New test shows promise in identifying mystery illnesses.
William Smith’s disease has grim milestones.
At two, the Gambrills triplet known as Mick couldn’t walk or talk as well as his siblings. In kindergarten, he started losing language and motor skills. At 12, he needed a wheelchair and a feeding tube.
Doctors at Johns Hopkins Hospital dedicated to treating his symptoms said he had an undiagnosed progressive neuromuscular disease.
But a new test may provide something the family has long sought: a name.
“The idea that there is something out there that can tell you (what’s wrong) is huge,” said Cathy Smith, Mick’s mother. “There is a lot of pain that comes from not knowing what is wrong with your kid.”
The test, called whole exome sequencing, stems from the decades-long push to map all the genes in the human body and translate that knowledge into diagnostic tools and therapies.
The test has been commercially available for less than three years, and doctors say it still doesn’t offer definitive information for most patients with genetic disorders.
The largest published study, by scientists at Baylor College of Medicine in Houston, found diagnoses a quarter of the time, though the success rate appears to be rising.
Data analysis takes three to four months, and the test is so new there is no insurance billing code and often no coverage for the average US$7,000 (RM22,400) cost – even though insurers may pay more for a series of smaller genetic tests and potentially ineffective therapies.
Unlike tests that look for one or a small number of genetic mutations, such as the BRCA test for breast cancer, exome sequencing allows analysis of thousands of genes at once.
The exome is composed of about 22,000 genes, about 1% of the human genome. But it is believed to be where functionally important DNA is housed, and where 85% of harmful mutations are found.
“It’s considered by the majority of physicians as a last-resort test, but maybe it should be the very first test because it’s got a much higher yield and it’s more cost-effective,” said Dr S. Ali Fatemi, paediatric neurologist and director of the Neurogenetics Program at the Kennedy Krieger Institute in Baltimore, a specialty hospital for children with genetic and other disorders.
“It’s extremely important to the family because they know what the cause is,” he said. “It may not lead to therapy – many of the diseases do not have therapies – but it affects management of the patient.”
Fatemi said patients come to Kennedy Krieger after they have gone to specialists who have ordered tests piecemeal in the hunt for answers.
The institute has diagnosed about 40% of 150 children given the exome test and has obtained useful information in another 30%, he said. Four new diseases were identified.
Mick was referred to the institute six years ago, and doctors believe his test will reveal useful information.
Even absent a cure, doctors can often improve care with drugs, therapies or other tests, Fatemi said.
For example, if doctors know liver disease is linked to the gene mutation, they can begin monitoring and treatment early.
Unhelpful or harmful, often expensive, treatments can stop and families can end their “doctor shopping” for a diagnosis, he said. Families may also learn their odds of having other children with diseases.
Simply identifying the disease is “quite a strong emotional benefit to families”, who often form communities surrounding common gene mutations so they can support and guide one another, said Daniel MacArthur, a geneticist at the Broad Institute of MIT and Harvard who researches rare muscular diseases.
And there are societal benefits, he said. For example, testing already found muscular dystrophy manifests itself differently in patients because they have different harmful gene mutations.
MacArthur’s lab plans to sequence 1,500 exomes in the next year to uncover all of them, potentially prodding pharmaceutical companies to research drugs for the disease subsets.
“It’s safe to describe exome sequencing as transformative,” he said.
The tests are done by taking blood samples from the patient and family members to rule out mutations that are not harmful.
Data analysis is likely to become more efficient and effective over time as the test and pool of trained scientists evolves, said Dr Leslie Biesecker, a researcher at the US National Human Genome Research Institute.
Maybe in a couple of years, scientists will routinely test not only the exome, but the entire genome, he said.
For now, he said the exome test doesn’t even include the entire exome, but up to 92% of it.
There are about 20 well-established private and academic labs that handle testing and the expensive, complex analysis, said Biesecker, chief and senior investigator of the institute’s Medical Genomics and Metabolic Genetics Branch.
The US National Institutes of Health funded some of the labs and has been training more scientists.
Mapping the entire human genome, considered complete in 2003, may have been a slog, Biesecker said, but the pace of technology continues to accelerate.
“In 2003, no one said we’d be doing an exome sequencing routinely to figure out neurological disorders, and we are,” Biesecker said. “We’ve made more progress than we ever thought we would.”
Mick’s Kennedy Krieger doctor, Richard Kelley, who has spent years studying the boy’s biochemistry, believes useful information would be uncovered by the test.
He said Mick’s condition is metabolic, meaning the chemical process his body uses to make energy from food is disrupted. The enzyme that breaks proteins down into amino acids used to support bodily processes won’t switch off as normal. Diet changes, supplements and medications haven’t helped.
Mick likely has a rare gene mutation inherited from both parents, who are recessive carriers, said Kelley, who ordered the exome test after narrowing the suspects to two dozen genes.
If he learned the culprit, Kelly said, treatment could likely reverse many of the boy’s problems, possibly allowing him to talk, use his hands and do more for himself. The cost of his care could drop sharply.
Without treatment, his seizures could escalate, damage his still-developing brain and further rob him of abilities, which include smiling, watching activity around him and bonding with family, Kelley said.
The window for improvement dims at puberty, and complications from his weakened state, such as pneumonia or aspiration, could imperil him.
“I can’t guarantee I can fix Mick’s problems if I got a diagnosis, but there is a reasonable chance I could,” said Kelley.
“Mick is a very nice kid even though he can’t do very much, and has an especially wonderful relationship with his father,” he said. “One feels more motivated in a family like that and the academic puzzle becomes more frustrating.”
Cathy Smith and her husband, Michael, are hopeful the test helps other children as well. Cathy, a clinical laboratory scientist at Hopkins, knows research is cumulative. But that doesn’t mean the Smiths don’t badly want a name for Mick’s disease – and a treatment.
“I’ve had to adapt each time to what my son has lost,” she said. “It would be amazing to see my son walking again or running. But I’m fine if he doesn’t walk again. I just want him to live.” – The Baltimore Sun/McClatchy-Tribune Information Services