Dr. Mróz has his doubts about (relatively) quick solutions, given the high complexity of looking at the entire genome. “In our experience it takes more than just a single individual to interpret those cases. I think the biggest value here is the team we put together, and the know-how and experience we’ve developed over time working together analyzing those complex cases. I don’t think you can replace easily the value of a team with a black-box solution.”
And even if a cheaper solution can find those slam-dunk answers, says Bower, “You still have to ask if it’s a slam-dunk answer to the question the clinician is asking. Even clear answers require thought—is this explaining what’s actually going on right now?”
“Now” is a fluid concept. For some NICU patients, certain phenotypes may not present for several years, making it hard to match the genotype results with a particular syndrome.
And with any whole genome sequencing report, Dr. Mróz says, “You always have to keep in mind who your audience is.” Not everyone will understand the limitations of the testing, particularly the unexpected findings, which can have consequences for other family members. “That’s the audience you have to have in mind when you’re dealing with results that are not quite the actual answers, but we think might be the answer,” he says.
Bower feels torn at times. “In some cases,” he says, “you just desperately want to find an answer. And sometimes you’ve got to learn where your own internal biases are. Am I reporting these variants because I think there should be an answer and this is the closest thing we’ve got?”
Over time, he’s learned that some families want any and all information; others don’t. Some want only explicit answers, he says; others are fine with exploring every last avenue. Given that reality, he says, “It’s important to be aware that different patients, in different situations and with different stories, may have different tolerances for the amount of uncertain information the lab presents.”
Incidental findings add yet another complication. These aren’t unusual from a laboratory perspective, says Dr. Guha. But the clinical team, focused on the patient presentation, may not be thinking about the broad scope of results that genome sequencing returns.
While guidelines provide guidance for how labs should handle such information, clinicians and patients’ families will have their own perspectives for how to manage unexpected results. Some families may decline information about secondary findings. That can put labs in an uncomfortable position, Dr. Mróz says, if they’re unable to report, say, a BRCA1 or BRCA2 pathogenic variant.
“It can be hard,” Bower agrees. “Sometimes you lose sleep at night when you know those things are floating around some of those families.”
It’s also possible that findings may include something that is pathogenic for a phenotype the patient is not clearly manifesting, and which might not warrant medical intervention currently—a pathogenic variant in the coagulation cascade, for example, that could put the patient at higher risk for venous thrombosis but likely won’t change their immediate medical management.
These are difficult, at times agonizing, conversations, Bower says. Overreporting information may overwhelm families and not be helpful in the NICU moment. But that same information might help prevent a future adverse outcome, or otherwise help clinicians optimize care in the meantime.
The only real slam dunk, says Bower, is finding two pathogenic variants in a recessive gene. “That takes about five minutes—easy peasy.”
More commonly, every genome will—depending on how the filters are set, says Bower—turn up dozens, if not 100 to 200 rare variants that are variants of uncertain significance. “Typically we’re trying to whittle that down to a handful—maybe three to five—in a case where we don’t have a clear explanation,” he says. That allows for a beneficial conversation in the group about whether any of them could be the answer. The consensus group will report VUSs if there’s strong agreement that “there’s a very good likelihood they’re somehow contributing to what’s going on.”