There are more than 7,000 rare disorders, and many cannot be diagnosed in a doctor’s office.
That’s why genetic sequencing is so important.
Now The Jackson Laboratory in Farmington is able to sequence the entire genome, an advance that will roughly double the number of rare diseases that can be positively diagnosed. It’s the only whole-genome sequencing test offered in Connecticut.
Until next-generation genome sequencing became available about 10 years ago, there was no way for many rare disorders to be accurately diagnosed, according to Melissa Kelly, clinical laboratory director at the Jackson lab.
Previously, Sanger sequencing, developed in 1977, was too slow to be useful.
“There’s been studies on this actually, how many missed diagnoses patients will have prior to getting their actual diagnosis from a genome, and it’s something like seven,” Kelly said.
“It’s crazy how many times these patients get told the wrong thing, or get told nothing,” she said. “No one can tell them an answer at all. And that’s the problem with current clinical care is the genome isn’t the first step and so these patients are going through test after test after test and being told different things and not really getting the right answer, and that takes a toll on the patients and on their family.”
There are as many as 7,000 rare diseases, according to the National Organization for Rare Disorders. A rare disease is one carried by no more than one in 200,000 Americans, and includes Duchenne muscular dystrophy, hemophilia, cystic fibrosis and Hodgkin’s disease, according to the organization’s database.
Not all rare diseases are genetic, but many are, Kelly said. Sometimes sequencing is called for because of “unusual facial characteristics,” she said.
“It might be that their nose is a little misshapen or their forehead’s really tall,” she said. “Ears are rotated funny or something. So it’s just the facial features that are ‘normal.’”
The issues one patient has could resemble more than one disease, so until you know the genetic mutations, “you don’t really know, can you do anything about it. It’s just sort of a guessing game,” she said. One example is Niemann-Pick disease.
Before the whole-genome sequencing was developed, the best that next-generation sequencing could do was to sequence the exome, or the proteins in the gene, which, while it contains most of the information, is about 1.5% of the genome.
That yielded a positive diagnosis about 25% of the time. “The rest of them are left on what we call the diagnostic odyssey,” Kelly said. So they’re getting test after test after test, but never getting a diagnosis. And those are the perfect candidates for whole-genome sequencing,” which can get an answer at least 40% of the time.
“There have been some reports where there are situations where they’re looking at a particular cohort where they have gotten higher, but I would say across the general rare disease scope, I wouldn’t say higher than 40 or 50%,” Kelly said.
“It seems crazy because, if we’re sequencing the entire genome, why aren’t we capturing 100%, right? So that’s another area that’s still being explored,” she said.
“One of the issues is, there are factors in the environment that can affect genes,” known as epigenetics, she said. “That’s a whole area of study that’s going on now. And I’d love to bring on clinical tests that can target more of the epigenetic and other factors to diagnose additional patients as well.”
The bottom line is to help families “who have been searching for oftentimes years to find the answers,” Kelly said. “Even when those answers mean it’s not treatable, and they really can’t do anything about it, to have the answer is just invaluable to them. That’s what this is for. We want to get patients the answer.”
The Jackson lab’s research into rare diseases goes further at the Rare Disease Translational Center in Bar Harbor, Maine.
“What we do is we take that genetic information, and we engineer that mutation into a mouse model,” said Cat Lutz, vice president of the center. “And that creates essentially a patient avatar. We have mouse models for cystic fibrosis. We have mouse models for Duchenne muscular dystrophy. We have mouse models for Huntington’s and ALS and Friedrich’s ataxia.”
This way, the genetic mutations can be studied “to understand genetic pathways,” she said. “We can look at disease course. … We can find so much about what that patient is experiencing just by looking at the avatar of the mouse. And then, most importantly, we can take therapeutics, like gene therapy … FDA-approved drugs, and we can test them in the mouse and see if there’s a benefit that might be had in the patient.”
The center has helped develop three FDA-approved drugs for spinal muscular atrophy, which causes death among young children.
“If you don’t treat an SMA baby in the first few weeks of their disease, they’re not necessarily going to have the benefit of the therapy,” Lutz said. “If a therapy’s given early, patients can lead almost a normal life. If it’s given too late, it can have very little effect or no effect at all, and patients can be wheelchair-bound or succumb to the disease perhaps a little bit later.”
‘The diagnostic odysseys’
One problem with genetic sequencing is the expense. Next-generation sequencing of just the exome can cost up to $4,000, according to Dr. Ed Neilan, chief medical and scientific officer of NORD, and the full genome sequence will cost much more than that.
A spokeswoman for The Jackson Laboratory issued a statement about pricing, saying, “While we do not comment on specific customer pricing since it can vary with testing volume and turnaround time requirements, as a nonprofit biomedical research institution, our focus is and always has been on improving human health. JAX endeavored to make this crucial testing available as cost-effectively as possible knowing the financial responsibility will, in many cases, be patient-based.”
Lutz believes every baby should have its genome sequenced in order to avoid the emotional pain and hardship families experience when they are faced with an unknown disease.
“I think it is economically possible,” she said. “You think about the cost of that sequencing compared to the cost of doctor’s visits, emergency room visits, and then the sustainability of the health care of a very sick child. I think it’s very worth it.”
Concerning the lack of insurance coverage, Lutz said, “I think that’s where we have some changes that we need to make in our health care system, quite frankly. I mean, we screen for other things, right? We screen for breast cancer. We screen for colon cancer. … We’ll even screen prenatally for cystic fibrosis and I don’t think it makes sense to have tests that are done one by one.”
She added, “Wouldn’t it be more economical to try to take a single drop of blood, do the whole genome sequencing and try to figure out if this child is going to have Batten’s disease or some other inborn error of metabolism and not spend the six years and the doctor’s visits and the diagnostic odysseys … I mean from a health care perspective.”
Neilan cautioned not to set expectations too high with the whole-genome sequence test compared to the former test. “You get maybe 80% of the answer from looking at that 1.5% of the DNA, which is why it’s cheaper and more common right now to order a whole exome test,” he said.
“I think though the world is sort of waiting for a whole-genome test to become cheap enough that you could order it for the same as an exome,” he said.
Ed Stannard can be reached at estannard@courant.com.
