PRNP and prion disease: For example, GoF mutations causing genetic prion disease have a genetic prevalence of approximately 1 in 50,00036 and have been known for three decades, with thousands of cases identified, making it unlikely that a comparably severe and penetrant haploinsufficiency syndrome associated with PRNP would have gone unnoticed to the present day despite being more than twice as common (roughly 1 in 18,000).