PRNP allelic series from 19 years of prion protein gene sequencing at the MRC Prion Unit.

Mutation of the human prion protein gene (PRNP) open reading frame (ORF) accounts for almost all reported familial concurrence of prion disease. The more common mutations globally: octapeptide repeat insertions, P102L, D178N, E200K, and V210I have occurred in large multigenerational pedigrees and display autosomal dominant inheritance, however, many rare genetic changes have been reported that are of uncertain pathogenicity. Based on 19 years of PRNP sequencing at the MRC Prion Unit, London, and analysis of 3664 samples from patients referred with suspected prion disease and healthy populations, we present novel allele combinations, healthy control population data, results of screening the PRNP ORF in DNA from the entire referral series and the CEPH human genome diversity cell line panel. Of the 10 alleles detected in patients for which detailed cases histories are presented, 4 are unreported (G54S, D167N, V209M, Q212PP), two changes are thought to be pathogenic but have not been described in our regions (P105L from the UK, G114V from India and Turkey), and the remainder reported in healthy control populations or in trans to known pathogenic mutations suggesting non- or low pathogenicity (G54S, 1-OPRI, G142S, N171S, V209M, E219K). New genotype-phenotype correlations and population frequencies presented will help the diagnosis and genetic counselling of those with suspected inherited prion disease.