Kira Walker was born with a condition that stumped her doctors. Her pancreas was pumping out too much insulin, keeping her blood sugar dangerously low.
Medications weren’t working. If her blood sugar remained uncontrolled, she risked brain damage. Surgery to remove her pancreas would leave her diabetic for life.
“She would wake up absolutely starving, screaming — her blood sugar was so low,” said her mother, Amanda Webb. “It was her body saying, ‘I need nutrients or I’m going to die.’”
Then doctors at Children’s Mercy Hospital used new technology to quickly sequence Kira’s genome, the complete set of her DNA, including the 20,000-plus genes that direct the work of every cell in the body. They discovered a mutated gene that was making portions of Kira’s pancreas hyperactive. Surgeons removed 40 percent of the organ to bring her insulin levels down to normal.
Now nearly 2, the rambunctious Lake Waukomis toddler is healthy and happy and tough enough to mix it up with three older siblings.
Kira is a prime example of the promise genomic sequencing holds for diagnosing critically ill infants and discovering genetically based conditions that routine blood tests used to screen every newborn baby cannot detect.
Standard newborn blood tests look for chemical changes and typically screen for a few dozen disorders, such as sickle cell anemia and cystic fibrosis, that are caused by a gene mutation. But researchers have tallied more than 6,000 such inherited disorders caused by a single mutated gene. And other genes are associated with higher risks of certain conditions, such as heart disease.
Imagine being able to anticipate your child’s health all the way to adulthood.
With the time it takes to sequence a human genome being cut from years to days and the price dropping from $95 million at the turn of the century to less than $5,000 last year, scientists — and parents — are thinking along those lines.
Last year, Francis Collins, director of the National Institutes of Health, predicted that the price of genome sequencing would soon drop below $1,000. And over the next few decades, every baby’s genome will be sequenced and used “to shape a lifetime of personalized strategies for disease prevention, detection and treatment,” Collins wrote in a Wall Street Journal op-ed piece.
But this brave new world is fraught with technical and ethical issues that have other scientists questioning whether every baby should have its genome sequenced and what information children and parents should receive about the results.
Every individual’s genome is loaded with “variant” genes, and harmful mutations make up just a small fraction of them. Researchers have only begun to catalog which variants cause problems.
Questions arise about the wisdom of telling parents and children about conditions for which there’s no effective treatment or of letting them know about disorders that won’t affect a child until adulthood.
Telling a child that he or she will develop the incurable brain deterioration of Huntington’s disease in the prime of life might offer time to prepare for the worst. And the diagnosis could help parents, who also carry the mutation, weigh the risks of having more children.
Or it might turn out to be more like a curse out of a fairy tale, said Josh Petrikin, a neonatologist at Children’s Mercy.
“Children have a right to an open future, not to be treated as a ‘fragile child,’” he said.
No easy answers
Children’s Mercy is one of four medical centers across the country that are part of a five-year, $25 million NIH research project to study how genomic sequencing might best be used among newborn children.
The centers will be seeking parents to volunteer to have their babies’ genomes sequenced, comparing the results to those of conventional blood tests, following how the sequencing affects the children’s medical care and surveying parents on the effect genomic sequencing has on relationships with children and spouses.
The project is an attempt to gain a scientific understanding of the issues before falling prices make genome sequencing of newborns a fait accompli. It grew out of discussions the NIH had with outside experts in 2010, a year when the cost of sequencing fell from about $47,000 to less than $21,000.
“Just because it’s inexpensive doesn’t mean it’s the best way to go. There is a need to look at what the concerns are and is it appropriate to do,” said Tiina Urv, program director for the Eunice Kennedy Shriver National Institute of Child Health and Human Development, which along with the National Human Genome Research Institute is financing the research.
“No one has explored in infants how clinically relevant the sequencing information is,” Urv said. “Are you looking at just sick kids or also healthy kids? What do parents want to know? The NIH doesn’t magically have the answers.”
At the University of California, San Francisco, researchers are making a head-to-head comparison of conventional blood tests and genomic tests. They’re delving into the California health department’s repository of newborn infant blood spots, the samples made by placing small drops of blood on filter paper, to repeat the routine tests on 1,400 children and sequence their exomes — the part of the genome responsible for most genetic diseases.
The researchers also have access to records on which children developed genetic illnesses, so they will be able to gauge the accuracy of the blood tests and see whether sequencing improves on it.
To catch as many cases as possible, newborn screenings have deliberately low thresholds for positive results, said UCSF researcher Barbara Koenig.
That means there are many false positive results that can leave parents anxious. In some cases, a gold standard test can be used to verify the results; in other cases, not. Genome sequencing may prove useful as a verification, Koenig said.
“I think our group doesn’t see this as a substitute for conventional tests for healthy kids, but that doesn’t mean there won’t be pressure from companies offering parents tests for their children.”
Too much information?
How much genetic information parents and children should receive is a question being addressed at all four research centers. Each is taking a different approach.
“Is this a positive thing? We hope so. Or are there some families who find it upsetting or confusing?” asked Alan Beggs, a genomics researcher at Boston Children’s Hospital.
As part of the NIH project, Boston Children’s and Brigham and Women’s Hospital, teaching hospitals of Harvard Medical School, are offering parents of both healthy and hospitalized newborns the option of genome sequencing.
The hospitals will follow up with the parents to see how the information has affected their children’s medical care and relationships within their families.
The Boston researchers weighed whether to tell parents if their child has a genetic condition that could affect them in adulthood.
“After all, parents may also develop these conditions, such as breast cancer” from mutated BRCA genes, said Ingrid Holm of Boston Children’s. “The best interest of the child may be to have their parents around.”
But the researchers chose to protect the future autonomy of the children by not disclosing information about what may be in store when they are grown.
“We don’t want to take away their right to decide for themselves” whether they want to know, Holm said.
Researchers at the University of North Carolina plan to offer parents of newborns the option to have their babies’ exomes sequenced and to receive information about it from a large menu of options.
To make sure that families receive information only about gene variants that are likely to cause diseases, the UNC researchers are going gene by gene, scoring them for what is known about their role. They have looked at several hundred conditions so far and hope to have about 1,000 done by the time they start enrolling families.
“Ninety-nine percent of DNA variations don’t cause a problem,” said UNC researcher Cynthia Powell. “We’ll have a very high threshold and only report out variations we’re confident are associated with a disease.”
Parents may choose to be informed just about diseases already covered by routine blood tests or to receive information on all childhood diseases, either treatable or untreatable.
They also may choose to learn whether their child is a carrier of a disease gene or has a treatable condition that will appear in adulthood.
“For years, people have said you shouldn’t do genetic testing in children for adult onset conditions,” Powell said. “But there have been few studies of parents’ choices and on the ramifications for the children. Will they be angry with their parents? Will they face discrimination?”
Powell already has a sense that concerns about what parents may want, or not want, to know about their children’s genomes may be more academic than real. A series of focus groups with about 1,000 parents UNC has done in collaboration with the RTI International research institute has found that whether a condition is treatable is not an issue for most parents.
“A lot of parents want to know everything,” Powell said. “They don’t like that a researcher has information they’re not giving them.”
At Children’s Mercy, parents and doctors in the NIH project face more urgent choices. The hospital is sequencing the genome of severely ill infants like Kira Walker whose conditions have defied diagnosis. It’s applying technology it helped develop that can sequence a genome in as little as 50 hours.
Children’s Mercy began using the technology several years ago and already has results on some infants, like Kira, whose genome was sequenced before the NIH study started.
Children’s Mercy researchers reported on their first 35 genome sequencing cases in a study published last month in The Lancet. Rapid genomic sequencing was able to diagnose 20 of the infants. In 13 of the cases, the new diagnoses led to significant changes in treatment, such as different medications, surgery or changes in the baby’s diet.
“Until the hospital started this program, most of these children wouldn’t have gotten a diagnosis and would have died without one,” said Stephen Kingsmore, who directs the Children’s Mercy genomics program.
In four cases, including Kira’s, a diagnosis from genome sequencing led to a new course of treatment and dramatic improvement in the babies’ condition.
But in most cases, no treatments were available. Half the babies died within 120 days.
Even for the families of these infants, the diagnoses were still valuable, Kingsmore said.
“Many of these parents are racked with guilt. Is it God is angry with them? Did Mom smoke a cigarette and drink a glass of wine during pregnancy? No, it’s just a disease. It’s nothing they did. It’s a mechanical disease,” he said. “That can help parents work through it.”
And having a diagnosis can end the anxieties and frustrations of what doctors call the “diagnostic odyssey” of inconclusive tests and futile treatments.
Shortly after Eliana Lewis was born in December 2013, she started having seizures.
“I was holding her one day and I noticed this weird thing,” said her mother, Michelle Lewis of Kansas City. “She would move her head a little bit and move her arms and legs a little bit. I started watching the clock. It was happening every four or five minutes.”
Neurologists at Children’s Mercy discovered that what Lewis had noticed was happening to her daughter around the clock.
“Then came a plethora of tests,” Lewis said. “Viral, bacterial, endocrine, metabolic. Hundreds. Everything they thought of.”
Some of the tests took weeks for results.
“We had to watch our daughter seize every day for six, eight weeks. Everything was coming back normal, but we knew it wasn’t normal.”
Doctors decided to sequence the genomes of Eliana and her parents. The unhappy results came back about a week later.
Eliana has Ohtahara syndrome, a form of epilepsy with severe brain damage that often leads to an early death.
“You go through the grieving process. You have expectations for your kid,” Lewis said. “Without this rapid genome sequencing, we would have sat in that undiagnosed purgatory for another two months. Having it, we know what we’re up against.
“Now we can go into battle for our child.”
Michelle Lewis is part of an organization for parents of children who have a harmful mutation of the same gene, SCN2A, that is causing her daughter Eliana’s epilepsy. Information about the group, FamilieSCN2A, can be found at SCN2A.org.