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When the boy was brought to the San Diego emergency department one night last October, he was inconsolable. Within about half an hour, clinicians had a clue of what was wrong: A CT scan showed signs of disease in the 5-week-old’s brain.

There was another clue, too, but also a portent: A decade earlier, the parents’ infant daughter had presented with some of the same symptoms at around the same age, but never received a diagnosis. She developed seizures and died at 11 months.


All that pointed to a genetic condition. But those warning signs in the brain, called encephalopathy, could be caused by some 1,500 such diseases.

Just a few years ago, there would have been little doctors could do to urgently whittle down that list, even as they raced against the progression of the disease. But this time, the medical team at Rady Children’s Hospital simply ordered up a rapid sequencing of the boy’s DNA.

Less than 36 hours after the boy showed up to the ER, they had their diagnosis: a rare disease called THMD2 that was easily treatable. From the start of the sequencing to the diagnosis, the process took just 13 hours — a figure, unimaginable even a few years ago, that highlights the remarkable progress in sequencing technology and how quickly it can turn around answers.


“It’s a proof of concept of what can happen when we have access to this very powerful test,” said Gregory Costain, a medical geneticist at the Hospital for Sick Children in Toronto, who was not involved in the case. Families sometimes spend months or years trying to identify their children’s genetic conditions — what’s often referred to as the diagnostic odyssey — but the case underscores the power of rapid sequencing when used for the right type of patient, Costain said.

The tale, described last month in the New England Journal of Medicine, is not typical of every child’s experience, the medical team stressed. Less-resourced hospitals might not have access to the technology. Insurance can also get in the way. Rather, the story from Rady presents the best-case scenario of the potential of rapid and accessible genomic sequencing.

“This is one in a hundred, where everybody goes home saying, ‘We just saved a little baby’s life — let me tell you about it,’” said Stephen Kingsmore, one of the authors of the case report and the CEO of Rady Children’s Institute for Genomic Medicine.

It wasn’t just that the boy got his genome decoded so quickly. The sequencing flagged misspellings in his DNA that in turn pointed to a specific diagnosis; often, reading someone’s genes doesn’t turn up anything so clear-cut. Plus, THMD2, which can cause seizures and loss of movement control and ultimately death, had a simple therapeutic antidote: two supplements called thiamine and biotin that in high doses can resolve the issue.

Only about a third of sick babies with a suspected genetic disease who have their genomes sequenced get a firm diagnosis, Kingsmore said. And only 10% of those babies have treatment options once the condition is identified.

But in this case, about six hours after he was started on the supplements, the baby was calm and drinking a bottle, and the seizure activity that had developed during his hospital stay had quieted. The boy, who was not identified in the paper, was released a few days later.

The boy’s case of THMD2 — which doctors now suspect killed his older sister — was caused because he inherited a faulty copy of the SLC19A3 gene from each of his parents, who, as carriers, had one healthy copy and one copy of the mutated version. The parents were first cousins, and it’s likely that the specific mutation they both had and that their children inherited had been passed down in their family to them.

The hope is that doctors identified and addressed the boy’s illness before it caused any permanent brain damage. The boy, who will have to take high doses of the supplements for his entire life, is not yet a year old, but he appears healthy and has been meeting developmental milestones.

While “every case of rapid sequencing isn’t going to give you such clean answers,” said Nancy Spinner, the chief of genomic diagnostics at Children’s Hospital of Philadelphia, the new paper is a “perfect example of why we are so excited about this technique.”

“This is what we all have hoped — that you would be able to sequence and provide treatments to our patients who are suffering to ward off the worst outcomes,” said Spinner, who was not involved with the case. “Doing this rapidly for our sickest children in the intensive care unit is a very good goal.”

Companies now offer whole genome sequencing for under $1,000. But Kingsmore likened that method to a Volkswagen, whereas the clinical approach the specialists used to diagnose the boy, involving a range of experts and an accelerated process, was more of an Aston Martin — one that comes to about $8,500, he said. And indeed, the 13-hour technology used in the case report is still a prototype under a research protocol; Rady’s standard clinical offerings include a range of different levels and speeds of sequencing that can take a few days.

Access to sequencing technology of any sort is not universal for children who might have genetic diseases. Some state Medicaid programs have experimented with pilot initiatives to expand sequencing, and specialists are pointing out that sequencing very sick kids when there’s a reason to suspect they might have a genetic disease can often help point to a diagnosis that can inform treatments, even if there’s not a cure.

But the technology is so new that experts are still trying to sort out how widely rapid sequencing should be made available, and to which patients. To get insurance companies on board, they’ll need to show that broader access to sequencing can save money overall or lead to better outcomes.

“We have to make very careful decisions about where we allocate our resources,” said Marc Williams, the president of the American College of Medical Genetics and Genomics and a professor at Geisinger Health’s Genomic Medicine Institute. “If we put all our money into rapid sequencing, that might take money away from other interventions that are more impactful in terms of health outcomes.”

Still, said Costain, the hope is that the right subgroup of kids can be identified and sequenced, so that an outcome like the one in the case report “that was so special it got published in the New England Journal becomes more routine and less exciting.”

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