A few hours after she was born, Sebastiana Manuel turned blue and began to scream. Her mom, Dolores Sebastian, tried feeding her but the infant wouldn’t eat. “Her little lips were very dry,” her mother said. “She wasn’t moving.”
Then the baby’s body twisted. Her neck wrenched the opposite direction. Sebastiana wailed again and passed out. It was the first of a series of debilitating seizures. Doctors sedated her to keep the spasms at bay but didn't know what was wrong. One neurologist told the family to say goodbye: Sebastiana likely wouldn’t survive.
But clinicians proposed an experimental test. If doctors had a full blueprint of the baby's genetic makeup, they might find the answer to the mystery disorder in Sebastiana's DNA.
Years ago, that would have been impossible: sorting out the whole genetic makeup of a patient could take weeks or months to get results — way too long for an infant at death’s door. But doctors at Sebastiana’s hospital in San Diego had pioneered a new method, called “rapid whole-genome sequencing” (rWGS) that can make a copy of an entire genome in roughly one day.
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If the test could quickly identify Sebastiana’s disease, doctors had a shot at saving her.
Now, for the first time, the same cutting-edge DNA sequencing method is available in Miami.
This spring, Nicklaus Children’s Hospital launched two new genomic research studies aimed at helping diagnose newborns and infants with unexplained illnesses. Nicklaus will work with Rady Children’s Institute in San Diego — the hospital where Sebastiana was treated — to make rWGS available for patients in South Florida. They are now the seventh hospital in the country to offer the test, and the only one east of the Mississippi River.
Genetic diseases are rare but also the leading cause of mortality for newborns in North America, accounting for around four percent of those deaths. Of the approximately 11,000 babies born daily in the United States, the Centers for Disease Control and Prevention estimates 3 percent have an undiagnosed genetic conditions. Those rare disorders also make up about 15 percent of patient admissions to children’s hospitals — so streamlining the genetic sequencing process has big implications for families and pediatric medicine.
Right now, genetic testing is common in hospitals but usually it is confined to checking for a specific condition, like cystic fibrosis or epilepsy. If a patient’s genome is like the operating manual to their body, most genetic tests only look at a single page. Whole-genome sequencing makes it possible to read the entire manual start to finish, checking for multiple conditions at once.
Jennifer McCafferty, director of the Research Institute at Nicklaus, compared the process of pinpointing a rare disease in a patient's genome to looking for a typo in the manual.
“And the typo has to mean something,” McCafferty said. “There are some typos that don’t make a difference. But other typos can be really important. If you put the period in the wrong place in a sentence, for example, it totally changes the meaning. It’s the same concept in DNA sequencing. The instructions change.”
The ability to examine a person’s entire DNA is especially important for patients with rare conditions, McCafferty said, where doctors don’t know exactly what they are looking for.
Under the two trials — one for newborns, the other for older infants who have gone months without a diagnosis — clinicians at Nicklaus will be able to send samples overnight to Rady’s Children’s Institute, whose labs are so swift they literally won the Guinness World Record for fastest genetic diagnosis in February. It came back in 19.5 hours. Of course, the hospital’s only competition was its own record from two years earlier. But the point is: they do it fast, much faster than genetic testing has ever been before.
The procedure still comes with an expensive price tag and it’s not yet reimbursed by insurance companies. But parents who need it at Nicklaus won’t have to pay it under the terms of the twin medical trials. Both are entirely funded through grants and philanthropy.
Down the road, the hope is that rapid whole genome sequencing could actually save money for families dealing with a child fighting a rare disease. If the test helps doctors determine a diagnosis more quickly, it could cut down on further testing or costly overnight stays in intensive care units.
Having a hospital in ethnically and racially diverse Miami participate in the research could also help solve a national problem with genetic testing: so far, DNA data bases for medical research tend to be very white.
That could hurt accurate diagnosis for patients who aren't white. When a patient’s DNA is sequenced, clinicians often compare the patterns to a pool of what they call “reference genomes” — in other words, they compare the patient’s operating manual to a library of other manuals in order to see what’s different. The problem is that somewhere between 94 and 96% of the reference genomes in use come from patients of northern European descent.
“That means that anyone who is not from northern European ancestry is at a decided disadvantage when it comes to genetic testing,” McCafferty said.
A patient might come into the clinic with symptoms that seem like cystic fibrosis, a genetic disorder that causes persistent lung infections. They might meet all of the criteria on paper, but the genetic tests might be inconclusive.
“The test comes back grey,” McCafferty said. “You get this thing called a ‘variant of undetermined significance.’ We believe that’s largely because the reference genome does not broadly reflect the population of South Florida.”
As the genomes of more and more South Florida patients are sequenced, they will be added to the pool and contribute to a national effort to make the reference genomes more diverse and better reflect the people they serve.
“We just had our first rapid whole-genome sequencing baby enrolled,” McCafferty said. “The sample was sent to San Diego, we may get results back today. We don’t know, it’s usually about a 24 hour swing. But it could save this baby’s life.”
The test results wound up proving proved crucial to saving Sebastiana, the California baby hit with mysterious seizures.
On her second day alive, Sebastiana had her blood drawn. Four days later, armed with her DNA roadmap, doctors were able to pinpoint genetic markers for Ohtahara syndrome, a neurological disorder.
The doctors changed her medication. Within hours, she woke up. Within days, she could eat. In a fast and unanticipated turnaround, Sebastiana went home with her family 19 days after birth.
“Before the results came back, we were praying like crazy,” Sebastiana’s father, Pascual Manual said. “But after this test, we had an answer. We had hope.”
Herald Writer Tarpley Hitt can be reached at firstname.lastname@example.org