Q&A: ‘We are not as good as we think’ at identifying genetic conditions in babies

Key takeaways:

• Standard care relies on physicians suspecting genetic diseases in infants and referring them for testing.
• An exclusion-based approach detected genetic diseases in eight times more infants.

Researchers at the University of Washington and Seattle Children's found that using exclusion-based criteria to refer infants for genetic testing in the NICU led to more diagnoses and at earlier ages.

In most hospitals, infants are referred for genetic testing when a neonatologist suspects they may have a genetic condition, according to Tara L. Wenger, MD, PhD, professor in the department of pediatrics at University of Washington’s School of Medicine and associate medical director for inpatient genetic services in the division of genetic medicine at Seattle Children’s.

“Babies are not born with every feature of the genetic condition that they have,” she said. “If you wait for them to have enough features of a genetic condition to be recognized by a neonatologist or clinical geneticist, that is much later than you could potentially get a diagnosis, start precise therapies and be able to take better care of them.”

In a study published in the American Journal of Human Genetics, Wenger and colleagues developed an exclusion-based workflow, which called for rapid genome for all infants aged younger than 6 months who came to the NICU with symptoms that were not fully explained by physical injury, infection or complications of prematurity. They compared 126 infants (58.7% boys; median age at admission, 2 days) who were cared for under this new workflow with 114 infants (49.1% boys; median age at admission, 1 day) who received conventional care from January 2021 to February 2022.

Overall, 49.2% of babies in the intervention group received a precise genetic diagnosis, compared with 9.7% of infants receiving conventional care. The researchers reported that infants in the intervention group were nearly nine times more likely to receive a genetic diagnosis compared with the control group. Additionally, 26 of the infants in the intervention group who had received genetic diagnoses would have been missed with standard care, they found.

Healio spoke with Wenger about the study and what happens next.

Healio: What is the current inclusion criteria for infants to get genome testing?

Wenger: The criteria for getting genetic testing at most hospitals in the United States today is really based on the neonatologist suspecting a genetic condition and then having access to a geneticist, consulting the geneticist, the geneticist choosing a test, that test being approved by the hospital and then it getting sent during the stay. So, it is not a set group of criteria for each individual genetic condition that might be suspected but instead is based on the suspicion of the neonatologist who's taking care of that infant. At Seattle Children's, we have changed what we're doing based on what we found was most equitable and best practice in our study. We have been doing things in a different way now for a few years.

Healio: What was the exclusion criteria you used in your study?

Wenger: Any infant whose symptoms were not fully explained by prematurity, infection or trauma were offered rapid whole-genome sequencing. This includes children who had medical problems that would not typically be explained by a genetic condition in the way that we usually think about these conditions. For example, a baby who is having some trouble feeding and having a little bit of need for oxygen, but we don't have a good reason why. That's the kind of infant who may not have had a genetics consult before because they don't have any clear features of a genetic condition.

In our study, we compared the suspicion of a neonatologist — which led to a genetics consult, which then led to testing — with our simple, exclusion-based workflow, and found that we had about a nine times greater likelihood of having a genetic diagnosis when we use that simple exclusion-based workflow compared with the traditional workflow.

Healio: Did the exclusion criteria increase the volume of patients being referred for genetic testing? How did your hospital handle that?

Wenger: Yes, we are doing many more genetics consults per month than we were before initiating the workflow — not just in the NICU, but across the hospital. We are very lucky to have a hospital administration that has invested in resourcing our group to be able to keep up with that volume and to be able to reach more infants. We have required more personnel to be able to keep up with the volume, but we are making many more diagnoses per month, and so we really feel that it's the right thing to do.

Healio: What are your next steps in this research?

Wenger: We are in the process of implementing SeqFirst 2.0, the next phase of our study. In this phase, we're going to be using technology to better streamline the process of getting pretest counseling and return of results. In most hospitals across the country, there are not on-site genetics providers.

We have developed an app for pretest counseling, and we're working on how to integrate that into our clinical workflow. Our genetic counselors and our inpatient genetics team and the research staff have worked together to put the key information for each of those steps into modules in an app, so that families can expedite the process by watching the modules on their own device, on their own time, before meeting with the genetic counselor initiating the testing.

We are hoping to be able to roll out the refined workflow in other hospitals that might have less on-site gold standard genetic support than we are blessed to have at Seattle Children's.

Healio: What should pediatricians take away from your findings?

Wenger: We are not as good as we think we are at identifying genetic diseases in children who are too young to have manifested all of the features yet. And in medical school, we are taught to look for enough features of a condition to be able to suspect it. Now that we have this new technology, we've learned that being able to have an open mind and consider broader testing earlier is going to lead to better access to testing and better care.

We also found differences in who we are best at making diagnoses in. Some of the groups that we are better at making diagnoses in are children who have visible birth defects —things that we can see that are different — and major medical problems. There tends to be a difference in how good the conventional workflow is in identifying children of different racial backgrounds. One of the most exciting things about this study is that we were able to demonstrate that there is no difference in rates of diagnosis in children of different racial backgrounds when an exclusion-based method is adopted.

For more information:

Tara L. Wenger, MD, PhD, can be reached at tara.wenger@seattlechildrens.org.