“The first report from a big public-private project to improve genetic testing reveals it is not as rock solid as many people believe.”
Massive genetic sharing effort shows power but also shows how little we know
By Steven Salzberg on 5/31/2015 05:00:00 AM
Your genes are not your fate.
Nonetheless, genes can tell us a lot about our risk for disease, and sometimes they can tell us how to lead healthier lives.
The landscape of the human genome is vast and mostly unexplored. There is far, far more that we don’t know than we do know. This is why it’s so important that as we test people for genetic mutations, we share information as much as possible. Genes have different effects on different people, and a mutation that is harmful in one group might be harmless in another. If we’re ever to fill in all the gaps in our knowledge, we have to pool our resources by sharing data.
This is the goal of ClinGen, a new project described in this week’s New England Journal of Medicine. ClinGen relies on a public database called ClinVar, where researchers, clinical labs, clinicians, and patients can deposit information about genetic variants and their effect on disease.
What makes this effort so complex is that many disease-causing mutations are quite rare. If two patients share the same disease and the same genetic mutation, and if we’ve never seen that mutation before, can we claim that the mutation cause the disease? Not really: we might have to wait until we’ve seen many more patients before we can have any confidence in the cause-and-effect relationship. This is why sharing data is so important: more data means more power to discriminate between real effects and coincidences.
ClinGen has already shown us that our knowledge has flaws: perhaps 17% of the disease associations that clinicians have reported might be incorrect. More precisely, the NEJM paper reports that out of more than 118,000 mutations that have a clinical affect, almost 13,000 were reported by more than one lab. Of those, 17% were interpreted inconsistently, with some labs calling mutations "pathogenic" while other labs calling them benign.
I disagree with the headline of an AP report headlined “flaws in gene testing,” which reported that
This is a straw man argument: experts in the field don't think genetic testing is “rock solid”, and the 17% rate of disagreement in disease-mutation association is not that surprising. What's more, these conflicts don’t always represent flaws, but rather holes in our knowledge that we just haven’t filled yet.
Disagreements over the effects of a genetic mutation represent opportunities to clarify and improve our genetic knowledge base. And as the ClinGen authors emphasize, it’s only by sharing our findings that we can discover and correct these flaws. This is why clinicians, scientists, and labs need to adopt a culture of sharing results, as the ClinGen project has emphasized (see their “Wall of Fame” of labs and institutions that have shared data).
All of us have mutations in our DNA; geneticists estimate that each of us carries perhaps 30 new mutations that even our own parents don’t share. The vast majority of these, fortunately, are harmless. Even mutations that do affect our health usually only have a small influence, changing our risk for disease but not actually causing it.
I'd be remiss if I didn't point out that sometimes, your genes are your fate. If you have certain mutations in the CFTR gene, you will have cystic fibrosis, and some mutations in the HTT gene will inevitably cause Huntington’s disease.
As geneticist Luke Jostins cogently wrote, identical twins usually don’t die from the same thing. So even though genes may influence our fate, we still have control over it. Knowing your genetic risks can be valuable, but we have a lot more to learn about how our genes influence our health.