Genetic testing helped diagnose Nolan Wood, 3, with KCNQ3 epilepsy.
Even though Nolan Wood hadn’t experienced a seizure in more than two years, his parents still had questions about their son’s future.
“We wondered if there were others out there that have what Nolan has,” said Emily Wood, Nolan’s mom. “If so, what does their life look like?”
The Woods’ search for answers began when Nolan, 3, was diagnosed with infantile spasms and regression of his motor skills when he was 6 months old. Before receiving seizure medications, Nolan had hundreds of daily subtle, reflex-like seizures. Due to the regression of his motor skills, he had stopped rolling over, smiling and crying. A condition known as cortical visual impairment had also rendered him legally blind.
“When I first met Nolan, his epilepsy was under control, but the Woods had many other concerns about his progression,” said Dr. Edward “Rusty” Novotny, director of Seattle Children’s Epilepsy Program. “The information we could provide through conventional diagnostic tests, such as EEGs, only provided a limited explanation of his disease. The Woods sought information that could only come from knowing if there was a genetic cause of Nolan’s epilepsy.”
An end to the diagnostic odyssey
According to Novotny, this ‘diagnostic odyssey’ – the endless cycle of diagnostic testing leading to inconclusive answers – is often a source of anxiety for families. The Woods, having experienced their fair share of tests since Nolan’s initial diagnosis, can relate.
“That limbo of researching, speculating, trying medications and jumping from specialist to specialist is physically and emotionally exhausting,” said Wood.
At one of their early visits, Novotny suggested the family may benefit from genetic testing. He referred them to the Epilepsy Genetics Clinic – a pilot program underway at Seattle Children’s.
The Epilepsy Genetics Clinic brings together the expertise of neurologists, neurogeneticists and genetic counselors to offer genetic testing and counseling to young epilepsy patients with a high likelihood of having a genetic cause. The clinic is part of the comprehensive care Seattle Children’s offers to families with epilepsy, including neurosurgery, electrophysiology and developmental pediatric services.
Since launching the clinic in April 2016, 40 patients have received genetic testing. In about 50% of patients, testing uncovered previously unknown meaningful genetic information about the child’s epilepsy.
Getting meaningful results with genetic testing
Dr. Heather Mefford, a neurogeneticist in the Epilepsy Genetics Clinic, says these early numbers provide promising support for using DNA sequencing when first diagnosing epilepsy in infants and toddlers.
“By taking a thoughtful approach to which patients receive genetic testing, the probability we can reach a genetic diagnosis is much higher,” said Mefford. “This gives the families we work with a known genetic cause of their child’s epilepsy and can help guide immediate and future care.”
Mefford devotes her research to the discovery of novel genetic causes of pediatric epilepsy. She explains that for some, a genetic diagnosis can lead to a change in the patient’s medications, or can better predict the long-term health needs of the patient. Ruling out an inherited mutation can also help parents plan for future children.
When the Woods saw Mefford in the Epilepsy Genetics Clinic, she started by looking for any genetic clues behind Nolan’s epilepsy.
A broad assessment of the patient helps Mefford recommend the type of genetic test most likely to yield a genetic diagnosis. Whole exome sequencing, the broadest genetic test available, analyzes all 20,000 genes. On the other hand, an epilepsy panel sequences approximately 1,400 genes with known ties to epilepsy.
Before deciding on a test for the Woods, Mefford consulted with Novotny to learn about Nolan’s seizures and other contributing medical conditions. She also referred to a detailed family history a genetic counselor prepared with the Woods earlier that day. Meanwhile, the clinic worked to expedite pre-authorization from the Woods’ insurance provider to cover the cost of the test – an important step given genetic testing remains costly and coverage can vary vastly from provider to provider.
The first reported case of a KCNQ3 mutation
Nolan and his parents submitted DNA samples for whole exome sequencing – the test their insurance provider ultimately authorized. About three months later, which is the average time it takes to get results, Wood received a call from their Seattle Children’s genetics counselor.
They had found that the cause of Nolan’s epilepsy, developmental delay and regression was a spontaneous genetic mutation in the KCNQ3 gene. As Nolan was the only reported case of a KCNQ3 mutation at the time, little information about the diagnosis exists.
“It’s not a cure and it’s not a treatment, but it does give us an answer that we didn’t have before,” said Wood. “We now have a source that we can link everything else back to, and that’s a comfort.”
Since receiving the test results, Wood has connected with two other families with the same diagnosis.
“It’s incredible to have the chance to make sense of the condition with other families,” she said. “We’re finding that not having any others to look to for what to expect down the road can be a good thing. It means our kids have the chance to set their own bar for what’s possible.”
Wood has also started a KCNQ3 Facebook group with the hope that as genetic testing is more widely used to diagnose epilepsy, others with KCNQ3 mutations can connect to learn from each other. She draws inspiration from a group devoted to children with KCNQ2 mutations – a similar, though more common condition. What started as an online community organized by parents, the group is now an international consortium with registries and research programs to develop better treatments and a cure.
“You can’t underestimate the power of having an answer,” said Mefford. “Increasingly families use that information to connect with other families around a genetic diagnosis. That experience is really important for families to share. It can also open the door to future research opportunities.”
Genetics will one day direct therapies
While it’s not always possible today, the long-term hope of the Epilepsy Genetics Clinic is that providing a genetic diagnosis will help direct therapies.
“Oftentimes, families with a genetic diagnosis seek out research programs that are studying their child’s gene,” said Dr. Ghayda Mirzaa, a fellow neurogeneticist in the clinic and a researcher in the Center for Integrated Brain Research. “As we gather more information, we can better understand the genetic causes of epilepsy and more excitingly, translate this knowledge into more targeted therapies.”
Mirzaa and her colleagues made an important discovery along these lines when they unmasked a hidden link between epilepsy and genetic mutations in a molecular pathway also involved in certain types of cancer. Considering that cancer drugs targeting this pathway already exist, she is hopeful they may prove effective in treating epilepsy with this genetic mutation too.
“It’s the way of the future,” said Mirzaa. “Rather than focusing on the characteristics of the seizures such is the case with anti-epileptic medications, new therapies based on the underlying genetics of a patient’s epilepsy will address the root cause of the seizure.”
An infinite range of possibilities
The Woods are excited to see advances in genetics lead to new research avenues for Nolan and other children with epilepsy. But for now, the answer genetic testing gave them is allowing them to put their energy toward new adventures.
“Right now we’re transitioning,” said Wood. “Turning 3 has brought a lot of changes for Nolan. He’s about to start preschool and that’s big and exciting.”
With each sign of progress, Wood likes to raise Nolan’s imaginary bar one rung higher. This summer, Nolan’s vision unexpectedly returned.
“It was absolutely bananas,” said Wood of Nolan acing his recent vision test at Seattle Children’s. “When you don’t know what to expect, the future can hold an infinite range of possibilities.”
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