Q&A: Should genome sequencing be standard for newborns?
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Key takeaways:
- Genome sequencing detected treatable conditions in more than 3% of newborns.
- Traditional newborn screening missed some conditions that genetic testing found.
As genome sequencing becomes faster and cheaper, Wendy K. Chung, MD, PhD, is assessing whether it should be standard for newborn screenings across the United States.
The results of the Genomic Uniform-screening Against Rare Disease in All Newborns (GUARDIAN) study suggest this may be possible, and it could lead to better outcomes for infants, Chung and colleagues wrote.
“This, to me, is one of the important enablers to health equity, especially throughout the country, in communities that are underserved,” Chung, chief of pediatrics at Boston Children’s Hospital and Mary Ellen Avery Professor of Pediatrics at Harvard Medical School, told Healio. “This is the one place in health care where everyone is going through the same workflow. This really is the one way I know to be able to equalize things.”
In their pilot study, which was published in JAMA, Chung and colleagues completed genome sequencing for 3,982 newborns in New York City using the same dried blood samples collected during their standard newborn screenings. They screened all the infants for 156 treatable genetic conditions and offered additional screening for 99 neurodevelopmental disorders associated with seizures, which 90.6% of parents opted into.
Overall, 147 (3.7%) of infants had a positive screen, and 120 were true positives. In comparison, traditional newborn screening detected conditions in 26 infants. Genome sequencing did not yield any false-negative results, according to the researchers.
The study is only the beginning, Chung said. Healio spoke with her about what she learned from the preliminary results and where she plans to go next with the GUARDIAN trial.
Healio: What genetic conditions can providers detect with standard newborn screenings?
Chung: The current standard screens for about 50 conditions. Forcyanotic congenital heart disease we screen for the manifestation, not the genes directly. We look directly at the single genetic factor, for about 50 conditions. We included those genetic conditions in standard screenings as a quality control, plus 200 additional conditions .
Healio: Tell me about the GUARDIAN study. How was it set up, and what were the outcomes?
Chung: We started GUARDIAN in September 2022, and it is currently being done in New York City. It is a very diverse population in many ways, and the report that came out in JAMA included the first 4,000 infants. We have now gone up to 14,000 infants. We are using the same dried blood spot that we already collected for the regular newborn screening, so there are no additional sticks or burden to the family. It is a consented research study, so we get parents’ permission to do this screening in addition to their regular newborn screening. Most parents want to do that additional screening — usually between about 72% to 74% of parents consent.
We can now generally get the testing done within 3 weeks, then we return that information back to the families and their pediatrician to confirm the diagnosis. This is just a screening test; it is not a final diagnosis. We still must do a definitive test to confirm the diagnosis. Within GUARDIAN, we get them to the right specialist to be able to help support them for whatever treatment they need longer term.
In doing this, we have been finding that there are many conditions that are very treatable. One of the most common conditions is G6PD deficiency. There is nothing we actively have to do — it is a matter of avoiding certain things like medications that can cause hemolytic anemia. There is another condition called long QT syndrome, which can cause crib death or sudden infant death syndrome. By knowing about that, we have been able to do ECGs to confirm that diagnosis and avoid medications that cause an arrhythmia.
In virtually all the cases, we have seen that diagnosis confirmed, so the screening test looks reliable. We had some false-negative results on standard newborn screening that we picked up on GUARDIAN. One of those babies that we missed in the standard screening had what could have been a lethal condition associated with an immunodeficiency, but he got a bone marrow transplant, and that should be lifesaving for him.
Healio: What else did you learn through doing genome sequencing on so many babies?
Chung: At the very beginning, as we screened for cystic fibrosis, we saw some genetic variants that we had not seen before, and we saw it not just once, not just twice, but we saw it repeatedly. Cystic fibrosis is a recessive condition, so you must have both genes affected to have symptoms. We quickly realized that both genetic variants travel together on the same copy of the gene. Although we saw two genetic variants, it was one copy of the gene that was affected, not two copies, so we knew these babies were just carriers. In the first 1,000 babies, we did not know that, but we intentionally said we were going to stop and look at the data after the first 1,000 babies and adjust, then make sure that we can filter the data so that we do not miscall things repeatedly. That was our most common false-positive result. It happened to affect specifically our Hispanic population, and we learned that is something that had not been cataloged.
We are finding we know less about individuals of Asian and African ancestry, so there is more of a gap to fill in terms of being able to do this equitably, accurately and efficiently. We hope to be able to screen not just the 4,000 we reported or the 14,000 we have done to date, but we hope to eventually get to 100,000 babies to get enough experience for people from around the world.
Healio: What are your next steps?
Chung: I anticipate expanding outside of New York in part for generalizability to demonstrate that this is something that could be done with our National Public Health newborn screening system. Even though we are at about 3 weeks turnaround time now, we need to get it down to 1 week. And we need to drive the cost down. We have driven the cost down substantially in doing this, but for something that might be close to 4 million babies per year across the country, we need to continue to drive the cost down and continue to increase the accuracy.
We need to get follow-up information about these children, how they do over time, who becomes symptomatic, what symptoms they have and how we can best support them. Part of the research is also longitudinally seeing how these individuals and their families do over time to make sure we understand what needs to be done.
Healio: Do you think it will be feasible to make genome sequencing available nationally? What needs to be done to make that happen?
Chung: If it is just drawing a blood sample, almost any doctor's office can do that. They can draw the blood sample, get it to a specialized laboratory and we can work together as a collective community to bring the resources to the children who need it. Even if you are in Montana, you could have someone down in Florida who is an expert in that condition to help you. Not just with the interpretation of the data, but when it comes to management of that condition, you can phone a friend. We have national panels of experts for those conditions you can reach through telemedicine or video medicine.
Healio: What else should providers know about this research?
Chung: We are not perfect, and we readily admit that. We continue to improve as we are doing this, and we want feedback. So, as people may be reading about this, hearing about this, they can go to our website and tell us what they think. As it becomes more of a public discussion, I think it is important, because if this were to become part of newborn screening, that is a big deal, and we really need to be very thoughtful so that the next generation of children gets the benefits and that we minimize — if not eliminate — the harms that could come.
For more information:
Wendy K. Chung, MD, PhD, can be reached at wendy.chung@childrens.harvard.edu.
References:
- GUARDIAN study. https://guardian-study.org/. Accessed Nov. 22, 2024.
- In pioneering study, gene technology outperforms standard newborn screening tests. https://www.eurekalert.org/news-releases/1062238. Published Oct. 24, 2024. Accessed Nov. 1, 2024.
- Ziegler A, et al. JAMA. 2024;doi:10.1001/jama.2024.19662.
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