Pregnancy comes with many unknowns. Perhaps one of the most harrowing is whether a child will be born healthy. Now, preconception screening—looking at the genetic risk factors of both partners before they conceive—is starting to answer that question.
Many companies offer an array of screens to prospective parents. But these typically focus on a few hundred conditions, and couples often have to select which they’d like to be tested for. The problem is that some recessive conditions don’t show up in family histories, and the partners themselves may never have symptoms—making it unlikely they’ll ask the right questions. Now, researchers at the National Human Genome Research Institute’s Clinical Sequencing Exploratory Research Consortium are trying to expand screening options using whole-genome sequencing, which allows researchers to look broadly for carrier risk rather than screening specific genes or targeted panels.
Science spoke with Sue Richards, a clinical medical geneticist at Oregon Health & Science University in Portland and a leader of the project, about findings published today in The American Journal of Human Genetics. This interview has been edited for length and clarity.
Q: How is your screen different than other preconception screens?
A: We screened for many genes that are not on any current carrier screening panel … using whole-genome sequencing. Laboratories like mine have been offering carrier screening for many, many years, [but] the paradigm is shifting now from doing screening for single genes and targeted well-known variants [for disorders such as cystic fibrosis] to really a very large number of genes. [With whole-genome sequencing], we had the opportunity to cast a very, very large net.
Q: What did you want to find out from this study?
A: We wanted to know how patients choose what they want to learn about. And then, when they get their results, how do they use that information? The goal is to really empower people so they can make informed decisions about reproductive choices.
Q: What did you do?
A: Anyone who chose to be in the study would be screened for any life-threatening … genetic disorders. Then those results would be reported back. Then, we gave them a whole list of other types of genetic disorders that they could get carrier testing for—more than 700—and asked them if they wanted to know their results … for severe disorders, mild disorders, adult-onset disorders, and unpredictable disorders, where you wouldn’t be able to be sure about the phenotype. One of the findings … was that most people, over 90%, wanted all categories returned.
Q: What else did you find?
A: We found that the majority of people carry a variant, at least one. Some [carry] up to five disease-causing variants for a rare disorder. Between 3% to 4% of people had findings that were medically important for themselves. They had some gene [variant] that [meant] later in life they could develop cancer or cardiac disease or something like that.
Q: What are the upsides? Why would people want to get this new kind of testing?
A: Because we were using this technology of whole-genome sequencing, we were able to screen and offer people additional information about their own personal health. If you have a clinically actionable variant that for example is going to predispose you to have breast cancer or colon cancer, then we would report that finding if they wanted that. It was interesting that 99% wanted [medically actionable] information back. I think it speaks loudly to the fact that people want to know this information when they’re given that choice.
Q: What are the downsides?
A: A general practice in genetics for diagnostic testing is to also report those variants we can’t interpret, and we don’t know if they actually cause disease or don’t cause disease. … This is a huge problem. What we wouldn’t want to end up doing is having patients with great anxiety or having a prenatal diagnosis done for a variant of uncertain significance because you wouldn’t be able to interpret anything and that’s not making an informed choice. That’s not good knowledge—that could be harmful.
Q: When will whole-genome prescreens be commercially available?
A: It might be a little premature yet to do that. It’s close to being ready, but there were some regions of the genome that even this technology doesn’t get yet. There’s some common genetic disorders where the genes are very similar to other genes … this doesn’t work well for that. If there’s a repeat region, like in a fragile X, or Huntington disease, those kinds of regions are hard to screen for. In a very few years, we’re going to be ready, certainly technology wise.
Q: Would you recommend this new kind of testing?
A: Just because you can do more, should you do more? In this study, we were conservative in our approach, and we only reported variants we were quite confident were pathogenic, disease-causing variants. There’s going to be a discussion that continues in the genetics community. … When is the appropriate time to offer it? Let’s [not] do it until we’re really ready to do it right, because we don’t want to make mistakes.
*Correction, 11 May, 9:47 a.m.: The image has been updated; the previous image showed an incorrect DNA helix.