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International Team Characterizes Prion Risk Variant Penetrance

NEW YORK (GenomeWeb) – An international research team reporting in Science Translational Medicine today tapped large-scale sequence data sets to tally up penetrance patterns for glitches in a gene implicated in prion disease risk.

For the effort, which focused on dozens of variants in the prion protein-coding gene PRNP, the researchers combined targeted sequence data for individuals from more than 16,000 affected families with exome sequences from some 60,706 unaffected individuals and SNP profiles for almost 531,600 23andMe customers who agreed to research participation.

The team, which included a researcher with a potential prion disease risk variant and her husband, reasoned that more accurate penetrance estimates for PRNP variants may help in conveying appropriate risk information to affected families, while identifying biological features of prion disease that could lead to new treatment options.

Based on their findings so far, for example, the study's authors concluded 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."

Penetrance estimates can be tricky for variants linked to Mendelian diseases, in part because such associations are frequently first identified in groups of affected individuals or families, the team noted. Indeed, broader studies that bring genetic data from the general population to bear hint that penetrance may be far lower than anticipated for variants identified in some more common Mendelian conditions.

To untangle penetrance patterns for variants in PRNP — rare sporadic or inherited mutations that can cause a fatal disease marked by prion protein misfolding and neurodegeneration — the researchers relied on exome sequences for 60,707 unrelated individuals from the Exome Aggregation Consortium (ExAC), along with genotypes for 531,575 23andMe customers who did not appear to show close family ties.

Through a literature search, meanwhile, the team tracked down 63 rare PRNP variants that have been implicated in prion disease cases.

When they scoured the ExAC sequences for these genetic glitches, the team identified 52 individuals carrying PRNP alterations that are expected to be pathogenic — far more than the 1.7 pathogenic PRNP variant carriers that would be expected if the variants were fully penetrant.

Likewise, 23andMe customers appeared more prone to potentially pathogenic PRNP variants than anticipated from prion disease rates and life expectancies for individuals affected by the disease.

Through a series of follow-up analyses, the team estimated the penetrance of PRNP variants based on allele frequencies in such unselected populations and in 16,025 individuals with confirmed prion disease.

Of 63 variants in the prion protein-coding gene PRNP, for example, they found four variants with roughly 100 percent penetrance, while re-classifying three variants that were previously presumed to be pathogenic as likely benign. Still other variants showed incomplete penetrance.

"Although our estimates are imperfect because of population stratification, they accord well with family history rates and … indicate that PRNP missense variants occupy a risk continuum rather than a dichotomy of causal versus benign," senior author Daniel MacArthur, a medical and population genetics researcher affiliated with the Broad Institute and Massachusetts General Hospital, and his co-authors wrote.

In an accompanying editorial in Science Translational Medicine, Robert Green, a genetic researcher affiliated with Harvard, Brigham and Women's Hospital, the Broad Institute, and Partners HealthCare Personalized Medicine, and his colleagues noted that "[i]n strictly scientific terms, the new findings better refine variant pathogenicity and penetrance of disease across disease-causing mutations in the prion protein (PRNP) gene."

"Of perhaps greater consequence, the story of this research stands as a testament to the generosity of unrequited data sharing from thousands of individuals and scientists around the globe," they added, "and to the unflinching devotion of a young couple to alter their seemingly unalterable genetic destiny."