New DNA techniques end mystery of what ails baby Patrick

BOSTON — Chris Butters was changing a diaper for his son, Patrick, last November when he felt something in the two-month-old's abdomen. It was about the size of a marble or a peanut M&M candy.

“What in the world is that?” he recalled thinking.

Butters and his wife, Melissa, suspected the growth in Patrick's abdomen was a new chapter in a 36-year-old medical mystery that began in the 1970s, when Melissa herself was a little girl battling unexplained tumors.

This time the mystery was solved in a matter of months, thanks to faster, cheaper genetic sequencing that is revolutionizing the diagnosis of rare, previously unexplained conditions in babies. The new approach is spreading through major medical centers and can ease the concern of parents like the Butters who often embark on painful medical odysseys searching for answers. It also holds out hope for eventual treatments, doctors say.

Babies with baffling conditions should have large swathes of their DNA sequenced, said scientists and doctors at the recent annual meeting of the American Society of Human Genetics in San Francisco. At least 50,000 babies born every year in the United States might benefit, said Jimmy Lin, a geneticist at Washington University in St. Louis.

“Everyone who has a child with an unexplained condition should have access to this,” said Lin, who established the Rare Genomics Institute to help families pay for their children's sequencing when insurers won't. “We're at a point where anyone at a medical center with the right people can do this.”

While the excitement of solving genetic riddles runs high, the power of sequencing babies also raises concerns. Only in rare cases, does knowing the genetic cause of a condition lead to better, let alone any, treatment.

Still, parents can at least know what is wrong and the hope is that by mapping a baby's genes, scientists may eventually find cures, doctors say.

“It's just a matter of time until this becomes a first-line test for babies with undiagnosed disorders,” said Columbia University geneticist Wendy Chung. “As costs fall and insurers become more comfortable, this will become the go-to test.”

The human genome is a code for making all the body's cells and proteins. Sequencing all the relevant portion of a child's DNA costs about $2,500, said Lin, at Washington University. That's a fraction of the bill for a day in the neonatal intensive care unit — about $8,000, he said.

For Patrick Butters and his parents, who live in East Setauket, N.Y., the new approach meant finally solving the family's medical mystery.

Unexplained tumors had tormented Patrick's mother, Melissa, since her birth in 1976. At the time, she had four small growths in her cheek, upper back, armpit and abdomen. Three were cut out, and the one in her cheek, which was never removed, disappeared on its own by the time she was 4, leaving her with a small dimple.

Melissa's doctors were stumped. Norma Wollner-Sternberg, Melissa's pediatric oncologist at Memorial Sloan-Kettering Cancer Center in New York, said she wasn't sure at the time whether Melissa's condition was inherited or whether it would worsen. Physicians didn't have the diagnostic tools available today, she said.

Wollner-Sternberg suspected that the tumors might be part of an inherited condition, Melissa said.

“She said, ‘I don't know if you want to consider having children,'” Melissa recalled.

As Melissa grew, her tumors recurred less frequently and presented few problems. She remained healthy and active, and now practices law. After discussions with her husband, it seemed reasonable to have a child.

In 2010, to be on the safe side, Melissa approached Columbia's Chung about using DNA analysis to get to the bottom of the condition.

Chung analyzed Melissa's DNA, looking for mutations in genes that were already known to cause the types of tumors that had appeared in her body over the years. The tests yielded nothing.

When Patrick was born without any growths, the Butters were relieved. Then, the first tumor appeared in his abdomen. Samples from Patrick's and Melissa's tumors were sent to Harvard-affiliated Brigham and Women's Hospital in Boston, where they were classified for the first time as myofibromas, a type of connective-tissue tumor that usually strikes children.

The Butters family is insured by Cigna Corp. through Chris's employer, a software company, which paid for Patrick's treatment. Chung paid for Patrick's sequencing using about $1,000 in research funds along with time from her colleagues that wasn't reimbursed.

After Patrick's initial tumor was removed, his parents found eight more growths on Patrick's head, left shoulder and back. Then, in July, Melissa was playing in the pool with Patrick when he yawned, revealing something unfamiliar and white in his mouth. She looked more closely and reached in with her finger, touching what appeared to be a new growth.

Picking up Patrick, Butters rushed to the phone to call his pediatrician. She referred Butters to an ear, nose and throat surgeon, who advised taking Patrick to Memorial Sloan-Kettering as soon as possible. It was the same cancer hospital in Manhattan that had followed his mother's unexplained tumors through her teenage years.

Patrick was seen by a pediatric surgeon, and within a week, he was in the operating room having the growth removed. Chris Butters cried outside the operating room, thinking of what their young child was enduring.

More and more, the parents were anxious to find out whether the tumors were inherited, and if so, which mutation was behind it. While it was unlikely they'd be able to seek treatment, they hoped the information could be used so that Melissa, or even Patrick, might have a child that wouldn't be affected by the mysterious condition.

Chung, at Columbia, redoubled her efforts to find the source of the problem, tapping into technology that was making the hunt for DNA mutations faster every month.

She sent samples from Patrick's case to the Columbia Genome Center, opened 18 months ago and run by Olivier Couronne, a computer scientist who had worked on the Human Genome Project. The volume of work done by the center is increasing by a third to a half every three months, he said. Samples come to Columbia's sequencers from across the U.S. and five other countries.

Couronne's workers analyzed Patrick's genes — the chemical coding that tells cells how to construct all the body's tissues — using a sequencer made by Illumina Inc., the world's biggest maker of such DNA analysis equipment.

Couronne analyzed the samples with a process that is rapidly becoming a leading approach to diagnosing unknown conditions, called RNASeq. The technique focuses on a complementary molecule to DNA, called RNA, which tells cells exactly which proteins to make. By looking for flaws in RNA, scientists can sometimes quickly backtrack to corresponding DNA mutations.

The analysis yielded almost 7,000 genes in Patrick's tumors that appeared to vary from known, healthy DNA sequences. While most of these would turn out to be normal variations in DNA and posed no danger, any one of these mutations might be the one that caused the tumors in Melissa and Patrick.

To determine which was causing the unexplained growths, Columbia scientists then used computer databases of known genes that might be related to tumors like those seen in the Butters. The researchers quickly narrowed the list to about 10.

Then they found the culprit. The most likely genes to be associated with their myofibroma tumors was called PDGFRB, named for its product, a protein called platelet-derived growth factor receptor. It's been related to tumors before. All Patrick's tumors have at least one mutation in the gene.

Melissa has a mutation in the same PDGFRB gene. Neither of her parents did. That meant the mutation likely took place at some point during Melissa's conception, Chung said. Because all her tumors are on the left side, it's possible her mutation occurred soon after the embryo started dividing, in the cells that became the left side of Melissa's body. Patrick inherited that mutation.

Late one evening in September, Chung emailed Melissa to say that she had located the flaw in the PDGFRB gene. She then reached out to about a half-dozen doctors worldwide who had reported similar disorders in their patients. Did those patients have mutations that matched the Butters'?

The answer came three weeks ago. A family in Australia and another family that had been analyzed by McGill University scientists in Montreal had the same tumor disorder and the same mutation.

The Butters' medical mystery was solved. Now that the gene had been located, what could they do?

While doctors said they couldn't stop Patrick's tumors from growing, they could prevent the mutation from being passed on to future children.

Using a procedure called pre-implantation, doctors can take a few eggs from a woman and fertilize them with the father's sperm and let them grow in a laboratory until they reach the 8-cell stage. In a condition such as the one that affects Melissa and Patrick, only about half of the eggs will carry the defective gene.

Doctors then remove a single cell from an embryo and sequence its DNA to see which embryos carry the flawed gene and which don't. They then select one or two of the unaffected embryos for implantation and effectively halt the inheritance of a disease in the family, permanently.

In addition to Patrick, the Butters family has a 13-year- old daughter, Angela, who came from a relationship Chris was in before he married Melissa, and now lives with them year-round. The family still want to have more children, Melissa said, and while the procedure is expensive, at about $25,000 per attempt, the family would like to try it.

“I'm enjoying the baby years with Patrick, much more than I even thought I would,” she said. “And we'd love to have a brother or sister for Patrick to play with.”

Patrick remains a happy, healthy child even with his condition, Melissa said. Chung's effort to find the gene behind the disorder may continue to pay benefits years from now, if he, himself, decides to have children, she said.

“Unfortunately, I can't stop it in Patrick,” Melissa said. “Perhaps the pre-implantation diagnosis will be easier 20 years from now, when he's ready to have children.”