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More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. We assess the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. We show that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show that truncating variants in PRNP have position-dependent effects, with true loss-of-function alleles found in healthy older individuals, a finding that supports the safety of therapeutic suppression of prion protein expression.

Original publication

DOI

10.1126/scitranslmed.aad5169

Type

Journal article

Journal

Science translational medicine

Publication Date

01/2016

Volume

8

Addresses

Program in Medical and Population Genetics, Broad Institute of Massachusetts Institute of Technology (MIT) and Harvard, Cambridge, MA 02142, USA. Analytical and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA 02114, USA. Program in Biological and Biomedical Sciences, Harvard Medical School, Boston, MA 02115, USA. Prion Alliance, Cambridge, MA 02139, USA. eminikel@broadinstitute.org macarthur@atgu.mgh.harvard.edu.

Keywords

Exome Aggregation Consortium (ExAC), Humans, Prion Diseases, Genetic Predisposition to Disease, Prions, Risk Factors, Case-Control Studies, Cohort Studies, Penetrance, Mutation