By Audrey Maynard

When Noah Wagstaff was born in May 2022, there was nothing to suggest anything was wrong. His mother, Claire, experienced a normal pregnancy and delivery, just as she had with her four previous births. But when Noah failed to regain his birth weight at his one-week checkup, Claire had a nagging feeling that something was off.

“I’m not a panicky person,” she says. “So when I felt that unnerved about Noah’s weight, I started to think maybe my intuition was trying to tell me something.”

As a pediatric nurse and mother of five, Claire understood infant behavior, and Noah’s wasn’t typical. He did not cry or signal hunger, and he seemed content to sleep for hours on end. At six weeks, Noah could not lift his head or push back when Claire pressed his feet against her knees. Because he ate so little, Claire began pumping and measuring every ounce he drank by bottle–a demanding routine made more challenging by the needs of her other young children.

With little improvement after three months, Claire asked Noah’s pediatrician for referrals to neurology, feeding therapy, and physical therapy, a request she feared sounded alarmist but knew was necessary.

Noah began therapy right away, but the neurology waitlist stretched more than six months. Drawing on her innate tenacity and experience as a nurse, Claire was able to secure an appointment with a neurologist in Boise within two weeks.

“He ruled out anything degenerative or life threatening,” she says. “But he validated my concerns and agreed that Noah’s muscle tone wasn’t where it should be. He said we’d have to watch and wait.”

Not wanting her six month old to fall further behind, Claire sought a second opinion at both Primary Children’s Hospital and Shriners Children’s in Salt Lake City. The night before Noah’s evaluation at Shriners, he became acutely ill. Claire rushed him to Primary Children’s where he was diagnosed with RSV, a life-threatening respiratory virus. During his week-long hospitalization, imaging revealed Noah had a congenital vascular ring: his aorta was wrapped around his trachea and esophagus, constricting both.

“Strangely, that was the calmest I had felt in months,” Claire says. “I knew my husband and I could use that time to ask specialists for help in finding answers.”

A scope revealed Noah’s esophagus was nearly pinched closed, and in February 2023, he underwent corrective heart surgery. The procedure was a success, and once he was home, Noah rolled across the room for the first time. With thickened formula—and five months of rehabilitation and therapy—he began feeding successfully and gaining weight.

Yet, despite his physical improvements, one troubling symptom persisted: Noah remained completely silent. He did not babble, cry, or make any sounds at all.

Between Noah’s hospitalization and heart surgery, Claire learned that a new geneticist at Primary Children’s, Stacey Cole, MD, had availability to see him. Cole ordered rapid whole genome sequencing (rWGS), a test that analyzes a person’s DNA to look for disease-causing genetic changes, as well as a targeted methylation test to examine chemical markers that influence how genes are turned on or off. In Noah’s case, both came back normal. Because he was making some developmental progress, his care team urged patience, especially since insurance would only cover one resequencing.

When Noah was two, Claire took him back to his neurologist in Boise, which proved to be a pivotal moment in his diagnostic journey. Learning that Noah still made no sounds, the neurologist raised the possibility of Continuous Spike Waves of Sleep, a rare condition causing seizure-like brain activity during sleep. An EEG confirmed the presence of continuous spike waves near the speech centers in Noah’s brain.

For Claire, this finding felt miraculous—not because it was unexpected, but because it verified something she had suspected for a long time.

“I was told to watch for seizures in Noah when he was a year old, but these spike waves were virtually undetectable to us,” she says. “The EEG was a huge piece of the puzzle in confirming that Noah, indeed, had a genetic condition.”

At this point, Cole ordered a WGS reanalysis along with a cutting-edge new expanded methylation study. The reanalysis came back negative, but the methylation test reported an abnormal methylation pattern consistent with Ohdo syndrome, which is caused by mutations in the KAT6B gene.

Curiously, Noah’s symptoms did not fully align with those consistent with this variant. Out of clinical options, Cole referred Noah to the Utah Neo/ReSeq Project at University of Utah Health. This “cold case” research study is part of a multidisciplinary team of pediatric specialists and genomics scientists who use WGS reanalysis to identify genetic variants suspected of causing disease.

The Utah Neo/ReSeq Project was created for children like Noah: patients who have undergone whole genome sequencing but who remain without answers.

“We take the unsolved cases and try to figure out answers for families that otherwise would fall through the cracks of our health care system,” says Sabrina Malone Jenkins, MD, associate professor of pediatrics and principal investigator of the Utah Neo/ReSeq Project. “Because we are a research study, not a clinical laboratory, we face fewer constraints and are able to dive deeper into the genome.”

In Noah’s case, when the Utah Neo/ReSeq team examined his existing genomic data, they didn’t find any mutations in KAT6B like they expected. Instead, using advanced analytic tools, they unlocked the true culprit behind his condition: a KAT6A mutation. The difference came down to a tiny disruption buried in the non-coding regions of Noah’s DNA, areas often overlooked in routine clinical analysis, in part, because such variants are difficult to interpret. However, by analyzing Noah’s RNA, the team confirmed that this subtle variant was altering how the KAT6A gene functioned, finally confirming a diagnosis of Arboleda-Tham syndrome.  This condition fit well with Noah’s clinical presentation and has a methylation signature that overlaps with Ohdo syndrome, explaining the previous methylation result.

“We found the KAT6A mutation because it was predicted to disrupt gene splicing, but you can’t make a diagnosis based solely on a computational prediction,” explains Steven Boyden, PhD, director of research and science with the Utah Center for Genetic Discovery and lead analyst for the Neo/ReSeq Project. “Our ability to follow up on a suspicious DNA result by experimentally confirming the consequence of this variant at the RNA level sets this program apart from standard WGS testing.”

Today, the Wagstaff family has clarity on Noah’s diagnosis and a roadmap for his care. He takes daily medication to control seizure activity and receives specialized therapy for a speech disorder called apraxia. He is an energetic, joyful toddler who plays with his siblings, counts to ten, and is learning his ABCs.

“The Utah Neo/ReSeq Project completely changed the trajectory of my child’s life,” Claire says. “We could not have built such an amazing therapy team around Noah, and he would not be as healthy as he is today, if this program did not exist.”

Breakthroughs in cases like Noah’s are largely made possible through philanthropic support, which empowers researchers to pursue advanced testing that insurance often will not cover, as well as develop novel analytic approaches that are not yet part of standard clinical care. Malone Jenkins is grateful to those who have invested in the Utah Neo/ReSeq Project, specifically Mark and Kathie Miller and the R. Harold Burton Foundation.

“It takes enormous resources—people, time, and technology—to do this research,” Malone Jenkins says. “But when it brings peace of mind to a family, can you really put a price on it?”

For Chelsea Solorzano, RN, the project coordinator for the Utah Neo/ReSeq Project and liaison between families and the scientific team, the relationships she forges with parents are what have brought the most meaning to her work.

“My favorite part is building connections with parents,” she says. “When they share their gratitude, I get the privilege of bringing that back to the team—it just means everything to us.”

Malone Jenkins agrees wholeheartedly, adding that a success like Noah’s diagnosis provides the fuel her team needs to keep going.

“One win can carry us for quite some time,” she says. “It’s what makes those stressful, frustrating days completely worth it.”