Gene sequencing can speed the diagnosis of rare genetic disorders in newborns and find causes of mental retardation in cases with unknown origins, according to two studies that move DNA mapping closer to clinical use.
Researchers at Children’s Mercy Hospitals and Clinics in Kansas City, Missouri, scanned the DNA of sick infants using a new speed-reading method to diagnose rare genetic illnesses in two days instead of weeks, results published in Science Translational Medicine found. Dutch scientists reported in the New England Journal of Medicine how they found genetic answers for 16 of 100 patients with mental retardation of unknown cause.
The new research supports an effort to bring gene-sequencing technology, mostly used in academic, government and company laboratories, into hospitals and doctors’ offices for diagnostic purposes. The studies were made possible in part by technology from San Diego-based Illumina Inc. and Carlsbad, California-based Life Technologies Corp., the two biggest makers of gene-sequencing machines.
“This is the biggest breakthrough in this technology for clinical applications we have seen in a few years,” said David Dimmock, a geneticist at the Medical College of Wisconsin and Children’s Hospital of Wisconsin in Milwaukee, about the study of newborns. “The ability to sequence and interpret a genome in less than week is huge.”
The researchers at Children’s Mercy Hospitals and Clinics created software that takes raw data from DNA scanning machines and combs though hundreds of genetic disorders to spot disease-causing mutations. The system provided likely diagnoses for three of four sick babies in about two days.
The new method has the potential to make genome sequencing practical for neonatal intensive care units, enabling doctors to diagnose mysterious genetic diseases more quickly, said Stephen Kingsmore, director of the Center for Pediatric Genomic Medicine at Children’s Mercy and a study senior author. Fast diagnoses of sick babies may lead to life-extending treatments sooner in some or help avoid futile, costly therapies in others.
Dimmock, who wasn’t involved in the study, said researchers at his institution were working on a similar fast genome interpretation system, but hadn’t published the results yet. “They beat us to the punch,” he said.
The colossal volume of raw data generated from gene sequencing must be analyzed by expert genetic researchers, a process that previously has taken weeks or months.
Kingsmore and his team tackled that issue by devising smart software that allows treating doctors to enter in a sick baby’s symptoms. The software then matches these reported symptoms to known genetic diseases that have similar symptoms, and scans through the baby’s genome results for likely harmful mutations in relevant genes.
“We think this is going to transform the world of neonatology,” Kingsmore said during a conference call with reporters. “Until now, this was just not possible” to get whole genome scan results quickly enough to help sick newborns in intensive care units, he said. “Babies either died or else got better and were discharged home before the results of a gene test were returned.”
For cases in which treatments are available, spotting the cause of a disease sooner may allow treatments to be started before it is too late, he said. Kingsmore estimated the total cost of the test to be about $13,500.
The software so far includes 600 genetic diseases that affect children, Kingsmore said in a telephone interview. His team plans to have all 3,500 genetic diseases where the precise genetic cause is known entered in the system by the end of the year. There are thousands more genetic diseases where the causes are still unknown.
The projected two-day turnaround for the test doesn’t include the time to express-mail DNA samples to Illumina and for the company to send back the results on a hard drive. Including this transit time, the process took about a week, Kingsmore said. Kingsmore said he hopes to achieve the two-day time after Children’s Mercy gets its own copy of the new Illumina machine later this fall.
Though results from the newborn study “push the envelope,” the two-day turnaround represented a “best-case scenario,” that is unlikely to be achieved in most real-world circumstances, said Wendy Chung, a molecular and clinical geneticist at Columbia University.
A more realistic time for genome results would be a week, given practical considerations such as the fact that most hospital labs close over the weekend, she said. This still would be a big improvement over current methods, she said.
Chung also cautioned that there only are a minority of cases in which super-fast gene scans will lead to life-saving treatments. Most severe genetic diseases don’t have good treatments, and the ones that do often can be diagnosed by other methods that don’t require every gene to be scanned.
The study was sponsored by Children’s Mercy and the Marion Merrell Dow Foundation. Illumina provided free DNA sequencing for the babies in the study and several of the company’s researchers were co-authors on the study.
In a separate study, Dutch scientists sequenced the genomes of 100 individuals with mental retardation with no known cause and found genetic reasons for 16 of them.
While more than 400 genetic mutations are known to cause intellectual disability, they are responsible for less than half of the cases, said Han Brunner, a study author and head of human genetics at Radboud University Nijmegen Medical Centre in the Netherlands.
The study shows how gene sequencing can improve diagnosis in patients with mental disabilities. Knowing the genetic origin can help patients and families understand the prognoses and may lead to specific treatment options, the authors said in the study.
“Half of the children and adults with intellectual disability never have an explanation of why they are retarded -- that’s a big problem,” leading many parents on a quest to numerous doctors looking for answers, Brunner said in a telephone interview. “This is what people call the diagnostic odyssey, and people can put that to rest,” by using genetic sequencing, he said.
Researchers scanned the DNA of children with mental retardation, defined as having an IQ of less than 50, as well as their parents, and looked for differences. While all children have some mutations, few lead to intellectual disability, Brunner said. Once the culprits are known, it can help direct some therapies or dietary changes.
“We had two cases where the type of mutation would suggest that you might try a treatment for a metabolic disorder, and another with epilepsy,” he said.
For instance, patients with a mutation in the PDHA1 gene would benefit from a ketogenic diet, which is high in fat, and those with SCN2A mutation should avoid sodium-channel blockers to better control their epileptic episodes and improve cognitive function, according to the study, which was sponsored by the European Union.