Background on whole genome sequencing and review of the GUARDIAN study

Paul Kruszka, MD, MPH, FACMG, chief medical officer at GeneDx and clinical geneticist at Children’s National Hospital, explained the role of genetic testing in improving pediatric care. Speaking on the potential of whole genome sequencing, Kruszka emphasized its value in diagnosing rare diseases earlier and more effectively.

“One out of 10 people in North America are affected by a rare disease, that’s 30 million people in the [United States],” Kruszka noted, highlighting the prevalence of rare genetic conditions. “There is a lot of genetic rare disease. So certainly, this is in the wheelhouse of a general pediatrician and all the pediatric sub-specialties, whether you’re a neonatologist, a pediatric neurologist, [or] a developmental pediatrician.”

Kruszka detailed the GUARDIAN study (NCT05990179), a multisite, single-group, prospective, observational investigation of supplemental newborn genome screening, in which data has been reported on the first 4000 families that have participated across 11 months. Data were from newborns in 6 New York City hospitals between September 2022 and July 2023.¹

“We used targeted whole genome sequencing to expand the newborn screening for more rare diseases," said Kruszka, who is also a GUARDIAN study investigator. "Typically, we screen for 30 to 60 conditions. With the GUARDIAN study, we bumped that up to almost 250 conditions. These are diseases that are treatable, actionable.”

The study objective was to report interim results of acceptability, feasibility, and outcomes of an ongoing genomic newborn screening in a diverse population, with the primary endpoint being screen-positive rate.¹

“Some examples that we found: there were children with long QT syndrome that we found. This is treatable with medications such as beta blockers. This is a cause of sudden cardiac death in children,” Kruszka said. “We found another child who required a bone marrow transplant. We found severe combined immune deficiency in another child before symptoms started that was missed by typical newborn screening.”

In the study, testing was completed successfully for 99.6% of cases, with a screen-positive rate of 3.7%, which included treatable conditions that are not currently included in newborn screenings, according to study results.¹

“This is identifying kids that would have taken, on average, 6 years to be diagnosed,” Kruszka said. “The idea behind this study is really to eliminate the diagnostic odyssey, to give diagnoses before symptoms even start, to prevent damage, [and] to allow for better health outcomes.”

“It’s unacceptable to wait 1–2 years to see a clinical geneticist or have a genetic test. There’s no reason for that," he said while expressing hope that the GUARDIAN study would inspire change.

“This is a long time coming… It’s more important than ever for all of us in the pediatric community to understand genetics [and] genomics," said Kruszka. “Our newborn screening system is fantastic, but it only really captures a slice of rare disease. With whole genome sequencing, we’re opening up a whole new spectrum of diseases that we’re going to be able to identify early.”

Paul Kruszka, MD, MPH, FACMG, has the following disclosures:

Employment - Chief medical officer at GeneDx

Reference:

Ziegler A, Koval-Burt C, Kay DM, et al. Expanded Newborn Screening Using Genome Sequencing for Early Actionable Conditions. JAMA. Published online October 24, 2024. doi:10.1001/jama.2024.19662