Estimating the Penetrance of PRNP Mutations in Chinese Prion Disease Patients based on the Genome Databases

Genetic prion diseases (gPrDs) are directly caused by mutations in the prion protein gene (PRNP). Although several mutations have been strongly linked to disease manifestation, the penetrance of many variants remains uncertain. This study aimed to clarify the penetrance of PRNP variants by analyzing data from the Chinese surveillance system and comparing them to large genome databases representing East Asian and global genetic backgrounds. Our analysis included 301 gPrD cases with PRNP point mutations alongside 96,462 individuals of East Asian genetic descent and 784,714 from a global cohort. Notably, the D178N, E200K, and P102L mutations exhibited high penetrance irrespective of genetic background, underscoring their pathogenic potential. T188K, the most frequent variant in Chinese gPrD cases, also showed high penetrance across all cohorts despite its regional specificity. Conversely, estimates of E196A penetrance were low, particularly in the Chinese and East Asian cohorts. Variants such as S97N and R148H showed extremely low penetrance across all cohorts, while V180I and V210I displayed distinct regional and ethnic variations in both prevalence and penetrance. However, the penetrance of rare mutations could not be reliably estimated due to insufficient case numbers. These insights highlight the complex interplay between genetic variation and disease risk, necessitating further investigation into the genetic epidemiology of gPrD.