No one knew what was wrong with the one-week-old infant in the summer of 2012. Born healthy, he had come down with a soaring fever and severe diarrhea. There was no sign of an infection — and he was getting worse.
Desperate for a clue, the baby’s physician at Yale-New Haven Hospital appealed to a team of Yale genetic specialists. If a flaw in the baby’s genes was causing the mysterious illness, scouring his family’s DNA for the mutation could provide insights that might save his life.
Researchers worked furiously, but the infant’s body was shutting down. Just 23 days old, he passed away a day before the results came back.
The DNA analysis in the tragic case, however, was not for naught: It would help the researchers understand the disease — and ultimately have ripple effects that no one expected.
In the space of a few short years, DNA sequencing has changed from a technology whose medical promise is largely theoretical to a tool that is regularly used to gain insight into unexplained and rare diseases.
“This is truly a revolution; it’s a fundamental revolution in how pediatricians are looking after patients,” said Dr. Stephen Kingsmore, director of the center for pediatric genomic medicine at Children’s Mercy Hospital in Kansas City, Mo., who was not involved in the Connecticut case. “We now have this ability to take children with a mystery disease and apply genome. . . sequencing and identify the cause of their disease fairly routinely.”
At Yale, Dr. Richard Lifton, chairman of the genetics department at the university’s medical school, estimates his team has used sequencing in about 500 clinical cases over the past year. Even so, he called this case, described Sunday in the journal Nature Genetics, “one-of-a-kind.”
When Lifton’s team got its first look at the DNA data from the baby and his parents, there was no eureka moment, no obvious unique mutation in the infant.
The researchers reviewed the case with Dr. Neil Romberg, a pediatric immunologist who had begun working on the case hours before the infant died. They were intrigued by a never-before-seen mutation in a gene called NLRC4 that was known to be involved in the body’s response to infection. But because the father — who was healthy — carried the same mutation, it did not seem likely to be the cause.
Then, a few days after his son’s funeral, 43-year-old Erik Drewniak came down with a fever that rapidly worsened.
“When my research coordinator came in and said, ‘I just got off the phone with the referring hospital and the father is in the ICU with severe respiratory failure and they don’t know what the cause is’ — boy, that’s one of those moments that you won’t forget,” Lifton said.
Suddenly, the gene mutation that father and baby shared seemed like it could be the key. The baby’s gastrointestinal symptoms had distracted doctors from a clue in the father’s medical history. Drewniak, an attorney who lives in Fairfield, Conn., had a history of very high fevers.
“Whenever I got sick, I went to the doctor — another fever, whatever,” Drewniak said in an interview. “We never thought of it as being something bigger, like a syndrome or a disease.”
The medical team immediately decided to test whether his immune system was raging out of control the way his son’s had. Based on the insights from his deceased son, they began treating Drewniak, who was in a coma, with a slew of powerful drugs that suppress the immune system. Nine weeks later, he needed to learn how to walk again — but he was alive.
Researchers began testing other family members, discovering evidence that bolstered the idea that the mutation was the cause of the illness and also made sense of the past.
As a baby, Drewniak, who grew up in Fall River, had spent time in Boston Children’s Hospital with fever and severe diarrhea. Those symptoms eventually resolved, but his parents had never known why.
When researchers analyzed the DNA of Drewniak’s parents, things began to fall into place. Neither of them carried the mutation, meaning it was unique to him within his family, and that he had passed it down to his infant son.
Drewniak also had another son, who had experienced similar symptoms and fevers. That son, now 7, had been diagnosed with a form of inflammatory bowel disease, but the new discovery suggested that the problems stemmed from this gene.
Researchers began to pick apart the biological details of how the mutation caused the immune system to go into overdrive and learned that a particular class of drugs developed for other purposes could be used to prevent the disease. They have also designed a treatment plan in case Drewniak or his son gets a high fever.
Lifton mentioned the work at a conference last fall and was surprised to get a call from a research team at the National Institutes of Health that had discovered a slightly different mutation in the same gene in a young patient from Canada. That gave both teams more confidence in their results.
They hope the information could be used to identify more patients, which the Yale researchers have proposed to call SCAN4.
Drewniak said that even after two years, it has not all sunk in.
“I’m still processing it, I would say — not only because of the death of my son, but what happened to me,” Drewniak said. His greatest hope is that others will benefit. “If they have unexplained fevers and symptoms similar to mine and my son, their doctor can say, ‘Maybe it’s this mutation.’ ”Carolyn Y. Johnson can be reached at firstname.lastname@example.org.