If I have the mutation, will I get the disease? New research looks at genetic ‘penetrance’

genetic penetranceRecently announced preliminary results of the BabySeq study included pathogenic or “likely pathogenic” variants linked to heart conditions in three apparently healthy babies. Two are being followed at Boston Children’s Hospital and have had cardiac testing. But is this testing necessary, and are these infants truly at risk? It’s too soon to tell.

Then, last week, a report from the Mayo Clinic raised an alarm about overzealous use of genetic testing in healthy individuals. After a 13-year-old boy died from a heart syndrome, about two dozen family members had genetic testing. All tested positive for variants in a gene linked to long-QT syndrome and were diagnosed with the disease. Yet none had cardiac symptoms, and only one had a positive EKG at any point — the boy’s brother, who had a defibrillator implanted. When the Mayo team reanalyzed the test results using a more up-to-date genetic database, they concluded the variant is harmless.

And this week, in Science Translational Medicine, researchers at Brigham and Women’s Hospital, Boston Children’s and Massachusetts General Hospital address the question: If people carry a genetic mutation linked to a condition, what are the chances they will develop that condition over time? As part of the genomes2people project, the researchers tested participants in two long-term population studies — the Framingham Heart Study and the Jackson Heart Study — for 56 genes representing 24 hereditary cancer and cardiac syndromes. They did not know the participants’ actual health status. As it turned out, carrying a mutation increased risk for the related disease 4.7-fold in African Americans and 6.4-fold in European Americans, who had longer follow-up. This was true regardless of family history.

Vector sat down with Nina Gold, MD, a senior resident in Pediatrics and Medical Genetics at Boston Children’s, for her perspective. Gold is a first author on this week’s report.

Q: Looking at these findings, what’s the take-home message about genetic testing?

When describing genetic tests to parents, we often use the analogy of a library. Each gene on a chromosome is like a book on a shelf. When we identify a variant in a gene, we often tell families that it is like a misspelled word, a single spelling error that clouds the meaning of the text.

Even ‘pathogenic’ variants don’t always cause disease. In truth, though, variants are a bit more complicated than that. A given genetic variant may be more like an alternate spelling — different, but not necessarily wrong. To gauge the likelihood that it’s harmful, we compare each variant to a reference genetic sequence and then look at a number of different attributes, such as its rarity, its effect on the production of protein, and whether or not it has previously been found in another person with the same disease. If a variant meets these many criteria, it can be considered pathogenic.

But here’s where it gets murky. Even “pathogenic” variants don’t always cause disease. This concept has long been recognized in genetics and is referred to as “variable expressivity,” meaning that the same genetic variant can cause different symptoms in different people, or “incomplete penetrance,” in which some proportion of people with a pathogenic variant don’t develop symptoms at all.

Some factors that can influence penetrance are interactions between genes, epigenetic modifications affecting expression of the gene, factors in the environment and behavioral factors like lifestyle modifications.

Q: What lesson do we learn from the cases at the Mayo Clinic?

Nina Gold, MD
Nina Gold, MD

What happened there is a good example of how variant classification has changed over the years. We used to have a less stringent, unstandardized way of classifying variants. This has become more uniform over time, and, as a result, some people who were once told that they had a pathogenic variant in a disease-causing gene might now be told that they have a “likely benign variant,” which is really just like writing “neighbour” instead of “neighor” and is unlikely to cause disease.

As we enter an era of considering genetic sequencing to predict future risk of disease, the need to understand the likelihood that a variant will lead to morbidity is becoming much more urgent. The hope is that we could take action to prevent a condition before it causes suffering or sudden death, as in these individuals who were thought to have a variant linked to a fatal arrhythmia. Now that we have improved the classification of variants, the remaining barrier is understanding incomplete penetrance and variable expressivity.

Q: So is there any value in genetic testing?

Widespread screening for genetic variants is only useful if they are also linked to disease in the general population. Our paper in Science Translational Medicine demonstrates that people with pathogenic variants in well-known cancer and cardiovascular disease genes are, in aggregate, far more likely than people without such variants to develop the disease. To a layperson, and even to many clinicians, this may sound obvious. But for those familiar with the grey areas in genetics, this is a crucial finding. Most pathogenic variants are established in the type of people who come to a genetics clinic, who tend to have symptoms of disease or a strong family history. But widespread screening for these variants would only be useful if they are also linked to disease in the general population. Our work is an early step toward using genomic variants to predict and prevent future illness in someone who isn’t sick.

It’s important to keep in mind, however, that even people with variants highly associated with disease — such as a variant in the notorious BRCA1 gene — do not develop the associated cancer 100 percent of the time.

For now, the bottom line is that having a genetic mutation, even one tightly linked to a disease, is a weighty risk factor. But it’s not a guarantee that one will develop the disease.

Identifying a person’s genetic variants may eventually become a routine part of health care. It will take active, ongoing research to determine how best to use this information to support our patients’ goals of care.