Genetic testing yields epilepsy cause sooner
By Molly Rossiter
When Sebastian Hoffpauir was just 2 months old, his parents brought him to the emergency department at University of Iowa Children’s Hospital and learned he had been experiencing seizures.
Though Addie and Cody Hoffpauir were grateful to know that a type of epileptic encephalopathy was the reason behind their son’s symptoms—eyes moving from side to side, almost constant irritability, and occasional stiffening of the arms—a larger question remained: What caused the epilepsy?
As recently as 2010, few parents received an answer. Now, through genetic testing, doctors are able to not only find the cause of certain epileptic encephalopathies, like Sebastian’s, but also determine the risk of the same condition occurring in future siblings.
The Hoffpauirs got their answer with the help of the Iowa Institute of Human Genetics (IIHG) in the UI Carver College of Medicine, where researchers extracted DNA from blood samples from Addie, Cody, and Sebastian, and then tested the DNA for variants that could cause a genetic condition. From there, a team of researchers, scientists, doctors, and a genetic counselor scanned the results to look for variants that determined the diagnosis. Out of the 3 billion DNA bases in the human genome, the team was able to identify the two that were altered in Sebastian’s DNA that were causing his seizures.
“Today, 85 percent of known disease-causing variants, or mutations, are located in the protein-coding regions of the human genome known as the exome,” says Colleen Campbell, PhD, MS, CGC, assistant director of the IIHG and a board-certified genetic counselor. “We do an exome test to see if we can find a genetic cause for the person’s disease or symptoms—in this case, their epilepsy. Finding a genetic cause of a person’s disease may help physicians manage their patient’s symptoms better since we know that patients with certain gene mutations may respond to certain treatments. We can also tell parents the chance of having another child with the same condition.”
Exome testing gives families answers and, in some cases, a road to treatment and therapy.
For Sebastian and his parents, the results were astounding. They discovered Sebastian is one of just three children in the world known to be identified with KARS deficiency. He has two DNA variants in the KARS gene, which disrupts the function of an important enzyme. Individuals with one KARS mutation are healthy; however, an individual who inherits two DNA variants in this gene can develop epileptic encephalopathy.
Campbell says Sebastian’s answers arrived through the persistence and determination of the scientists involved in the testing.
“We initially thought it would be a negative report to send to Dr. Joshi, because we didn’t find anything,” she says.
Charuta Joshi, MBBS, director of pediatric epilepsy in the Division of Pediatric Neurology in the Stead Family Department of Pediatrics at UI Children’s Hospital, was out of the country, as was Richard Smith, MD, director of the IIHG, so the group meeting to discuss the results was postponed for a month.
“Over that next month, we just knew there had to be something there,” Campbell says. “We kept going over the results, looking at everything, including DNA variants that are normally just sequencing artifacts. The day before we were to present the results to Dr. Joshi, we pulled up the raw sequencing data and realized there was a big deletion in the KARS gene.”
It wouldn’t have been detected, Campbell says, if the team hadn’t persevered.
“We knew we had a result that made sense based on the genetics. When Dr. Joshi joined the team meeting she was able to confirm the result made clinical sense based on her patient’s specific epilepsy symptoms.”
Because his diagnosis is so rare, there is no KARS-specific treatment plan for Sebastian. He follows a ketogenic diet, which is a high-fat, adequate-protein, low-carbohydrate plan frequently used in patients with epilepsy to help control seizures.
What’s more, during the post-test genetic counseling appointment when Sebastian’s results were presented to Addie and Cody, they had just learned Addie was pregnant with their second child. Jenni Mancuso, MS, CGC, a prenatal genetic counselor with UI Hospitals and Clinics, helped the Hoffpauirs arrange for genetic testing, which showed the baby is healthy and doesn’t carry the KARS DNA mutations found in Addie and Cody.
“It’s really a great story about how genetic testing is changing their lives,” Campbell says.
The early years
While genetic sequencing isn’t new—the international Human Genome Project, which determined the sequence of the DNA base pairs making up the genome, was completed in 2003—it continues to be refined, developed, and used in research and medical centers around the world.
Next-generation sequencing, a catchall term describing a variety of sequencing technologies, was invented in 2005, though it didn’t really capture the interest of the science community for another two years. In 2007, DNA pioneer James Watson’s genome was the first full human genome to be sequenced using next-generation’s fast sequencing technology. It took just two months and cost only $1 million— about $99 million less than a whole genome sequence done earlier that same year by J. Craig Venter using previous-generation technology.
In 2010, the UI began offering the first clinical next-generation sequencing test in the United States with the OtoSCOPE, which simultaneously screens 134 genes and microRNAs known to cause certain forms of hearing loss.
The first clinical whole exome test to sequence the protein-coding genes in a genome became available in the United States in 2011, and the IIHG was founded a year later.
“At the beginning, we used to be able to sequence only one gene at a time. It was expensive and it took a long time,” Campbell says. “Now we can sequence all of them at once. It took some time to get to this point.”
“This point” makes a world of difference to families like the Hoffpauirs. Just five years ago, before exome sequencing was available, infants and children faced myriad tests —some invasive—to try to determine the cause of their epilepsy: MRIs, EEGs, muscle biopsies, nerve biopsies, other tissue biopsies, blood draws. Answers sometimes took years to find, or were never found. Families could expect tens of thousands of dollars in medical bills, only to walk away empty.
“A child born today doesn’t need to go through all that invasive testing. They don’t need to have muscle biopsies, and parents don’t have to go years thinking, ‘What did I do wrong?’ We can now test all of the genes at once, which is a lot faster, and can help providers either make a diagnosis or rule out several diagnoses at one time,” Campbell says.
Families look ahead
Most families—particularly younger families—want to know if future children could have the same disorder or if it could appear in generations further down the line.
“Where the research comes in is that if we can find a cause, we can treat it accurately, and that’s called precision medicine,” Joshi says. “We are not very far ahead in terms of precision medicine to say, ‘You have this particular genetic problem and I have this fix for that particular problem.’ We’re just not there with the science. But what helps a lot for the families is they’ve come such a long way that this gives them closure as to what caused the illness and they have answers to questions like, ‘Was it my fault? Did this happen with just this baby?’ And if it was just this baby, it opens the future for them in a certain way.
“These families are still always interested in going further,” Joshi says. “One aspect of this is closure, but the second aspect is genetic counseling, with a hope that if we find a cause, possibly we could find a way to treat it accurately.”
Genetic counseling is part of most tests done through the IIHG. A genetic counselor explains medical and genetic information to families in a way that is easy to understand, detailing how genetics affect health. The family’s doctor is invited to the meeting to observe the counseling session and to be “on the same page” as the family.
Unexpected findings may create anxiety about potential illness in the future that families feel may be predestined. For families working with Joshi and Campbell, however, the focus is on the condition they face now. “When we do the testing at the IIHG laboratory, we look only at primary findings,” Campbell says.
“When we do this for Dr. Joshi’s patients, we only look at the genes for epilepsy. We’re not looking for anything else, like cancer, heart disease, diabetes, or Alzheimer’s.”
Paving the way
Despite the availability of exome sequencing and genetic counseling, it isn’t for everyone. At a cost of $5,500 for the three-person test—both parents and the child—or $4,000 for just the child, exome sequencing isn’t ordered in every case, Campbell says.
“Because it’s an expensive test, the physician identifies a possible patient who may need the test, contacts us, and we all decide whether this is an appropriate fit,” she says. “This test is good, but it shouldn’t be ordered for every single patient and does have limitations. Depending on the condition, there might be a better test to start with.”
Some diagnoses can be made without the sequencing. Campbell helps physicians understand the results of genetic testing so they realize how and when to order an exome test.
“The lab can develop a test—a great test—but if the physician doesn’t know when or how to use the test, it’s never going to be used,” Campbell says. “And if patients can’t pay for it, and insurance won’t pay for it because it’s a new technology—and there’s always going to be that lag with something new—then the test isn’t going to get used. So when you develop a new test like this you really have to think of everything: What are all the things that go into this? Do we have a patient education brochure? Do we have the counseling? Are the doctors ready? How does insurance cover this? It’s the whole picture. And it really does take a team to do that.”