Researchers at the HudsonAlpha Institute for Biotechnology in Huntsville have pinpointed a previously unknown cause of a serious seizure disorder most common in babies, potentially opening the door to new diagnostic and treatment options for infants who show signs of epilepsy.
They found the genetic cause hidden in the SCN1A gene, one of the most heavily studied genes for seizure disorders. The discovery offers an end to the diagnostic odyssey for affected patients, but it also reveals a genetic mechanism for disease that could uncover the cause of other genetic disorders that are not well understood.
Scientists in Greg Cooper’s lab at HudsonAlpha, along with collaborators from across the country, published their findings in the American Journal of Human Genetics. They identified a variant that cues a “poisonous” piece of genetic code, called a poison exon, to be included in the final instructions for making a crucial protein. When the poison exon is incorporated, it prematurely cancels the protein’s production, which disrupts neural function, leading to seizure disorders.
The lab found the mutation on the SCN1A gene after performing whole genome sequencing for a patient who showed symptoms of a disease called Dravet syndrome, a serious seizure disorder that most commonly appears in infants. This particular variant would not show up on any of the more common genetic tests, and it was identified only because the entire genome was sequenced.
After this initial discovery, the Cooper lab contacted collaborators about the potential for more patients with the same variant. A team of scientists, including the University of Alabama at Birmingham’s Dr. Martina Bebin; the University of Washington’s Dr. Heather C. Mefford; and Northwestern University’s Gemma L. Carvill, was able to assemble enough cases to link the discovered variant to Dravet syndrome and other patients with closely linked symptoms.
The initial patient who brought the variant to the Cooper lab’s attention was enrolled in HudsonAlpha’s Clinical Sequencing Exploratory Research (CSER) project, which is aimed at identifying the genetic causes of undiagnosed conditions and funded by the National Institutes of Health.
“This particular subject that we identified in the NIH CSER project has done extremely well,” Bebin said. “Initially, they had several prolonged seizures yearly, which required treatment at the local ER. It was a frightening experience for the family.”
Bebin said the patient loves school, has been off seizure medication for more than three years and takes a keen interest in sports.
“The family is very grateful to understand the SCN1A diagnosis, and their child has done so well,” Bebin said.
“We’re grateful for the families who participated in this research, and excited that the results may offer some clinical benefits to them,” Cooper said. “But we’re also excited to have figured out a whole new place to look for genetic variants capable of causing disease.”
By discovering that genetic variation in poison exons disrupts crucial protein processes in the developing brain, Cooper’s lab and collaborators from across the country have created a blueprint for efforts to discover the molecular causes of other genetic diseases and potentially develop treatments for them.