Genetic Creutzfeldt-Jakob disease in Sardinia: a case series linked to the PRNP R208H mutation due to a single founder effect

Neurogenetics. 2020 Oct;21(4):251-257. doi: 10.1007/s10048-020-00618-1. Epub 2020 May 26.


In genetic prion diseases (gPrD), five genetic variants (E200K, V210I, V180I, P102L, and D178N) are responsible for about 85% of cases. The R208H is one of the several additional rare mutations and to date, only 16 cases carrying this mutation have been reported worldwide. To describe the phenotypic features of 5 affected patients belonging to apparently unrelated Sardinian (Italian) families with R208H gPrD, and provide evidence for a possible founder effect are the aims of this study. The R208H PRNP mutation has a much higher relative frequency in Sardinia than elsewhere in Italy (72% vs. 4.4% of gCJD cases). Our cohort shared similar phenotypic features to the previously described patients with R208H-129M haplotype with most patients showing the classical Creutzfeldt-Jakob disease (CJD) phenotype. The analysis of 10 controls and 5 patients by NGS sequencing identified 4 haplotypes, 3 associated with the wild type variant, and one (H1) shared by all patients carrying the 208His variant. This is the first report of a regional cluster for R208H mutation in gPrD and the first report of the presence of a common ancestor for this Sardinian R208H cluster, confirming the probable consequences of genetic isolation process even for rare diseases.

Keywords: CJD; Creutzfeldt-Jakob disease; Founder effect; Genetic; Prion; Sardinia; gCJD.

Publication types

  • Case Reports

MeSH terms

  • Aged
  • Alleles
  • Cluster Analysis
  • Creutzfeldt-Jakob Syndrome / genetics*
  • Family Health
  • Female
  • Founder Effect*
  • Haplotypes
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Italy / epidemiology
  • Male
  • Middle Aged
  • Mutation*
  • Phenotype
  • Prion Proteins / genetics*


  • PRNP protein, human
  • Prion Proteins