetrant disease. It put lifetime risk at under 0.1 percent for some variants and near 100 percent for others, and it gave early human genetic evidence that carrying one non-working copy of PRNP is tolerated, which bears on PrP-lowering drugs. The record and abstract were read from PubMed and Crossref; the open-access PMC text was read in part (first 100,000 of about 157,600 characters), and the supplement was not opened. Information only, not medical advice.

Key facts

  • Citation verified: Sci Transl Med, volume 8, issue 322, article 322ra9, published 20 January 2016, DOI 10.1126/scitranslmed.aad5169, PMID 26791950, PMCID PMC4774245.
  • The queued citation (authors, journal, volume, article number, PMID, DOI) matches PubMed and Crossref; the registries give no page range.
  • Data: 16,025 prion disease cases, 60,706 population control exomes and 531,575 people genotyped by 23andMe.
  • Variants previously reported as pathogenic were at least 30 times more common in the population than genetic prion disease prevalence predicts.
  • For the reported pathogenic missense variants, about 1.7 carriers were expected in the exome control set but 52 were found; in the consumer-genotype set about 15 were expected and 141 alleles seen.
  • The authors attribute part of the excess to benign variants wrongly labelled pathogenic and part to variants that raise risk only partly.
  • P102L, A117V, D178N and E200K showed strong evidence of pathogenicity, being absent or very rare in controls; the E200K estimate overlapped earlier published survival-based figures of roughly 60 to 90 percent.
  • M232R, V180I and V210I showed weak to moderate risk, with lifetime estimates of about 0.1, 1 and 10 percent against a baseline lifetime risk near 1 in 5,000.
  • Overall lifetime risk by variant spanned from below 0.1 percent to about 100 percent.
  • Truncating variants behave by position: C-terminal truncations from residue 145 on cause disease by gain of function, while N-terminal truncations (residue 131 or earlier) were found in older people free of overt neurological disease.
  • Four control individuals carried N-terminal truncations, three validated, aged 52 to 79 without overt neurological disease; the authors concluded heterozygous loss of PrP function is tolerated.
  • The authors present this as the first human genetic data on roughly 50 percent PRNP dosage reduction and as preliminary support for PrP-lowering strategies (RNA interference, antisense oligonucleotides, small molecules), while noting a small sample and that lifelong gene inactivation differs from drug treatment.
  • The discussion notes implications for genetic counselling and low rates of predictive testing; the paper reports no clinical trial or presymptomatic study results and does not mention trials.

Timeline

  1. 2016Published 20 January 2016 in Science Translational Medicine.
  2. 2016Open-access author manuscript indexed in PubMed Central as PMC4774245.

People

Last checked 1 November 2026

Sources for this page