Scanning the genes of children with inherited brain disorders pinpoints the precise cause more than a quarter of the time, often changing the diagnosis, according to one of the largest studies of child DNA sequencing.
The study published today in Science Translational Medicine examined the genes in 118 people with child-onset brain development disorders where obvious causes had been excluded. Researchers found new disease-causing mutations in 22 patients. In 10 more people, the scans found rare genetic diseases that had been misdiagnosed because symptoms were atypical. In two cases, the new diagnosis led to changes in treatment.
The study “is a remarkable demonstration of the power of sequencing in the clinic -- precise, molecular, root cause diagnosis,” said Eric Topol, a professor of genomics at the Scripps Research Institute in San Diego in an e-mail. “Virtually all diseases” will be more precisely defined through gene sequencing in the not-too-distant future, he wrote.
The research shows how often DNA scans can improve diagnosis in kids with brain disorders such as autism, severe epilepsy, or intellectual disability, said Joseph Gleeson, a child neurologist and study author. Brain development disorders afflict as much as 4 percent of children and are often genetic, yet the precise causes can be elusive, he said. Sequencing lets researchers examine all genes for abnormalities, instead of testing for one genetic disorder at a time as done now.
The biggest surprise is that some children with genetic brain disorders have diseases that have been known for a long time, said Gleeson, of the University of California, San Diego. The kids weren’t diagnosed correctly because “frequently their symptoms don’t match those in the textbook.”
As a consequence, doctors may not have thought of ordering gene tests for those rare diseases, Gleeson said.
“This is taking the whole medical field by surprise,” Gleeson said. “It used to be that the gray-haired professor was the gold standard, and if patient didn’t respond to treatment then patient was an anomaly.”
Gene sequencing eliminates the problem of misleading or vague symptoms by testing all genes, Gleeson said. “It will change the way we practice medicine,” he said.
The study follows research published in the June issue of the Journal of Medical Genetics, where scientists at Duke University used sequencing to diagnose six of 12 kids with genetic disease of unknown origin. In five of the cases, the children had had mutations in genes known to cause disease, said David Goldstein, the study leader and director of the Center for Human Genome Variation at Duke’s School of Medicine in Durham, North Carolina. One child had been diagnosed with autism, yet turned out to actually have Pitt-Hopkins Syndrome.
For diagnosing pediatric genetic disease, sequencing “is an absolutely transformational technology,” Goldstein said in a telephone interview.
“It is a much larger, more important application than people were anticipating,” Goldstein said. Today’s study confirms that sequencing can revise the diagnosis in many cases, he said.
Gene sequencing produces huge volumes of data that can be hard to interpret, UCSD’s Gleeson said. In the Science Translational Medicine study released today, Gleeson and colleagues simplified the analysis by studying sick children of married cousins in countries in the Middle East, North Africa, and Central Asia, where such relationships are common. The families had multiple relatives afflicted by genetic disease, making it easier to find inherited mutations, he said.
The California researchers worked with scientists at Broad Institute in Cambridge, Massachusetts, to scan the genes in the 118 patients. This technology is called exome sequencing and looks at the 1 percent of the DNA that contains genes that create proteins. The researchers used equipment from San Diego-based Illumina Inc. and elsewhere to perform the sequencing.
Translating the sequencing technology into everyday medical practice will be a challenge, Gleeson said, as doctors are “sorely prepared” for the data onslaught. “We don’t have computational algorithms that can manage the analysis and we don’t have doctors that can interpret the data,” he said.
Duke’s Goldstein said the technology can be applied rapidly. ‘There is nothing that prohibits this from being done on scale,’’ he said.
The technology may save money because the raw cost of sequencing the 1 to 2 percent of the genome that contains genes now cost less than $1,000, not including cost of interpreting the data, Goldstein said.
For some patients “it is clearly less than has been spent on gene-by-gene tests” that cost several thousand dollars per gene, Goldstein said.