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Published on: March 12, 2018
Quantifying prion disease penetrance using large population control cohorts
Eric Vallabh Minikel1, Sonia M Vallabh2, Monkol Lek3
1Program 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.
Genetic variants in the prion protein gene (PRNP) show varying risks for prion disease. Some loss-of-function variants are safe, supporting therapeutic strategies.
Area of Science:
- Genetics
- Neuroscience
- Human disease genetics
Background:
- Penetrance of human genetic variants causing Mendelian disease is largely unknown.
- Prion protein gene (PRNP) variants are associated with prion diseases.
Purpose of the Study:
- To assess the impact of PRNP variants on prion disease risk.
- To determine the penetrance of pathogenic PRNP variants.
Main Methods:
- Analysis of 16,025 prion disease cases and 60,706 population controls.
- Utilized exome sequencing and genotyping data from 23andMe Inc.
Main Results:
- Missense PRNP variants reported as pathogenic are 30x more common than expected.
- Variant effects on disease susceptibility range from <0.1% to 100% lifetime risk.
- Truncating PRNP variants show position-dependent effects; loss-of-function alleles found in healthy individuals.
Conclusions:
- Many PRNP variants have unknown or low penetrance, challenging disease classifications.
- Loss-of-function PRNP alleles do not cause disease, supporting therapeutic approaches.
- Findings support the safety of therapeutic prion protein expression suppression.
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