Dr. Mróz adds another wrinkle: finding a novel variant in the right gene—in the right clinical context, in the right domain of the gene that’s responsible for the disease. Though it might be the culprit, it can’t be reported as likely pathogenic because it is novel, Dr. Mróz says. “It’s either not been described or there’s no functional status, or there is not enough data to support our belief that it is likely pathogenic.” But otherwise the gene fits the clinical profile—if the domain were disrupted by the variant, it would cause symptoms.
These cases, with their slender certainty, are the ones Dr. Mróz says merit discussion, to decide as a group “if we’re sure enough to say, ‘We didn’t find a slam-dunk answer, but given all the information we have and the clinical presentation, this could be responsible—we are just limited by the knowledge of what this variant does.’”
Otherwise, they try to keep from reporting too many VUSs, Dr. Mróz says, since they’re likely not immediately helpful to the clinical team but they can cause anxiety on the patient/family side.
In New York, Dr. Guha says he and his colleagues also take a cautious approach to reporting VUSs. But when they see a VUS they suspect might be important, “We certainly discuss it with the provider to get their viewpoints. We go through all possible evidence associated with the VUS, including functional studies if available, phenotype spectrum, and prognosis of the associated disease, et cetera. We try to go through everything, and then we decide if it’s reportable or not.”
Adds Dr. Jobanputra: “We are not reporting just any variant of uncertain significance. We are reporting only very strong variants, and always in discussion with the provider.” Even with that collaboration, she says, “We are careful and deliberate in what we report, following extensive analysis and curation.” In the nearly 10 years the lab has been doing its genome testing, she says, “I haven’t seen any VUS that we reported” that has turned out to be benign.
It’s difficult to pinpoint the diagnostic rate of performing rapid genome sequencing in NICU patients.
But as Bower points out, even a negative result can be valuable. In his earlier example, a negative result can offer useful information about whether to proceed with a surgical intervention to fix, say, a heart defect. A negative result can also help the clinical team by suggesting that the presentation in the patient is related to prematurity rather than an underlying or overlapping genetic condition.
Naturally, a positive result can be useful as well. Some results can provide “a devastatingly clear diagnosis,” says Bower. “And while it’s difficult to get that news, it can provide some clarity to allow families to make a decision of, Do we keep on with heroic efforts?”
Dr. Mróz estimates that the lab can provide a clear answer in about 10 percent of cases. “This is not a hard number that comes from looking back at the data, but just what I’ve observed based on the cases I’ve signed out.”
It’s also difficult to know for certain how often a finding is linked to a change in patient management. In a review of the NY Genome Center’s own data and follow-up information they’re able to collect (not possible in all cases), the change in clinical management has been 50 to 60 percent, says Dr. Jobanputra. “We are very much in the range of what has been published by others.”
More studies are needed in the field as a whole. “There are not that many follow-up studies yet,” says Dr. Jobanputra. Neonates typically are followed for one or two years, she says. “But a five-year follow-up would shed more light on the care and management and the impact of these findings on patients,” though she worries that the current uncertainties around National Institutes of Health–funded studies may slow such research.
The recent Minnesota law mandating coverage appears to be stabilizing the clinical landscape. Dr. Mróz notes that clinical teams now seem to be more confident in ordering sequencing, reassured by the established reimbursement pathways. This shift, he observes, is a significant step toward more equitable testing.
Looking ahead, he suggests that achieving true equity might require evolving beyond the current model. “If we really care about the future of these babies,” he says, “there may be room for conversation around a prenatal package that includes whole genome sequencing as a standard of care,” potentially supported by broader public health frameworks alongside private insurance to ensure universal access.