By looking at genetic information from more than half a million individuals, researchers have gained new insights into the clinical risk associated with dozens of different mutations in the prion protein gene.

If the study is an example of extreme big data, it is also an extremely personal one. Co-author Sonia Vallabh is a carrier of one of the mutations her team looked at, and corresponding author Eric Vallabh Minikel is her husband.

In fact, both of the researchers left previous careers to enter the field of prion disease research after Vallabh's mother died of the prion disease fatal familial insomnia (FFI).

FFI is one of the prion diseases, a group of infectious diseases caused by misfolded prion proteins. But individuals who come down with prion diseases have mutations in their prion protein that predispose them to developing disease.

The study brings into stark focus a key conundrum of genetic counseling, especially but not exclusively where rare diseases are concerned; often, little is actually known about the so-called penetrance of many rare variants – that is, how likely someone with a mutation is to develop clinical disease.

The reason is that so-called "risk" genes are identified in a way that is biased toward finding an association.

"Historically, the people who have had their prion gene sequenced are patients having prion disease or being from a family where prion disease has been seen," Vallabh explained in an interview posted to the Science Translational Medicine website.

"That leaves a . . . missing half of the picture, which is, how common are these mutations in the general population, and what can that tell us about the odds of developing the disease if you have a mutation?"

The problem is not unique to rare diseases. The question of which BRCA mutations are worth a double mastectomy is one that many patients and genetic counselors have grappled with, and recent work on cardiac variants has shown that far from every so-called pathogenic mutation calls for a pacemaker. (See BioWorld Today, Jan. 11, 2016.)

Nevertheless, rare diseases, just like rare variants, necessarily take larger groups of individuals to be able to make statistically sound observations on the clinical significance of a given mutation.

In their study, which appeared in the Jan. 20, 2016, issue of Science Translational Medicine, the authors got those control data from two sources.

One was the exome aggregation consortium, which describes itself as "a coalition of investigators seeking to aggregate and harmonize exome sequencing data from a variety of large-scale sequencing projects, and to make summary data available for the wider scientific community." So far, the consortium has gathered exomes from roughly 60,000 individuals.

The team also collaborated with direct-to-consumer genetic testing firm 23andme Inc., which has data from roughly half a million individuals that have agreed to let their genomes be used for research purposes.

When the researchers compared the genomic data from those two populations to the data from another 16,000 individuals who had been sequenced because there was a suspicion they might have prion disease, they found that the mutations "seemed to occupy a spectrum" in terms of how much risk they conveyed, Minikel said.

Some variants that had been seen in a few patients were fairly common in the control population, suggesting that the genetic variant was benign.

A second group of mutations did increase risk of developing prion disease. But "from a genetic counseling standpoint, it [was] still very low-risk," Minikel said.

For a third group of mutations, the penetrance was near 100 percent, meaning that the mutation was a very strong predictor that a person would become afflicted with prion disease.

Tragically for Vallabh and her family, the specific mutation she has inherited from her mother was among four variants that the team confirmed as high-risk.

But there was also hopeful news for her in her team's findings with respect to treatments of prion diseases.

In animals studies, lowering the levels of prion protein delays the onset of prion disease.

But because the function of normal prion protein is still unknown, such an approach has been considered risky.

In their study, however, "we were able to identify three individuals who have one copy of their gene basically inactivated," Vallabh said.

While no data exist to directly confirm it, a reasonable hypothesis is that those individuals have prion protein levels that are approximately half of normal. And they appear to suggest that lowering protein levels is a feasible treatment strategy. "These individuals were older, and they were healthy," Vallabh said.

TOO MUCH INFORMATION?

The study also bears on the ethical discussions of how much individuals should know about their genetic destiny.

A commentary accompanying the paper noted that "by many published standards and expert perspectives, [Vallabh] should have been heavily counseled, if not dissuaded, about the potential psychological damage of learning whether or not she carried this mutation, with the underlying assumption that no medical good could result from such knowledge."

To be sure, Vallabh's story is noteworthy in part because it is so rare.

Other examples exist of individuals who have switched careers into biomedical development after the diagnosis of a family member.

The most famous example is Novazyme Pharmaceuticals Inc., which focused on lysosomal storage disorders and was acquired by Genzyme Corp. in 2001.

Lysogene SAS, which focuses on orphan CNS diseases, and Solid Biosciences LLC, developing gene therapies for Duchenne muscular dystrophy, are other companies whose founders have children affected with the diseases they are aiming to cure.

But those individuals are atypical, possessing a rare combination of abilities and resources that enable them to both devote their lives and have a high impact when a diagnosis explodes into their world.

Still, there is good evidence that even individuals who do not re-orient their lives to the same degree after receiving the information that they have a serious genetic disorder can benefit from information that is non-actionable in the narrow sense of there being no treatment.

"Accumulating evidence from disclosure of genetic risk for a single condition, for panels of genetic risk markers, and for potentially devastating unanticipated findings suggest that when individuals wish to know their genetic risks, they largely manage the information in highly constructive ways," the commentary authors wrote.

"The power of sharing of such knowledge with patients might, in some cases, be exaggerated by genetic testing companies," they acknowledged. "But patient empowerment also appears to be a tangible, quantifiable construct that can stir fundamental personal changes and breakthrough science."