By Lillie Mermoud

Brynn and Olivia Bradshaw started experiencing severe seizures a few months after birth. The seizures were not only anxiety-inducing for the girls but also for their parents, Laurel and Byron. Laurel and Byron knew the seizures could be causing permanent damage to their daughters’ brain development and function.

After five years of searching for answers, the Bradshaws learned that Brynn and Olivia have a genetic variant potentially linked to their seizures. “There’s a lot that goes into our story,” said Laurel. “Starting to find answers has helped all of our kids. It’s given us hope.”

Identifying this genetic variant gave the Bradshaws the answers they were waiting for and sparked a new research direction for pediatric genomic scientists at HudsonAlpha Institute of Biotechnology.

Family history

Brynn, who is six years old, and Olivia, four years old, have seizures ranging from febrile seizures brought on by fevers to tonic-clonic seizures, one of the most severe types of seizure. A lack of oxygen reaching the brain during a seizure can cause permanent damage, such as developmental and cognitive challenges. Brynn has not experienced severe side effects, but Olivia faces developmental challenges like speech delays, behavioral issues, and tendencies resembling attention-deficit/hyperactivity disorder (ADHD). “It’s extremely scary to watch your child have a seizure,” said Laurel. “Over time, you learn to cope, but it’s always just as scary.” 

The girls’ febrile seizures are not uncommon for children under five; two to five out of every one hundred children experience them and often outgrow them. However, these seizures are known to run through families — Byron’s side of the family has an extensive history of febrile seizures, and Laurel and Byron’s first child suffered from them.

Byron, Jr., the Bradshaws’ firstborn, had seizures brought on by fevers that lasted several minutes. One night, Laurel and Byron put their son to bed with a fever, but Byron, Jr. never woke up the next morning. He passed away at only two years old. “We suspect he experienced a seizure that was severe enough that he didn’t wake up from it,” said Laurel. “It’s been hard to process little Byron’s passing, especially when we didn’t have any explanation for why it happened.” When Brynn and Olivia also started having seizures, Laurel and Byron feared the symptoms seemed all too familiar to Byron, Jr.. “We needed to find a neurologist who would investigate this on a deeper level,” said Laurel. “We knew there had to be something more to it.”

Diagnostic ups and downs

When Brynn was first born and started having seizures, Laurel and Byron quickly sought the help of neurologist Martina Bebin, MD, MPA, a pediatric neurologist with UAB Medicine who works closely with HudsonAlpha and their team of certified genetic counselors to identify opportunities for patients to receive access to genomic testing. Given the Bradshaw’s family history of seizures, Dr. Bebin knew there was more to Brynn’s case than febrile seizures. After a gene panel was ordered for Brynn that came back inconclusive, Dr. Bebin referred Brynn to be a participant in HudsonAlpha’s pediatric genomic studies. 

HudsonAlpha Faculty Investigator Greg Cooper, PhD, and his lab are experts at identifying genes involved in rare developmental disorders. His lab is part of an ongoing partnership with UAB Medicine for the Alabama Genomic Health Initiative (AGHI), a statewide effort to provide free genetic testing to Alabama residents to identify individuals at risk for certain diseases and genomic abnormalities. When Brynn joined the AGHI study in 2017, she was given whole genome sequencing, a more thorough method of genetic sequencing than a gene panel that yields information about a person’s entire DNA. 

Through several research programs, including AGHI, Dr. Cooper’s lab, along with collaborating labs, has sequenced the genomes of more than 1,790 children, diagnosing about 27 percent of patients. Roughly 70 percent of children do not receive a diagnosis because many genes associated with neurodevelopmental diseases have not been discovered yet. Brynn was part of that 70 percent — her analysis came back without any clear genetic culprits for her seizures. 

When Olivia was born and experienced seizures after just a few months, she was referred to AGHI in 2019. Just like her older sister, her results were inconclusive. “The hardest part of my job is telling a family that there aren’t any answers for the symptoms their children are experiencing,” said Whitley Kelley, a certified genetic counselor at HudsonAlpha who worked with the Bradshaws to understand their genomic test results. “Sometimes the discoveries just haven’t been made yet, but the good news is that we get better at interpreting genomes over time.”

Answers come to light

Even though Brynn and Olivia’s initial analyses did not provide any answers, Dr. Bebin and Dr. Cooper’s team never gave up. “We suffered disappointment after disappointment,” said Laurel. “But we had advocates fighting in our corner. Dr. Bebin and the team at HudsonAlpha never gave up.” Dr. Bebin frequently checked in with Dr. Cooper on Brynn and Olivia’s analysis, knowing that Dr. Cooper’s team routinely reanalyzed the genomes of study participants who did not initially receive answers. In 2021, the Bradshaws’ patience paid off. The Cooper lab finally uncovered answers during a reanalysis of Brynn and Olivia’s genomes.

Dr. Cooper’s team identified a new variant in a gene called SCN1A. Scientists studying this gene have linked it with many cases of genetic epilepsy and febrile seizures, particularly with a genetic disorder called Dravet Syndrome. Dravet Syndrome is known to cause seizures, development delays, and behavioral abnormalities — symptoms that matched up perfectly with Brynn and Olivia’s phenotype. This particular variant in SCN1A is not yet conclusively tied to Dravet Syndrome, but it is potentially clinically significant. “Brynn and Olivia’s symptoms and family history match up with what we know about Dravet Syndrome,” said Kelley. “This gene variant is still very novel, but it’s a promising beginning of an answer.”

Learning about the SCN1A variant has given the Bradshaws peace of mind and eased some of their anxieties. Soon after Kelley shared the reanalysis results with Laurel and Byron, the parents enrolled their youngest daughter, Clara, who was eight months old, as an AGHI participant to test her genome for the same SCN1A variant. The results were negative; Clara is unlikely to suffer from seizures like her older sisters. 

New directions

News of the reanalysis has helped Laurel and Byron to adapt Brynn and Olivia’s treatment with Dravet Syndrome in mind. Brynn has not experienced seizures since 2021, and with some tweaks in her medication, Olivia has not experienced a tonic-clonic seizure for several months. 

Olivia still suffers daily from focal onset and absence seizures, types of seizures characterized by a lapse in consciousness that do not involve violent muscle spasms. Thanks to occupational and speech therapy, her day-to-day life has improved. “Since receiving the reanalysis results, we have been able to take even better care of each of our kids,” said Laurel. “Our questions about what happened to little Byron have been alleviated, and we feel empowered to plan for the future. This is important information our family can pass on to future generations.”

The revelation of the SCN1A gene variant greatly affects the Bradshaws’ lives, but it can also positively impact many others. The Cooper lab’s discovery sparked researchers to dive deeper into studying this gene variant. Further research will allow HudsonAlpha’s scientists to better understand the gene variant and to potentially identify more variants that could function like it in children who are experiencing similar symptoms. “This variant wasn’t previously on our radar. It may not have been found without Brynn and Olivia’s reanalysis,” said Kelley. “This gives us a chance to help even more families who face the same struggles as the Bradshaws.”

HudsonAlpha’s participation in AGHI, as well as many other pediatric genomic research programs, has allowed hundreds of children to receive answers to undiagnosed or misdiagnosed diseases. The HudsonAlpha Foundation’s 2023 Double Helix Dash raises funds in support of HudsonAlpha’s childhood genetic disorder research programs and the Smith Family Clinic for Genomic Medicine, LLC.