How a cutting-edge genetic test helps ill newborns, pregnant moms

It was weeks before anyone knew what was wrong with baby Charlotte. The newborn had been transferred by helicopter to UCSF Benioff Children's Hospital Oakland from California's Central Valley at six weeks old. She was malnourished, congested and wouldn't eat—and no one could figure out why.

Finally, a rapid whole genome sequencing (rWGS) test revealed the cause. Charlotte had inherited a rare genetic disease called prolidase deficiency from her parents, who were unaware they were carriers. The condition can cause skin lesions, recurrent respiratory infections and liver problems, among other things.

"Seeing her so sick, with nothing to do but wait for tests; it was horrible," said Charlotte's mother, Destinee, recalling the 2019 experience. "Before we got to UCSF, she was wasting away. I wasn't going to leave the hospital without knowing what was going on."

Stories like Charlotte's are one reason UCSF began implementing rWGS at in-house laboratories earlier this spring. In Charlotte's case, the testing had to be done at a lab in Southern California.

Unlike other forms of genetic testing, rWGS works by running a person's entire DNA sequence instead of looking at individual genes, a limited selection of genes or just the protein-coding regions of genes. It's more likely to get to a diagnosis and is also usually faster than other testing options.

"Without rapid testing, it can take months or even years for babies with unusual symptoms to get diagnosed," said Arthur D'Harlingue, MD, director of neonatology at UCSF Benioff Children's Hospital Oakland. "Sometimes the testing leads to treatment that can be lifesaving. Almost always, it gives families information they need to make decisions about next steps."

In newborns like Charlotte, rapid whole genome sequencing is ordered when the baby's level of illness can't be explained by other conditions, or when there may be a symptomatic or family-history reason to suspect a genetic cause.

Shorter hospital stays for infants

The move to in-house rWGS testing came after a 2021 pilot study of Medi-Cal patients by researchers from five California medical facilities, including UCSF Benioff Oakland. They found that when rWGS was used in infants with suspected genetic disease 40% got a diagnosis, usually in about three to seven days, greatly reducing the amount of time in the hospital. The results led to changes in medical care for 32% of the infants enrolled in the study.

Babies who have a metabolic disorder, for example, can be treated right away with enzyme-replacement therapy, thus limiting damage to their organs. "If you limit injury to the organs early on, the child can be a better candidate for interventions later," said Roberta Keller, MD, UCSF neonatologist.

In Charlotte's case, the diagnosis didn't lead to a treatment that cured her condition, because there is no cure. But getting the testing allowed the family to move forward, her mother said.

"When I learned about her condition, I learned what I needed to do to keep her healthy," Destinee said of Charlotte, who is now four years old and thriving. "I also learned the risk if I had another child."

While rWGS in babies is becoming more common, "UCSF is a pioneer in Northern California by offering this cutting-edge service in-house," said Aleksandar Rajkovic, MD, Ph.D., chief genomics officer at UCSF Health. "Moving ahead, we anticipate that hundreds of pregnancies and newborns annually at UCSF will benefit from the precision of rapid whole-genome sequencing."

Testing pregnant mothers can lead to early treatment in utero

UCSF began running rWGS testing during pregnancies in April 2023 at UCSF Genomic Medicine Laboratories.

The test is most often used when something looks amiss on an ultrasound and it is suspected that there might be a problem with the fetus. Alternatively, the mother may have had issues with a prior pregnancy that warrant testing.

About 2%–3% of pregnancies have a condition that could trigger the need for rWGS, said Mary Norton, MD, co-director of the UCSF Center for Maternal-Fetal Precision Medicine. So far, her team has found a genetic abnormality in about 20% of fetuses tested with rWGS.

"In some cases, there is in utero treatment available for the condition we find. When we get results earlier, we can get our patients in to see specialists earlier," Norton said. "It also speeds up the process of creating a game plan for the rest of the pregnancy. Does the patient need to deliver at UCSF, or can they safely deliver closer to home?"

The rapid turnaround of the test is also emotionally valuable to families when a red flag has been raised, she added. "Getting the test results back in a week versus a month makes a huge difference in relieving the tremendous stress and anxiety of expecting parents," Norton said.

"Not only do we do the lab testing here, we have a weekly conference with some of the world's experts asking, 'What does this gene mean for this fetus? What is the chance there will be a serious problem or a mild problem, and what should we do with this information?'" Norton added. "It is this incredible brain trust of people—pediatricians, OB-GYNs, geneticists, fetal medicine specialists—having heated discussions about how best to serve the patient."

Provided by University of California, San Francisco