Photo by Courtney Reese
Angie Auldridge noticed early on that her son Mark was very different from his older sister, Jillian. He was much smaller and slower to develop, not making eye contact the way his sister had. “It became abundantly clear that he wasn’t hitting gross motor skill milestones,” says Auldridge, who lives in Maryland.
At 18 months, Mark began a strange new ritual. “He would drop to the floor and spin in a very rhythmic movement,” Auldridge says. He also began to light filter, putting toys up to the sun and moving them back and forth.
At 20 months, Mark was diagnosed with autism.
The diagnosis helped to explain some of Mark’s issues. But Auldridge felt there was something else going on. Mark still wasn’t walking, and he had trouble holding toys in his hand. Standard genetic tests — microarray testing and screening for more common genetic disorders, such as fragile X, Prader-Willi and Rett syndrome — had come back normal. But the family had one more genetic testing option — whole exome sequencing. This test analyzes DNA in the parts of the genome that code for genes. When individual genetic tests come up empty-handed, whole exome sequencing offers a broader look at the genome.
Six months later, the Auldridges got the answer they had been searching for. Mark had a mutation in a gene called SCN2A. Variations in this gene are linked to a severe form of epilepsy that starts in the first year of life, as well as to intellectual disability and autism. Mark’s variant was de novo, meaning he didn’t inherit it from either of his parents.
The SCN2A gene produces a channel in brain cells that helps govern how excitable the cells are. Overly excitable brain cells can trigger seizures, which helps explain the gene’s link to epilepsy.
Mark, however, had never shown signs of seizures. His case highlights a more recent discovery: SCN2A variations can also be linked to autism without seizures.
Last year, scientists reported that changes within the SCN2A gene fall into two main categories, each with a different outcome. One type makes brain cells overexcitable — this type of change is most likely linked to early-onset seizures. The other category has the opposite effect — this type of change is more likely to be linked to autism.
Scientists don’t yet know why this second type of variation leads to autism. They note that some children with SCN2A variations have both autism and epilepsy. But SCN2A children with autism typically develop epilepsy after the first year of life. This is a different form of epilepsy than the severe infantile version that has traditionally been linked to SCN2A.
SCIENTISTS AND FAMILIES CONNECT
Scientists and families are working together to try to better understand how changes in the SCN2A gene can lead to these two conditions — and how best to help the children who have them.
In July, more than 100 people — 27 families and 40 scientists and clinicians — gathered in Wilmington, Delaware, for the second annual SCN2A Family and Professional Conference. The goal of the event, organized by the FamilieSCN2A foundation, was to encourage researchers to share information with one another and to connect with the families who will benefit from their research.
One of the speakers at the conference was Stephan Sanders, a scientist at the University of California, San Francisco. Sanders, who sits on SPARK’s medical genetics committee, and his colleague Kevin Bender developed the theory that one type of SCN2A mutation is linked to autism and another type to early-onset seizures. Their theory was based on data gleaned from databases and laboratory experiments. But when they developed the theory, they had had few interactions with SCN2A families. “You’re never quite sure how well it represents patients,” Sanders says.
His experience at the conference helped confirm that the researchers are on the right track. At the beginning of his talk, Sanders asked families to raise their hands if they had a child with early-onset seizures or a child with autism. Almost everyone fell into one of these two groups. “It’s gratifying to know all this work is capturing the characteristics of these patients,” he says.
Both Bender and Sanders say that meeting families is a powerful motivator. “It forces us to keep thinking about what we can do to help them,” Sanders says. “It also gives us a better impression of the problems these children are having. Reading about autism or epilepsy is very different from meeting a family. It helps you understand the data better.”
“The amount of fight that these families have in them and how much they work for their children is amazing — they are outrageously generous,” Bender says. “No kid is the same — some have severe autism and intellectual disability, some have severe seizures — but they are all trying to come together and promote research and awareness.”
AN EVOLVING PICTURE
One of the children Sanders and Bender met was Mark, Angie Auldridge’s son, who has autism and is so far seizure-free. Mark is currently in the minority among people with SCN2A variations. But Sanders predicts that will change as more children with autism get genetic testing. Infants with severe seizures are more likely to get extensive genetic testing than are children with autism. That may have skewed the SCN2A population toward those with early-onset epilepsy, Sanders says.
Indeed, evidence to date suggests that SCN2A may be one of the most common autism-risk genes, Sanders says. Current estimates predict it’s responsible for about 1 in 333 autism cases. SPARK will help more individuals with autism determine if there is a genetic cause for their autism, and what that genetic factor is. SPARK has already identified a participant with an SCN2A mutation.
These SCN2A findings show how quickly our understanding of a gene and autism risk can change as more people get access to genetic testing.
Sanders says that studying SCN2A may prove particularly useful in understanding autism. That’s because the gene has a well-defined function in brain cells; it produces a molecular channel in the cell that affects how likely the cell is to fire. Researchers can make changes to the gene — including changes that mimic specific variations in people — and study the outcome in cells or animals.
Auldridge is excited about scientists’ increased interest in the link between autism and SCN2A. She became active with FamilieSCN2A after learning of Mark’s diagnosis in 2015 and helped to organize the recent conference.
In addition to fostering research, she says it’s been helpful to meet other families, to share challenges and swap information about different therapies. For example, “kids with straight autism might not need the motor therapies that our kids do,” she says.
It’s also been helpful to meet children older than Mark who might give some insight into his development. “There are definitely other kids who were late bloomers, who were nonverbal and became more functional,” she says. “That gave us some hope.”
She continues to marvel at Mark’s progress. “Just when I think I have him figured out, he surprises us,” Auldridge says. Mark recently started grouping like things together, for example. When his grandparents visit, “he’ll group them together and smile and want them to stay together,” she says. On another day, “he suddenly pointed to a family photo and said ‘That’s me,’” she says. “He’s mostly nonverbal, so to see him put two words together and use them in context was so exciting.”