Earlier this month, doctors at Children’s Mercy Hospital in Kansas City were able to use rapid DNA sequencing and analysis to identify the genetic mutation keeping a baby girl from eating and growing.
The hospital team identified the cause of her problems—a genetic disorder that can be treated with intensive nutritional support and vitamins to stimulate her mitochondria, the powerhouses of cells—and ruled out other progressive and often fatal conditions. In other words, the genomic diagnosis helped shape her clinical care, pointing the way to the nutritional supplements the girl needed to improve and the best way to feed her.
The baby girl is one of two dozen critically sick infants whose genomes have been scrutinized using one of the fastest whole-genome analyses in the world. The hope is that such rapid genome analysis will help doctors better diagnose and then treat infants born with genetic disorders. Over the next five years, the Kansas City team of doctors and geneticists will analyze the genomes of hundreds of more babies born with serious disorders to evaluate the benefits of two-day genomic diagnoses to patients and their families.
The Children’s Mercy team is one of a few groups across the U.S. pioneering the use of genome sequencing in the care of children with puzzling conditions. Earlier this year, the hospital’s genomics center reported that it had developed a system to sequence and interpret a newborn’s genome in just 48 hours (see “Sick Babies Could Have Genomes Sequenced in Days”). The hospital has focused its rapid genome analyses on neonatal intensive care patients because a diagnosis could change the care of these infants at a critical time. “We can make more educated decisions,” says Sarah Soden, the medical director of the genome center. This could decrease the time a sick newborn has to spend in the stressful and expensive neonatal ICU.
The rapid diagnosis could also have lifelong benefits for newborns. In the case of the newborn girl who wasn’t eating, her muscles were so weak that she had trouble swallowing; she had to be fed through a tube. But once her condition was diagnosed, her doctors realized they could feed her a thickened formula, which will allow her to learn how to eat in a critical developmental window. “Kids who aren’t allowed to eat in the first months of life are really hard to later teach to eat,” says Soden.
Gene tests and whole-genome analyses often take weeks, but the Kansas City hospital has developed computational tools to more quickly identify the potentially medically relevant variations in a patient’s three billion base pairs. Whole-genome analyses, as opposed to targeted gene tests, can be especially beneficial for newborns because they may not yet show all the symptoms of a given condition. “The ability to cast a wide net and look at all relevant genes is very helpful for newborns who may not have fully presented with all of a disease’s classic features,” says Soden.
The analysis starts with a speedy 25-hour DNA sequencing process. The data is then analyzed by software developed by Children’s Mercy. The software first looks at genes known to be connected to symptoms exhibited by the infant. If none are found, the analysis is then expanded to all DNA variants known to potentially cause disease.
With a recent $5 million grant from the National Institutes of Health, the hospital will study the benefits and risks of using rapid genomic sequencing on severely ill newborns. The study will involve 1,000 infants; doctors will use the rapid sequencing for half of these newborns as part of their diagnostic workup.
Sequencing is still a relatively new medical testing tool, and this large study, along with three others underway at other NIH-funded centers, will determine how to best incorporate the technology into newborn care, or whether it should be incorporated at all, says Geoffrey Ginsburg, director of Genomic Medicine at Duke University’s Institute for Genome Sciences and Policy. These tests may help improve the accuracy, reduce the turnaround time, and lower the cost of such screening, says Ginsburg.
The Children’s Mercy team has already used its rapid sequencing analyses on two dozen patients. Soden and her colleagues say the results often help guide families and doctors. The rapid whole-genome analysis costs around $10,000 per sample. For less time-pressured cases where more is known about a child’s condition, Children’s Mercy also offers a lower cost and more targeted analysis. This screen focuses on 514 different genes that are each known to cause genetic disorders in young patients. That test, which takes a few weeks, can help families that have struggled with the mystery of undiagnosed and often debilitating conditions for years.