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Prenatal Whole-Exome Sequencing to Diagnose Children with Rare Diseases


illustration of whole exome sequencing

Is prenatal whole-exome sequencing worth the cost?

Whole-exome sequencing is faster and less expensive than it used to be, but it’s by no means easy to deploy. Matching a genetic anomaly to a real-life phenotype requires high-powered expertise in both the clinic and the lab — a level of experience few centers have. On the Anschutz Medical Campus, Children’s Hospital Colorado clinicians are collaborating with adult medicine colleagues and bench researchers at the neighboring University of Colorado School of Medicine to leverage these powerful tools for families facing an uncertain future with rare disease, from before birth throughout the lifespan.

Do the right thing

By the time the Colorado Fetal Care Center evaluated them for some mysterious findings at their 20-week ultrasound, the couple had already had one child, a son with a troubling array of symptoms: low muscle tone, developmental and cognitive delay, hyper-extensible connective tissue. He’d never been diagnosed. It was probably a genetic syndrome, but insurance wasn’t going to cover diagnostic whole-exome sequencing. That’s not unusual.

“Even when really truly indicated, it’s rarely covered,” says Michael Zaretsky, MD, Medical Director of the Colorado Fetal Care Center at Children’s Hospital Colorado. “Which means a lot of families are not getting answers.”

And not getting answers can have serious implications, not only on an infant or child’s ability to receive appropriate treatment, but on quality of life for families facing the anguish of suspicious findings and an uncertain future.

That’s why Dr. Zaretsky and a team of scientists and specialists from all over the Anschutz Medical Campus worked together to form one of the nation’s first fetal precision medicine boards.

“We get these cases that have fetal anomalies or suspicious findings where more targeted tests like karyotype and microarray have not provided a diagnosis, and we meet weekly to review them,” says Dr. Zaretsky. “We try to determine whether we missed anything or if there are other testing options, and if we ultimately decide to recommend whole-exome sequencing, we coordinate to get it done.”

The panel includes maternal medicine specialists, neonatologists, ethicists, genetic counselors, medical geneticists and bench researchers including developmental biologists and craniofacial surgeons on an ad hoc basis. They’ve been doing it about a year, and more research groups are getting involved all the time.

“It does take a lot of manpower to get an accurate interpretation of the results and to create specific recommendations for care,” says genetic counselor Kestutis Micke, MS, CGC. “Even with whole-exome sequencing, there are a lot of uncertain variants. The strength of the committee is having a lot of pairs of eyes.”

Whole-exome sequencing isn't a magic bullet

Very few centers are doing routine diagnostic whole-exome sequencing, especially in the prenatal space, so the literature is limited, but Dr. Zaretsky estimates the diagnostic yield rate nationally at about 20%. At the Colorado Fetal Care Center, the board’s rigorous algorithm and combined expertise has produced a yield of about 40%.

And it’s produced some unexpected results. When the couple mentioned above became pregnant again and the 20-week ultrasound presented some unusual findings, the board ultimately decided to recommend sequencing — and in the process diagnosed their older son.

Even so, “There’s not a disease-modifying treatment for his disorder,” says Austin Larson, MD, the patient’s geneticist at Children’s Colorado. “Which, unfortunately, is often the case.”

That’s because, Dr. Larson observes, the impetus for fetal whole-exome sequencing is twofold: lack of a diagnosis and some visual indication that something is wrong — which indicates the disease is both rare and fairly progressed. In one case, he recalls, the diagnosis produced by whole-exome sequencing was sufficiently grave that the family knew their baby wouldn’t live more than a few months.

“But they were able to bond with their baby understanding that his life would be limited, and they derived a lot of meaning from that,” he says. “Everyone I’ve talked to, including the family, believed that was the best possible outcome, and it was because of prenatal whole-exome sequencing.

“The truth,” he continues, “is that some of these conditions are never going to be treatable. They’re the result of an early fetal process that didn’t work, body systems that didn’t develop, and there’s no way to go back in time. We’re doing it because it’s the right thing to do. Sometimes the best outcome is just helping the family prepare and make decisions accordingly.”

And although many more rare conditions are not treatable currently, some may be someday — but first they need to be identified.

“There’s never going to be a treatment,” he says, “unless we diagnose and categorize and figure out the mechanisms that cause disease.”

Could whole exome sequencing lead to viable therapies even for novel variants?

Pure Potential

An interesting thing happens when you suspend stem cells in three-dimensional media: They start to build organs.

“We can take primary tissues from a patient and isolate and expand various tissues of interest,” says molecular and developmental biologist Sean McGrath, PhD, who manages the Organoid and Tissue Modeling Shared Resource at the University of Colorado School of Medicine. “Or if we can’t get at the primary tissue, we can take a patient sample, reprogram the stem cells into pluripotent stem cells, and then differentiate them into various tissues of interest. We do a lot of gene editing as well, where we can make patient mutations or correct them.”

Of course, the technology is still in its early stages, says Dr. McGrath. For now, his participation in the Colorado Fetal Care Center’s precision medicine board is exploratory: If whole-exome sequencing identifies a new mutation, for example, his lab could potentially build an organoid with it to see how the mutation might affect development or cause disease.

Other teams might incorporate the same mutation into animal models to understand how the mutation correlates with phenotype. Still other teams might do drug modeling, testing the effect of different therapies on animal models or organoids, like the ones McGrath grows in the lab.

“You could screen the best options while that baby is still developing and have a good idea of how to treat when the baby is born,” he says. “The holy grail would eventually be that you could identify a disease-causing mutation in utero, take a sample, grow it in vitro, correct the mutation and have a tissue you could use for regenerative therapeutics once the patient is born.”

That’s all decades down the road, he says. So far, his team has yet to identify a good candidate case for modeling in the lab.

“It’s all a pipe dream at this point,” he says. “But the potential is there.”