A personal journey in Genomics

Eric Minikel is lead author on a paper that came out in STM in January: Quantifying prion disease penetrance using large population control cohorts. The story is an incredibly personal one involving his wife Sonia, which Eric documents at the cureFFI.org blog. The paper reports on the penetrance of variants in the prion protein gene and the risk of actually getting prion disease. They analysed 16,000 case exomes and 60,706 population controls, and verified their findings in data provided by 23andMe (read their coverage as well) and found that missense variants in PRNP are 30x more common in the population than expected. Unfortunately Erik's wife Sonia Vallabh carries one of four of these variants that virtually guarantee the disease will develop, the same one that led to her mothers death from fatal familial insomnia, hence cureFFI.org.

Fig 1 from the STM paper: PRNP variant freq. is 30x higher in controls

Eric and Sonia were not scientists when they first heard about FFI or PRNP. But they retrained and are now both at the Broad Institute in Boston, Erik is in Daniel MacArthur's lab, and Sonia is in the lab of Stuart Schreiber. The STM paper is based on an analysis of the ExAC dataset.

The results reveal the penetrance of the many variants in PRNP and change the view many doctors may have had, that any variants were associated with a 100 percent risk for developing the disease. Erik et al identified benign missense variants and showed others spanned a spectrum of penetrance from 0.1 to ~100%. They provide quantitative estimates of lifetime risk and importantly in the paper they discuss the problems of assessing penetrance and risk. Even the ExAC dataset is only "approaching the size and quality required for such analyses" which limits the study, and the sequencing data generated today are imperfect with many genomic loci presenting challenges for sequencing technologies and variant calling.

Sonia's working in Stuart Schreiber's lab trying to find treatments for human prion diseases. The STM discussion suggests that reducing Prion Protein expression may be an option. Within the ExAC data they found heterozygous loss-of-function variants in three healthy people showing no effect from a 50% reduction in gene dosage for PRNP. Reducing PRNP dosage in patients may be tolerated. Whether they can develop small molecules or other methods to achieve this will be the focus of a lot more research.

The work would have been impossible without the groundwork laid out by the ExAc team, see their preprint on the BioRxiv: Analysis of protein-coding genetic variation in 60,706 humans.