Researchers who believe genomics can transform human health love to recount success stories. They’ll tell you about the 3-month-old boy whose heart was failing until researchers pinpointed what was ailing him. Or the baby girl who could have had a life-threatening reaction to anesthesia had researchers not sequenced her DNA ahead of time.
But a new study focuses on a much more somber set of stories: those of infants who died with genetic diseases and who in some cases could have been treated, perhaps even saved.
When researchers at Rady Children’s Institute for Genomic Medicine in San Diego examined the DNA sequencing data of 112 infants who had died, they found genetic diseases in 40% of these cases. For 30% of these conditions, there were treatments known to be helpful. And the authors concluded after a detailed review of eight deaths that five might have been avoided had researchers used genetic sequencing to diagnose these infants quickly and early.
The findings, published Thursday in the journal JAMA Network Open, are based on a review of only a small number of cases in a single geographic region. The study also doesn’t address broader questions about the challenges of implementing sequencing in health care, from the question of cost to gaps in scientists’ understanding of how certain genetic variants contribute to disease.
But the results are nonetheless stark and staggering, according to Stephen Kingsmore, CEO of Rady’s genomics institute and the study’s senior author. And to him, they’re a clear indicator that the health care system needs to embrace sequencing the genomes of sick infants — and perhaps even healthy ones — on a far broader scale.
“We’re still missing children who have genetic diseases, and who go on to die,” Kingsmore said. “We’d like the public health system to take notice of this — and to start to put its weight behind allocating resources for genetic diseases more than they’re doing currently.”
He’s played a major role in this push. Rady’s genomics institute has sequenced the DNA of 7,500 people to date, including critically ill infants and their parents. The institute has reported in the past that these efforts have allowed doctors to quickly diagnose sick babies and make better decisions about what procedures and treatments to administer, and which ones to avoid.
In this latest study, researchers took a different tack by examining whole-genome sequencing data from 434 critically ill infants who survived as well as 112 who did not. The data came from the health records of infants who received care at Rady Children’s Hospital in San Diego County between 2015 and 2020.
The authors found genetic diseases in 46 of the 112 infant deaths, roughly 40% of these cases. In 14 cases, sequencing wasn’t done until after the infant died. And in eight of those cases, researchers found that there were treatments that might have been helpful if they’d been administered.
When Kingsmore reviewed the health records for those eight cases, he concluded that five of the deaths might have been avoided had initial symptoms prompted doctors to order whole genome sequencing to make a speedy diagnosis.
“It’s a very sobering message,” he said.
There were also 32 infants who were diagnosed with genetic disease before death. In 11 of these cases, the authors determined there were treatments that could have helped them. It’s not entirely clear why they still died. Kingsmore says part of the issue could have been that, by the time doctors made a diagnosis, it was too late to intervene.
Speeding up the sequencing of DNA and the interpretation of genetic variants could help in those cases. Rady’s genomics institute has been developing artificial intelligence tools to partially automate this process. And it’s not alone. Researchers at Stanford last year reported a new world record time for using sequencing to diagnose a genetic disease — seven hours and eighteen minutes — shattering a record previously held by Rady.
The authors also found evidence that many of these genetic diseases went unnoticed. More than 80% of the conditions had been associated with childhood mortality in past studies. But researchers found that most of the death certificates for these infants made no mention of a genetic cause of death.
“It does improve on our current understanding of the scope of that problem,” said Jason Vassy, a researcher at Harvard Medical School not involved in this study but whose work lies at the intersection of primary care and genomics.
Vassy cautioned that this was likely not the final word on the proportion of infant deaths with genetic causes. Kingsmore agreed, adding that the study provided compelling but preliminary evidence that genetic disease is the leading cause of infant mortality.
These findings are now fueling a larger effort to test whether sequencing large swaths of the population is a good idea. Rady Children’s Institute in March plans to begin screening newborns for nearly 400 genetic disorders that have known treatments. The hope is that doing so will catch conditions missed by current methods, which screen babies at birth for dozens of disorders by taking a teeny drop of blood from a heel prick and running biochemical tests.
Kingsmore estimates that screening all 3.6 million babies born in the U.S. each year would save 15,000 lives annually. But it will take data from this effort, dubbed BeginNGS, a similar project in England, and many others to back up those potential benefits, and to know whether sequencing can be routinely used in health care.