By Barnaby Nicolas, MSIS
In our monthly “Article Spotlight” series, we’re showcasing achievements of Mount Sinai faculty and researchers using Altmetrics. This month, we’re looking at an article co-written by Dr. Pamela Sklar, MD, Professor, Psychiatry, Professor, Genetics & Genomics Sciences, Professor, Neuroscience, at Icahn School of Medicine at Mount Sinai. The article examines the use of shared data to provide insights into genetic-variant penetrance.
Citation: Minikel EV, Vallabh SM, Lek M, Estrada K, Samocha KE, Sathirapongsasuti JF, et al. Quantifying prion disease penetrance using large population control cohorts. Science Translational Medicine. 2016;8(322):322ra9.
Article Summary: This study analyzes vast amounts of shared data—from the Exome Aggregation Consortium and the 23andMe database—to provide insights into genetic-variant penetrance and possible treatment approaches for a rare, fatal genetic prion disease. This study was analysis was conducted by a patient-turned-scientist joined with a large bioinformatics team.
BACKGROUND: No longer just buzz words, “patient empowerment” and “data sharing” are enabling breakthrough research on rare genetic diseases. Although more than 100,000 genetic variants are believed to drive disease in humans, little is known about penetrance—the probability that a mutation will actually cause disease in the carrier. This conundrum persists because small sample sizes breed imperfect alliance estimates between mutations and disease risk. More than 100,000 genetic variants are reported to cause Mendelian disease in humans, but the penetrance-the probability that a carrier of the purported disease-causing genotype will indeed develop the disease-is generally unknown. The researchers assessed the impact of variants in the prion protein gene (PRNP) on the risk of prion disease by analyzing 16,025 prion disease cases, 60,706 population control exomes, and 531,575 individuals genotyped by 23andMe Inc. They found that missense variants in PRNP previously reported to be pathogenic are at least 30 times more common in the population than expected on the basis of genetic prion disease prevalence. Although some of this excess can be attributed to benign variants falsely assigned as pathogenic, other variants have genuine effects on disease susceptibility but confer lifetime risks ranging from <0.1 to ~100%. We also show 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.