DNA Sequencing: Is Science Fiction Becoming Medical Fact?

In two papers in major scientific journals, researchers today suggested pushing DNA sequencing into more routine use in the clinic, and not just as a research tool.

Dutch researchers are proposing that DNA sequencing replace older forms of genetic tests for diagnosing the cause of severe intellectual disability, the second time in a day that researchers have pushed the emerging technology as a first-choice diagnostic test for severe illness. Those results were published this evening in the New England Journal of Medicine.

"This is the new test for intellectual disability. There is no doubt about it," says Han Brunner of the Radboud University Nijmegen Medical Center, one of the Dutch study's authors. "This is a paradigm shift to genome-first medicine for patients who have complex problems that will not be easy to diagnose by conventional strategies."

Earlier today, a study in Science Translational Medicine proposed that DNA sequencing could become a standard first-choice test for infants in neonatal intensive care units, because a combination of new software and hardware could allow doctors to get results in just 50 hours, answering questions about what is making a baby sick far faster when time is of the essence.

"The bottom line of our research is that it’s now feasible to decode an entire genome and provide interim results back to the physician in two days," Stephen Kingsmore, the director for the Center for Pediatric Genomic Medicine at Children’s Mercy Hospitals and Clinics and a lead author of the paper, told reporters on a conference call yesterday. "We think this is going to transform the world of neonatology, by allowing neonatologists to practice medicine that’s influenced by genomes."

Brunner and his colleagues used a technique called exome sequencing, which extracts only known genes from the vast expanse of DNA in the human genome as a way to reduce sequencing cost. The Dutch researchers sequenced 100 patients with IQs of less than 50 and their unaffected parents. The technique found genetic mutations known to cause intellectual disability in 16 patients, and genes of unknown function that appear to be the cause in another 22 patients. This is at least as good as the current genetic technology available for identifying mutations in patients with severe intellectual disability.

In only two patients did the diagnosis change the way doctors were treating them. For one, a change in diet may prove helpful; for a second, the genetic diagnosis will direct which types of epilepsy drugs the patient will receive.

But there are several other benefits to diagnosis. Parents often desperately search for one, just because they want to know what went wrong. They also are often terrified of what will happen if they decide to have another child, and the test can tell them whether they are carrying a gene that caused the defect.

In most cases in this study, a bad copy of a gene from a parent was not to blame. One surprise is that most of the mutations that caused these cases are brand new – they didn't exist in the parents' genomes. In three cases, the gene was inherited from the mother via the X chromosome; because boys only have one X chromosome but women have two, such a bad copy is deleterious in boys.

On average, every child is born with one brand new genetic mutation. Most of them don't matter. But it may be, Brunner says, that there are 1,000 genes in which such a mutation can cause mental disability. So some unlucky kids suffer just because of the background mutation rate.

Brunner says that the cost of doing the exome sequencing was about $2,400 per patient sequenced; that doesn't include the cost of analysis. But that part of the cost is likely to come down. The sequencing in this study was done with the SOLID system made by Life Technologies. Using Life's forthcoming Proton system or the more widely used HiSeq from Illumina, the dominant player in DNA sequencing, should bring costs down further.

"Exome sequencing has already entered the clinical diagnostic realm," says Heather Memford, a pediatrician and geneticist at the University of Washington who wrote an editorial in NEJM about the result. "The question for us as clinicians is for which patients do we use it now versus later."

The researchers in the Science Translational Medicine paper, working directly with Illumina, first developed a diagnostic test that captured 600 genes that were likely to be the reason the babies wound up in the NICU. That panel is being sold as a kit by Illumina and will likely be used by some commercial laboratories that have government certifications to do diagnostic testing. But then they sequenced the whole genomes of two children who had already died and another five who were alive but undiagnosable. In all but one case, they were able to find a gene that either is or is likely to be causing the child's illness. The cost per test, including the cost of analyzing the data, was $13,500. That might sound like a lot, but the cost of a day in the NICU is $8,000.

The biggest question remains how quickly tests such as this will move from being essentially research tools to being real clinical tests that are conducted in commercial laboratories and are paid for by insurers. There are some accounts that this is starting to happen, but Memford says she still does all her DNA sequencing using research, not insurance, funding. Kingsmore says that he's not sure how the test will reach patients, but he thinks that Children's Mercy may eventually be able to offer it as a service to other hospitals.