Whole genome sequencing has been a helpful replacement for the targeted panels the Minnesota lab was using earlier. In the past, each specialist would make a request for genetic testing, leading to, essentially, serial testing. The more unified approach of whole genome sequencing is an improvement, says Bower.
But it’s not one-stop shopping, either, given the nature of genetic data. From the evolution of both the patient’s phenotype and medical knowledge, there can be reasons to reanalyze the data.
“Because these are neonates, some of the phenotype may not be present at the time they send the testing,” says Dr. Jobanputra, though it may emerge within several years.
She’s involved in writing recommendations for reanalysis of genome sequencing testing as part of the Medical Genome Initiative, a consortium of health care and research organizations. “But right now, just like any other lab, we do offer reanalysis of the data if additional symptoms come up,” Dr. Jobanputra says. “Or, if the test was negative and after two years, the provider wants a reanalysis because they think there could be a new gene associated with the phenotype.”
The data are interpreted in the context of current knowledge. That knowledge emerges quickly, and if a new disease-related gene is discovered—and they are—there might be cause to reanalyze the data and reevaluate whether something is now considered a pathogenic variant.
“This happened in one of our NICU kids a few months ago,” says Bower. Though the case was signed out as negative, the lab was concerned about several suspicious variants. When a paper was published with updated information about the variants and how they fit the phenotype in question, “we reanalyzed our data and reported that out.” Likewise, as a phenotype evolves over time, clinicians will ask the lab to reevaluate the data in light of new, significant findings that were not present at the time of initial analysis.
It’s hard to say where that should end, though. As a child ages, the clinical team may want to follow up on new clinical presentations by having the lab dive back into the genetic data. But when is closing time?
“It’s a double-edged sword,” says Bower. While he lauds the close relationship between clinicians and the lab, “One problem with genomes is, what exactly is the lab’s responsibility to reanalyze data?” Long-term responsibility brings its own burdens, including cost and time. “What other lab test is there where you almost have a lifelong subscription to reanalysis?”
Sequencing may be rapid, but the plot isn’t. Nor is it straightforward. Chekhov may have insisted that a pistol that shows up in the first act needs to be fired by the end of the play, but in sequencing, the early appearance of a variant may not matter later on. Or it may become a major character. Every turn of the page—every discovery, every question—lengthens the storyline.
Or, as Dr. Mróz puts it: “At the start of testing, it’s very easy to just focus on, is this variant pathogenic or not pathogenic? But that’s just the beginning of the whole story.”
Karen Titus is CAP TODAY contributing editor and co-managing editor.