Testing the complete DNA of critically ill infants can lead to significant changes in treatment strategy, according to a newly published article by researchers at Children’s Mercy Hospital.
Genetic diseases are the leading cause of mortality in infants, according to Dr. Laurel K. Willig, a Children’s Mercy pediatric nephrologist and a lead author of the study.
She says many of these diseases may go undiagnosed, however, because of inadequate testing of critically ill newborns.
“The incidence of genetic diseases in those infants is really largely unknown,” Willig says. “We suspect higher than what we would anticipate just because we’re not testing every baby.”
The article published Monday in The Lancet Respiratory Medicine describes the results of a study comparing the diagnostic effectiveness of rapid whole genome sequencing with traditional testing for individual genetic disorders.
Whole genome sequencing entails the mapping out of an individual’s unique DNA. It enables physicians to determine if a patient has a genetic disorder or is at risk for a disease.
The Children’s Mercy researchers found that genome sequencing led to a diagnosis in more than half of 35 infants. By contrast, traditional testing led to diagnosis in just 9 percent of 32 infants.
After arriving at a diagnosis, doctors altered their care approach in 62 percent of the cases, providing a treatment that improved outcomes or palliative care for infants who were unlikely to survive.
The study was funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development, the National Human Genome Research Institute and the National Center for Advancing Translational Sciences.
Dr. Richard K. Wilson, director of the McDonnell Genome Institute at Washington University in St. Louis, used a surfing analogy to describe the work as “out on the tip of the wave.”
Wilson, who was not involved with the study, says using whole genome sequencing as a diagnostic tool for infants will probably become a standard practice for doctors and hospitals, but it won’t happen overnight.
“You have to educate physicians,” he says. “You have to educate hospital administrators about the value of this. And you have to advance technology so that it becomes really simple.”
While the study showed a significantly improved diagnosis rate for whole genome sequencing versus traditional genetic testing, it did not show an improvement over what’s typically seen in exome sequencing. The latter only examines the parts of DNA that code for proteins, the body’s basic building blocks.
Right now exome sequencing is the more commonly used diagnostic tool because the technology is cheaper and more readily available.
Cost effectiveness was not examined in the study, but the costs of genome sequencing are falling rapidly. Currently, the best available cost runs around $4,000, but many genomic researchers say it could drop as low as $1,000 to $2,000 as soon as this year.
Willig says whole genome testing may prove a more useful tool than exome sequencing in the long run because it provides more complete information. Genes account for less than 25 percent of the DNA in the genome; the remainder includes areas that control how genes are turned on and off as well as “junk” DNA whose function isn’t fully understood.
The Children’s Mercy researchers used STAT-Seq testing, which can sequence a whole genome in fewer than 50 hours. The technology isn’t used in standard medical practice, and Willig says the researchers are still trying to determine if and when rapid sequencing methods lead to significantly improved outcomes.
“The applicability of rapid genome sequencing is probably dependent on how acutely ill the patient is,” Willig says. “And that’s something we’re trying to look at in a little more rigorous fashion in our ongoing study that we have right now.”
That study is a large-scale, blinded, randomized-controlled trial examining the usefulness of genome sequencing for a larger group of NICU patients. Willig says it may involve as many as 1,000 infants.
The Lancet Respiratory Medicine study has already generated some discussion about possible ethical issues raised by whole genome sequencing for infants.
Reached by phone, Dr. Danton Char, a Stanford University Medical Center assistant professor who coauthored a comment in the journal, praised the study as “really, really innovative work.”
But Char, who specializes in pediatric cardiac anesthesia, says technological innovation like rapid whole genome sequencing for infants is outpacing measured consideration of its ethical implications.
Among his concerns is when and how diagnoses derived from whole genome sequencing may be used to justify withdrawal of care or ration scarce resources, such as donated organs.
“What we’re hoping to do as a national science community is to supplement the kind of work that [this group is] doing with some sort of normative guidelines for ethics,” he says.
Alex Smith is a reporter for KCUR, a partner in the Heartland Health Monitor team.
