For Angela and Earl McWilliams, it had been a mystery from her birth why their daughter, Millie, kept running into one medical calamity after another.
She was born with diabetes. She had trouble eating. She needed surgery after the bones of her skull fused prematurely. She couldn’t walk, and she quickly lost what little speech she had. Doctors determined that she was autistic.
But after years of brain scans and endless blood work, doctors couldn’t identify the cause of 9-year-old Millie’s condition.
Then researchers at Children’s Mercy Hospital mapped Millie’s entire exome, the 1 to 2 percent of the human genome responsible for most genetic disorders. It revealed an exceedingly rare gene mutation, found in less than one in a million births. While there isn’t a special treatment for it, at least it now has a name: Bainbridge-Ropers syndrome.
“It’s like you’re in a dark room and a light, at least a dim light, starts to go on and you can see things,” Earl McWilliams said. “This is a beginning. I like to call it a unique beginning.”
On Wednesday, Children’s Mercy researchers published their groundbreaking findings on Millie McWilliams and 118 other children with neurological and developmental disorders, showing that mapping a child’s complete genetic information can quickly identify rare disorders that otherwise might go years without a definitive diagnosis.
In some cases, the tests were able to change the course of a child’s treatment for the better, the researchers found. They could have cut short years of inconclusive testing that ran into tens of thousands of dollars. And they gave parents answers where before there was only doubt.
That can be very meaningful for families that have gone on a “diagnostic odyssey” seeking reasons for their child’s condition, said Sarah Soden, lead researcher of the study published in Science Translational Medicine. “They can stop asking themselves, ‘Why?’”
“We were able to understand more of why (Millie) was going through the things she was that had appeared to be random,” Angela McWilliams said.
The genetic findings also relieved the McWilliamses, of Kansas City, of the feelings of doubt and guilt they had been carrying since Millie was born. Angela McWilliams has diabetes; could that have been why Millie has it? Did Millie inherit a genetic disorder from one of them?
“We were feeling like we were the cause of it,” Earl McWilliams said. “Dr. Soden let us know neither of us had anything to do with it. Neither of us had the gene.”
“There’s a phrase we use, ‘being able to put a name on it.’ It brings some closure, even if there isn’t a treatment,” said Mary Dunkle of the National Organization for Rare Disorders.
“For people with rare disorders, getting an accurate and timely diagnosis is a huge problem, and it creates a lot of anguish for patients and families. They go on an emotional roller coaster from doctor to doctor, from test to test, thinking they may have a lead.”
Soden said the Children’s Mercy researchers conducted the study to see how useful genomic sequencing would be in a broad array of children with neurological disorders. “Does this type of testing make sense? Is it useful? Is it worthwhile?”
More than 2,400 genetic neurological disorders already have been identified, and that number is growing. That makes it increasingly impractical to test patients for one genetic disorder at a time, particularly as the cost of genome and exome sequencing continues to decline, the researchers concluded.
“We’re in an era of a lot of new genetic disorders being discovered all the time,” Soden said. “A lot of conditions we found (in patients) were just discovered as we were doing the research.”
The Children’s Mercy researchers ran genetic tests on children with a variety of disorders such as intellectual disabilities, seizures, autism, developmental delays or poor muscle tone. They included 85 families with children who were, on average, about 7 years old and had never received a clear diagnosis before, as well as 15 families of infants who were born with symptoms and were in intensive care. Some of the families had more than one child enrolled in the study.
For each of the older children, like Millie, their whole exome was mapped. The infants had their whole genome mapped using rapid sequencing technology developed at Children’s Mercy and that is unique to the hospital. The technology, called STAT-Seq, can sequence an entire genome in about 50 hours.
The genomic tests yielded diagnoses for 73 percent of the families with critically ill infants and for 40 percent of the families of the older children. The families of the older children had previously spent an average of $19,100 — two families more than $50,000 — on tests that failed to yield a diagnosis.
After receiving the definitive diagnoses, doctors started or planned new drug or dietary treatments for 10 of the children.
Soden singled out one patient, a 6-month-old girl, whose muscle tone was so poor she couldn’t hold her head up. The genomic test discovered that she had an extremely rare metabolic disorder. She was started on a nutritional chemical used as a food additive that European researchers had reported to be effective.
The girl is now a little over a year old. Her muscle tone has improved, her eyelids no longer droop and she was able to return home.
“We don’t want to overstate this,” Soden said. “But when we can make a difference like that, that’s what drives us to keep looking for answers.”
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