Research ArticleMEDICAL GENOMICS

Quantifying prion disease penetrance using large population control cohorts

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Science Translational Medicine  20 Jan 2016:
Vol. 8, Issue 322, pp. 322ra9
DOI: 10.1126/scitranslmed.aad5169
  • Fig. 1. Frequency of reportedly pathogenic PRNP variants: >30 times higher in controls than expected on the basis of disease incidence.

    (A and B) Reported prion disease incidence varies with the intensity of surveillance efforts (13), with an apparent upper bound of about two cases per million population per year (Materials and Methods). In our surveillance cohorts, 65% of cases underwent PRNP open reading frame sequencing, with 12% of all cases, or 18% of sequenced cases, having a rare variant (table S1), which is consistent with an oft-cited estimate that 15% of cases of Creutzfeldt-Jakob disease are familial (43). Genetic prion diseases typically strike in midlife, with mean age of onset for different variants ranging from 28 to 77 (table S10) (22, 91); we accepted 80, a typical human life expectancy, as an upper bound for mean age of onset, and to be additionally conservative, we assumed that all individuals in the ExAC and 23andMe data sets were below any age of onset, even though both contain elderly individuals (fig. S1) (92). Thus, no more than ~29 people per million in the general population should harbor high-penetrance prion disease–causing variants; at most ~1.7 people in ExAC (A) and ~15 people in 23andMe would be expected to harbor such variants. Reportedly pathogenic variants were observed in 52 ExAC individuals (B) and on 141 alleles in the 23andMe database (table S5).

  • Fig. 2. Reportedly pathogenic PRNP variants: Mendelian, benign, and intermediate variants.

    Previous evidence of pathogenicity is extremely strong for four missense variants—P102L, A117V, D178N, and E200K—each of which has been observed to segregate with disease in multiple multigenerational families (1618, 9397) and to cause spontaneous disease in mouse models (98103). These account for >50% of genetic prion disease cases (table S1), yet are absent from ExAC (table S3) and collectively appear on five or fewer alleles in 23andMe’s cohort (table S5), indicating allele frequencies sufficiently low to be consistent with the prevalence of genetic prion disease (Fig. 1). Conversely, the variants most common in controls and rare in cases had categorically weak previous evidence for pathogenicity. R208C (eight alleles in 23andMe) and P39L were observed in patients presenting clinically with other dementias, with prion disease suggested as an alternative diagnosis solely on the basis of finding a novel PRNP variant (104, 105). E196A was originally reported in a single patient, with a sporadic Creutzfeldt-Jakob disease phenotype and no family history (36), and appeared in only 2 of 790 Chinese prion disease patients in a recent case series (106), consistent with the ~0.1% allele frequency among Chinese individuals in ExAC (tables S5 and S8). At least three variants (M232R, V180I, and V210I) occupy a space inconsistent either with neutrality or with complete penetrance (see main text and Fig. 3). R148H, T188R, V203I, R208H, and additional variants are discussed in Supplementary Discussion.

  • Fig. 3. Variants that confer intermediate amounts of lifetime risk.

    M232R, V180I, and V210I showed varying degrees of enrichment in cases over controls, indicating a weak to moderate increase in risk. Best estimates of lifetime risk in heterozygotes (Materials and Methods) range from ~0.08% for M232R to ~7.8% for V210I and correlate with the proportion of patients with a positive family history. Allele frequencies for P102L, A117V, D178N, and E200K were consistent with up to 100% penetrance, with CI including all reported estimates of E200K penetrance based on survival analysis, which range from ~60% to ~90% (19, 2326). Rates of family history of neurodegenerative disease in Japanese cases (table S10) and in European populations (21) are shown with Wilson binomial 95% CIs. *Based on allele counts rounded for privacy (Materials and Methods). Gerstmann-Straussler-Scheinker (GSS) disease associated with variants P102L, A117V, and G131V. Fatal familial insomnia (FFI) associated with a D178N (cis-129M) haplotype.

  • Fig. 4. Position-dependent effects of truncating variants in the human prion protein.

    Truncating variants reported in prion disease cases in the literature (table S2) and in our cohorts (table S1) cluster exclusively in the C-terminal region (residue ≥145), whereas truncating variants in ExAC are more N-terminal (residue ≤131). The ortholog of each residue from 23 to 94 is deleted in at least one prion-susceptible transgenic mouse line (107). C-terminal truncations abolish PrP’s glycosylphosphatidylinositol (GPI) anchor but leave most of the protein intact, a combination that mediates gain of function through mislocalization, which causes this normally cell surface–anchored protein to be secreted. Consistent with this model of pathogenicity, mice that express full-length secreted PrP develop fatal and transmissible prion disease (108, 109). By contrast, the N-terminal truncating variants that we observed retain only residues dispensable for prion propagation and are likely to cause a total loss of protein function.

Supplementary Materials

  • www.sciencetranslationalmedicine.org/cgi/content/full/8/322/322ra9/DC1

    Discussion

    Table S1. Allele counts of rare PRNP variants in 16,025 definite and probable prion disease cases in nine countries.

    Table S2. Rare PRNP variants reported in peer-reviewed literature to cause prion disease.

    Table S3. Allele counts of rare PRNP variants in 60,706 individuals in ExAC.

    Table S4. Summary of rare PRNP variants by functional class in ExAC.

    Table S5. Allele counts of 16 reportedly pathogenic PRNP variants in >500,000 23andMe research participants.

    Table S6. Phenotypes investigated in studies in which ExAC individuals with reportedly pathogenic PRNP variants were ascertained.

    Table S7. Inferred ancestry and codon 129 genotypes of ExAC individuals with reportedly pathogenic variants.

    Table S8. Inferred ancestry of all ExAC individuals.

    Table S9. Inferred ancestry of 23andMe research participants.

    Table S10. Details of Japanese prion disease cases.

    Table S11. Phenotypes of individuals with N-terminal PrP-truncating variants.

    Fig. S1. Age of ExAC individuals with reportedly pathogenic PRNP variants versus all individuals in ExAC.

    Fig. S2. Sanger sequencing results for individuals with N-terminal–truncating variants.

    References (110179)

  • Supplementary Material for:

    Quantifying prion disease penetrance using large population control cohorts

    Eric Vallabh Minikel,* Sonia M. Vallabh, Monkol Lek, Karol Estrada, Kaitlin E. Samocha, J. Fah Sathirapongsasuti, Cory Y. McLean, Joyce Y. Tung, Linda P. C. Yu, Pierluigi Gambetti, Janis Blevins, Shulin Zhang, Yvonne Cohen, Wei Chen, Masahito Yamada, Tsuyoshi Hamaguchi, Nobuo Sanjo, Hidehiro Mizusawa, Yosikazu Nakamura, Tetsuyuki Kitamoto, Steven J. Collins, Alison Boyd, Robert G. Will, Richard Knight, Claudia Ponto, Inga Zerr, Theo F. J. Kraus, Sabina Eigenbrod, Armin Giese, Miguel Calero, Jesús de Pedro-Cuesta, Stéphane Haïk, Jean-Louis Laplanche, Elodie Bouaziz-Amar, Jean-Philippe Brandel, Sabina Capellari, Piero Parchi, Anna Poleggi, Anna Ladogana, Anne H. O'Donnell-Luria, Konrad J. Karczewski, Jamie L. Marshall, Michael Boehnke, Markku Laakso, Karen L. Mohlke, Anna Kähler, Kimberly Chambert, Steven McCarroll, Patrick F. Sullivan, Christina M. Hultman, Shaun M. Purcell, Pamela Sklar, Sven J. van der Lee, Annemieke Rozemuller, Casper Jansen, Albert Hofman, Robert Kraaij, Jeroen G. J. van Rooij, M. Arfan Ikram, André G. Uitterlinden, Cornelia M. van Duijn, Exome Aggregation Consortium (EXAC), Mark J. Daly, Daniel G. MacArthur*

    *Corresponding author. E-mail: eminikel{at}broadinstitute.org (E.V.M.); macarthur{at}atgu.mgh.harvard.edu (D.G.M.)

    Published 20 January 2016, Sci. Transl. Med. 8, 322ra9 (2016)
    DOI: 10.1126/scitranslmed.aad5169

    This PDF file includes:

    • Discussion
    • Table S1. Allele counts of rare PRNP variants in 16,025 definite and probable prion disease cases in nine countries.
    • Table S2. Rare PRNP variants reported in peer-reviewed literature to cause prion disease.
    • Table S3. Allele counts of rare PRNP variants in 60,706 individuals in ExAC.
    • Table S4. Summary of rare PRNP variants by functional class in ExAC.
    • Table S5. Allele counts of 16 reportedly pathogenic PRNP variants in >500,000 23andMe research participants.
    • Table S6. Phenotypes investigated in studies in which ExAC individuals with reportedly pathogenic PRNP variants were ascertained.
    • Table S7. Inferred ancestry and codon 129 genotypes of ExAC individuals with reportedly pathogenic variants.
    • Table S8. Inferred ancestry of all ExAC individuals.
    • Table S9. Inferred ancestry of 23andMe research participants.
    • Table S10. Details of Japanese prion disease cases.
    • Table S11. Phenotypes of individuals with N-terminal PrP-truncating variants.
    • Fig. S1. Age of ExAC individuals with reportedly pathogenic PRNP variants versus all individuals in ExAC.
    • Fig. S2. Sanger sequencing results for individuals with N-terminal–truncating variants.
    • References (110179)

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