When Erik Drewniak’s infant son arrived at Yale-New Haven Hospital (YNHH)’s pediatric intensive care unit with a high fever and severe diarrhea, Mustafa Khokha, M.D., was worried. Tests ruled out infection, prompting Dr. Khokha, who specializes in critical care pediatrics and genetics, to wonder whether the illness could be genetic. Both of the baby’s parents were healthy, so he and Richard Lifton, M.D., Ph.D., chair of genetics at Yale, thought the baby might have a new genetic mutation that was causing his condition.
They performed high-throughput exome sequencing—a special technique to analyze the 21,000 genes that make proteins in a person’s DNA—on the baby and both his parents. Meanwhile, Neil Romberg, M.D., a pediatric immunologist, examined the baby for a rash, which he recognized as the first sign of a massive immune response. Lab tests indicated that the baby had widespread inflammation, another reason to suspect a genetic disorder.
The Yale Center for Genome Analysis rushed the sequencing and analysis. Completed in just a few days, test results arrived the day after the 3-week-old baby died. The analysis found no new mutations that explained his illness.
Father’s persistent fever
A few days after the funeral, Erik Drewniak was still reeling from the loss of his infant son when he came down with a fever. He didn’t think it was anything to worry about. He had suffered from periodic fevers that spiked as high as 106 degrees his entire life. But this time the fever persisted, and he was having difficulty breathing. At Norwalk Hospital, Drewniak’s condition deteriorated. He went into respiratory failure and was transferred to the intensive care unit at YNHH, where tests showed he was suffering from inflammation and hemorrhaging of the bowels, lungs and brain. His condition was serious, but he improved and went home nine weeks later.
Meanwhile, while reviewing the family’s sequencing results, Dr. Romberg recognized a mutation in NLRC4, a gene involved in the immune pathway that is the first line of defense in the body’s response to infection. That same day, he and Dr. Lifton learned that Erik Drewniak had been hospitalized with a severe illness. That was an “aha” moment.
From discovery to treatment
“We recognized at that point that the variant in NLRC4, which was shared between the father and the baby, might link their diseases,” Dr. Lifton said. It turned out father and son shared a genetic mutation causing an illness that had never before been described. In an impressive collaborative effort, Yale doctors were able to identify the mutation, home in on the pathway it affected, and devise a personalized therapeutic strategy that saved Drewniak’s life. The Drewniaks’ experience is an example of the ways in which personalized medicine, which is being supported by President Obama’s new Precision Medicine Initiative, is gaining ground.
The Yale team sequenced other Drewniak family members, including Erik’s parents and two children, who are his infant son’s half siblings. While his parents and daughter do not have the NLRC4 mutation, the sequencing showed that his son, now 7, does. Like his half brother, he was hospitalized as an infant, although in his case it was due to kidney failure. Like his father, he suffers from periodic high fevers. As doctors suspected, the mutation was new, but it first occurred in Erik Drewniak, who passed it on to two of his children.
Once a genetic mutation emerged as the likely cause of disease in three Drewniak family members, the next step was to understand how a single change in this particular protein code could wreak such havoc. Dr. Romberg and Barbara Kazmierczak, Ph.D., M.D., who specializes in infectious diseases and microbial pathogenesis, discovered that the mutated NLRC4 protein activates a powerful inflammatory pathway that sent the Drewniaks’ immune systems into overdrive, even though no bacterial infection was present.
No longer science fiction
Now that Yale doctors understand the mechanism of this disease, they are better equipped to treat the Drewniaks in the future. Beyond the therapeutic implications of these discoveries, the ability to pinpoint the cause of mysterious illnesses is invaluable. Fortunately for families like the Drewniaks, diagnosing rare genetic illnesses is becoming more common. “We’ve gotten to the point where genetic sequencing is fast enough and cheap enough, and we’ve done enough of it, that this is no longer science fiction,” said Dr. Romberg.
Yale physicians often see children with birth defects or unexplained illnesses that they are unable to diagnose. A new program called Pediatric MAP, supported by Yale School of Medicine, Yale Center for Clinical Investigation and YNHH, will allow them to carry out the research that was done for the Drewniaks on a broader scale.
For Erik Drewniak, the knowledge of what caused his infant son’s death is empowering. “Genetics is something you can latch onto as a definite explanation,” he said. “It’s not the environment, it’s not something you did or didn’t do; it’s genetics. It made me understand not just him, but all three of us. Everything just came together and now it all makes sense.”