Rikki and Josh Gutzdorf knew from prenatal testing that their child would have abnormally shaped bones.
After son Theo was born, other problems emerged: He could barely breathe and had a dangerously high fever. Tests, including a spinal tap, couldn’t identify a cause.
Doctors at Children’s Wisconsin hospital near Milwaukee turned to genome sequencing, mapping the protein-making parts of the baby’s DNA. The analysis showed Theo had Stuve-Wiedemann syndrome, a rare genetic disorder marked by curved leg bones, respiratory distress, poor regulation of body temperature, swallowing problems and, often, death within a year.
The finding helped doctors decide to adjust the boy’s oxygen level, start him on a medication to lower his temperature and give him a feeding tube. Since the disorder also involves a lack of the reflex to blink, they initiated eye drops. Theo spent his first 100 days in the neonatal intensive care unit, but he hasn’t been in the hospital since and turned 3 in September.
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“It was very much life or death,” said Rikki Gutzdorf, of Watertown. “We firmly believe that without the genetic testing, we wouldn’t have had a diagnosis and known how to treat it, and possibly would not have our son with us today.”
Doctors are increasingly sequencing babies’ genes in addition to newborn screening, especially in critically ill children whose symptoms aren’t explained by the routine screening a day or two after birth that mostly involves metabolic tests.
Charting the A, C, G and T bases in the DNA molecules of sick infants can yield answers — sometimes in three days or less, according to a California study — that can improve treatment and save lives. The technology, which often involves enzymes made in Madison by the company Illumina, offers the potential to sequence all babies — not just for childhood disorders but, as a Boston study showed, for risk of adult-onset diseases such as some types of cancer.
The prospect of universal newborn sequencing, and looking for adult-onset conditions, raises questions about personal autonomy, according to a federally funded ethics group. In 2018, the group said the evidence “does not support genome-wide sequencing of all babies at birth.”
At University Research Park, San Diego-based Illumina makes enzymes used in its DNA sequencers.
Still, “at some point, that’s going to be a reality,” said Dr. Donald Basel, medical director of genetics at Children’s Wisconsin. “We’re all going to have knowledge of our genomic data.”
For now, Basel said, genome sequencing at Children’s Wisconsin is done on about 200 patients a year, primarily children in the neonatal or pediatric intensive care units. The testing leads to a diagnosis about 43% of the time and often leads to better care, he said.
“We’ve definitely made some significant changes in treatment based on the genomic data we’ve gotten back,” Basel said.
At UW Health, doctors in April started sending blood samples from perplexing NICU patients to Rady Children’s Hospital in San Diego, which leads an effort to do rapid whole genome sequencing on sick infants. In July, UW opened an Undiagnosed Genetic Disease Clinic to identify rare diseases in children and adults, with the somewhat slower sequencing involved taking place on campus.
Each of more than 7,000 known rare genetic diseases affect relatively few people, but collectively the conditions are believed to be present in about 8% of the population, or roughly 450,000 Wisconsin residents, said Dr. Stephen Meyn, director of the UW Center for Human Genomics and Precision Medicine, which includes the new clinic.
Until recently, it took three to five years to diagnose one of the conditions, and doctors were successful less than 10% of the time, Meyn said. Now, with genome sequencing, the speed is quicker and the success rate is closer to 40%, he said.
“We are, as geneticists, thrilled with those numbers,” Meyn said. “But that means most patients walk out of the clinic without a diagnosis. We have a lot of work to do still.”
Rapid sequencing
A federal program that explored newborn genome sequencing in recent years included projects by researchers in San Diego and Boston.
Dr. Stephen Kingsmore, CEO of the Rady Children’s Institute for Genomic Medicine, led Project Baby Bear, which used rapid whole genome sequencing to analyze the genetic code of 184 infants at five NICUs in California covered by the state’s Medicaid program.
The sequencing produced a diagnosis for 74 babies, or 40%, in a median time of three days, the researchers reported in June in the American Journal of Human Genetics. The testing, which cost $1.7 million, led to about $2.5 million in savings in treatment, the researchers said. California has approved $3 million annually to expand the program statewide.
In one case, a scan showed problems in the brain of an inconsolable 5-week-old boy, whose older sister died at 11 months after seizures. Genome sequencing on the boy, completed in a record 13 hours in October 2020, identified a severe vitamin B disorder called THMD2. Soon the boy was started on a vitamin treatment and recovering from the condition that likely killed his sister, Kingsmore and colleagues reported in June in the New England Journal of Medicine.
“This case illustrates the potential for decreased suffering and improved outcomes through the implementation of rapid genome sequencing,” they wrote.
The BabySeq Project, at Boston Children’s Hospital, involved sequencing of nearly 1,000 genes on 127 healthy babies and 32 NICU patients. Some 8% of healthy babies and 9.4% overall had mutations for childhood genetic disorders, which were not predicted by clinical or family history, researchers reported in 2019 in the American Journal of Human Genetics.
Parents of more than half of the sequenced babies agreed to look for actionable adult-onset conditions. Three babies had such genetic risk factors, two for breast cancer and one for colon and endometrial cancer.
The information gleaned from the sequencing didn’t cause undue distress for the parents, including the 15 families whose babies had an unexpected risk gene for childhood disease, according to survey results reported in August in JAMA Pediatrics. Now, BabySeq2 aims to expand the research to more diverse families in Boston, New York City and Birmingham, Alabama.
Wisconsin doctors seek answers
In Michigan, Dr. Caleb Bupp heads up Project Baby Deer — which, like its California precursor, is named after the state animal. Eight hospitals in the state have sent samples from more than 80 children to Rady in San Diego for rapid genome sequencing, with analysis of the first 30 cases showing 40% led to diagnoses and 45% resulted in changes in treatment, said Bupp, chief of medical genetics at Spectrum Health Helen DeVos Children’s Hospital in Grand Rapids.
Michigan’s Medicaid program in September started covering genome sequencing for children up to a year old. Michigan’s project also involves private insurers, including the state’s largest carrier, Blue Cross and Blue Shield, for whom children with unexplained symptoms up to age 18 can be sequenced.
The testing helps parents by providing answers and doctors by providing direction, Bupp said. “It’s also good for hospitals and payers, because if we know why we’re treating folks, we give them better care and the cost of that care is lower,” he said.
UW’s American Family Children’s Hospital is among 10 hospitals in the Sanford Children’s Genomic Medicine Consortium — led by Sanford Health, based in Sioux Falls, South Dakota — that are sending samples to Rady for rapid genome sequencing, Meyn said.
Since April, sequencing has been performed on four NICU patients from UW, with three leading to diagnoses within five days, Meyn said. He said “the results led to major changes in medical management for all three of the diagnosed patients.”
UW doesn’t have enough cases to justify running costly sequencing equipment around the clock on site for the rapid results needed to help deteriorating newborns, Meyn said.
With older children or adults who have spent years trying to pinpoint the cause of their conditions, speed is not as vital, he said. That’s why genome sequencing for patients at the new Undiagnosed Genetic Disease Clinic is done at UW-Madison’s Biotechnology Center, which can run so-called “long-read” sequencing that can provide even more answers.
UW plans to study up to 500 patients at the clinic over five years, with the goal of diagnosing rare disorders and discovering new disease genes.
Children’s Wisconsin has been doing genome sequencing on some patients for more than a decade, Basel said. In 2009, the hospital received national attention for reading the genetic script of 4-year-old Nic Volker of Monona to diagnose his rare condition and treat him with a cord blood transplant.
Most sequencing at the hospital yields results in two or three weeks, but the timing can be sped up to about five days for urgent cases, Basel said. In those situations, scientists using the sequencing equipment for research are asked to temporarily give it up.
“They basically have to put everything they’re doing on hold so we can run our sample,” he said. “We flood the plate with just our sample for a quick turnaround.”
Adapting to a rare disease
At the Gutzdorfs’ house in Watertown, Theo climbed a step to arrange pots and pans in his play kitchen on a recent afternoon before scuttling across the floor to pet Phil, the family’s Lab mix.
Theo started walking on his own a year ago, a few months after he turned 2. Earlier, he used a walker Josh Gutzdorf fashioned out of PVC pipe. Medical walkers, even pediatric ones, were too big.
Theo is a little person, or dwarf, one aspect of his Stuve-Wiedemann syndrome. With his leg bones not only short but curved, doctors plan to operate on his hip to help him walk better. After surgery, he will need to be in a partial body cast for six weeks. His parents scheduled the procedure for January, when it’s cold.
Theo’s body temperature can still be hard to regulate, even with the medication he takes.
“It’s a lot easier to warm him up than it is to cool him down,” Josh said. When it’s hot, “we can only be outside for 15 minutes, maybe, before he starts showing a lot of distress.”
Theo is largely nonverbal but recently learned to say a few words, including “bye.” His parents are trying out communication devices and teaching him some American Sign Language. Signing is a challenge, though, because his condition makes it difficult for him to open his fingers. At rest, his hands form fists.
He goes to speech therapy, physical therapy and occupational therapy. Though he eats mostly by mouth, he still has a feeding tube, used for medication, hydration and, when he’s ill, nutrition, Rikki Gutzdorf said. His parents give him eye drops several times a day to prevent scarring of his cornea and hope he’ll learn to blink when he gets older.
Stuve-Wiedemann is exceedingly rare, especially in the United States, so Theo’s parents aren’t sure what to expect for his future. They credit genome sequencing for helping him so far.
Without it, “we wouldn’t be in the place we are today,” Rikki said. “I ache for the families that don’t have a diagnosis or a (disease) name.”
No time to lose: Finding rare diseases in infants
Wisconsin doesn't screen newborns for some disorders other states include, which can delay treatment that could prevent death or disability.
As parents urge state officials to expand the program to catch more ailments early, doctors are increasingly turning to genome sequencing to diagnose some critical conditions.
This three-day series explores the promise and limits of the state's newborn screening and testing.
Wisconsin doesn't test for Krabbe and Pompe diseases, deadly but treatable disorders detected in many other states.
Tardy tests can delay essential treatment, as a New London family learned.
Lawsuits over medical privacy in Minnesota and Texas forced those states to destroy millions of stored samples.
Other states say they test for more conditions, but a Wisconsin lab director said it isn't "a counting game."
Jenna and Kyle Heckendorf lost their son, Bryce, to Krabbe disease seven years ago when he was 18 months old
Atlas Faucher, 5, was diagnosed with Pompe disease at 4 months old
Jeremy Thoms, 21, has Krabbe disease and received a stem cell transplant at 4 weeks old
Wisconsin and most states test newborns for spinal muscular atrophy. But 12 don't, despite the need for prompt treatment.
The state started testing babies for severe combined immunodeficiency disorder in 2008.
Adults with spinal muscular atrophy can take two of three treatments, approved within the past five years.
Amy and Adan Medina’s children, Mateo, 10, Javier, 5, and Amelia, 3, were all born with SMA or spinal muscular atrophy
For the Gutzdorfs of Watertown, the situation for their son "was very much life or death."
At University Research Park, San Diego-based Illumina makes enzymes used in its DNA sequencers.
Rikki and Joshua Gutzdorf’s son, Theo, 3, was born with Stuve-Wiedemann syndrome that was diagnosed three weeks after birth through genome seq…