Mount Sinai Researchers Discuss Findings on Risk of Pathogenic, Loss-of-Function Clinical Variants

Ron Do, PhD, associate professor, Charles Bronfman Institute for Personalized Medicine at the Icahn School of Medicine at Mount Sinai, and Iain Forrest, MD-PhD candidate in Dr Do’s lab, discuss the results of their recent study measuring population-based penetrance of pathogenic and loss-of-function clinical variants.

Transcript

What were the results of your study?

Forrest: There were 3 primary findings that came out of this study that were really striking to us.

The first one was that when we looked at the penetrance, or disease risk, of specifically pathogenic variants—those that were deemed to have very high risk of disease—what we observed is that there was actually relatively low level of penetrance across the board for pathogenic variants, around 7% or 6%. This was more than what we found for benign variants, which was less than 1%, but still relatively low overall.

The second main finding that we got was we were able to assess a diverse set of individuals within our study. So individuals of diverse ancestral backgrounds. Besides just European individuals, those with African ancestry, Hispanic ancestry, and Asian ancestry. With that, we were able to identify variants that were specific to ancestries that were very diverse, specifically non-European ancestries, which have traditionally been underrepresented inside genetic studies. We found about 100 of these non-European and ethnic-specific variants, and some of them were also highly penetrant, which means that they were very relevant to clinical considerations.

A third major finding was that we took into account the age dependence of penetrance. What that means is, for certain diseases, these diseases are more likely to occur in later ages and the penetrance, or risk of variants for these diseases, might actually increase with age. For example, we found [that] various cardiovascular diseases, various types of cancers were associated with increased risk, or increased penetrance, with higher age of these participants.

I know I said only 3 main findings, but a fourth finding that was also very important was that we looked at penetrance not just at the gene level, but we actually went even more microscopic than that at a finer resolution, where we looked at penetrance at the variant's level. And what we found is that, if we look inside a given gene—for example, the breast cancer predisposition gene, BRCA1—we found there's actually a wide range of penetrance for different variants in this one given gene. So this really underscored the importance to us that you have to look at a very granular level in order to get the highest resolution and most information that's relevant for individuals.