Abstract:
: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.
journal_name
Sci Transl Medjournal_title
Science translational medicineauthors
Minikel EV,Vallabh SM,Lek M,Estrada K,Samocha KE,Sathirapongsasuti JF,McLean CY,Tung JY,Yu LP,Gambetti P,Blevins J,Zhang S,Cohen Y,Chen W,Yamada M,Hamaguchi T,Sanjo N,Mizusawa H,Nakamura Y,Kitamoto T,Collins SJ,doi
10.1126/scitranslmed.aad5169subject
Has Abstractpub_date
2016-01-20 00:00:00pages
322ra9issue
322eissn
1946-6234issn
1946-6242pii
8/322/322ra9journal_volume
8pub_type
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