Rare mutation in autism risk gene connects family with researcher

Ever since Franklin Henry was a baby, doctors had diagnosed him with one condition after another, including Tourette syndrome and a range of disorders: autism spectrum, bipolar, obsessive-compulsive, oppositional defiant. Repeated genetic and psychological tests over the years couldn’t narrow the diagnosis.

But Joe and Karen Henry, his parents, believed something specific explained their son’s explosive moods and compulsively repeated speech.

“We knew from the get-go that it was not regular autism," Joe said.

It wasn’t until Franklin was a young adult, and technology had advanced, that a fifth genetic test finally gave his parents a name for their son’s condition: NR4A2-related neurodevelopmental disorder.

Franklin, now 29, has an extremely rare mutation on the NR4A2 gene.

Joe wanted to learn more about the disorder. He armed himself with the book “Genetics for Dummies” and dove into the scientific literature.

He emailed the author of a particularly relevant study on rare mutations that contribute to autism spectrum disorder (ASD). That was Daniel Geschwind, MD, PhD, a distinguished professor of human genetics, neurology and psychiatry at the David Geffen School of Medicine at UCLA.

Nearly a decade ago, Dr. Geschwind and his colleagues were the first to identify NR4A2 as an autism risk gene.

They wrote in the study that a mutated NR4A2 caused “a highly penetrant form of syndromic ASD consisting of ID [intellectual disability], language delay, and ASD-like behavioral and cognitive deficits.”

They also noted the need to identify more individuals with the rare mutation.

The email correspondence between Dr. Geschwind and Joe provided an opening for that.

Last year, both Joe and Franklin had their blood drawn at home in Medford, Oregon, and delivered to Los Angeles. Franklin is the first patient in a new study by Dr. Geschwind’s research group to understand how NR4A2 affects brain development, and ultimately, to develop therapeutics.

“Our interests are very aligned,” said Dr. Geschwind. “The Henrys want to understand this disorder, and so do we.”

Autism genetics

Research on autism had once been confined to psychiatry and psychology, without much basic neuroscience. That changed with Dr. Geschwind’s focus on investigating autism as a biomedical disorder.

Patients and families have been an integral part of his work since his lab’s founding 27 years ago. Indeed, it was a group of dedicated and passionate parents who convinced him of a “huge unmet need to bring genetics and neurobiology to the table,” recalled Dr. Geschwind.

That launched the modern era of autism genetics.

He and the families, supported by the National Institutes of Health, created the Autism Genetic Resource Exchange. Biological samples from more than 2,000 families – most with two or more children on the autism spectrum – are included and available to researchers anywhere.

This data has helped scientists to identify more than 200 autism risk genes, what Dr. Geschwind likened to pieces of a jigsaw puzzle.

“We can begin to see parts of the image,” he said. “But we certainly don't see the whole thing yet, so there's still a lot of gene discovery to go.”

NR4A2 and a family

A mutation on one copy of his NR4A2 gene has had a profound impact on Franklin and his entire family.

The first hint came at less than a year old, when Franklin was late to reaching milestones like rolling over, crawling and talking. Later, because he could not verbalize what was bothering him, there was constant screaming. For 18 years, Joe and Karen did not spend even one night apart from Franklin and his younger brother, Theodore.

Franklin’s childhood was difficult, but every passing year after age 18 also saw marked improvements in his behavior.

These days, Franklin has a job at a local market. And he’s one of Medford’s most well-known and informed citizens. He regularly watches all city council meetings and local newscasts; joins a group of retired lawyers for their weekly lunches; and walks the town for miles, engaging anyone he can in conversation.

Brain organoids

NR4A2 and other risk genes can provide a roadmap to the mechanisms of autism. When and where a gene is expressed is crucial to understanding its function.

Dr. Geschwind explained that the first step is to study what happens when the gene is knocked out or reduced. The problem, he said, is that “so many of these things are so rare. It's really hard to get patient lines.”

That’s where Franklin’s mutated NR4A2 gene comes in.

Cells from his blood sample were reprogrammed to an embryonic state using induced pluripotent stem cell (iPSC) technology and then grown into organoids. These miniscule spheres mimic the cerebral cortex, the brain’s “gray matter” responsible for language, memory, and conscious thought.

Gene expression can be studied in an organoid model that mimics a neurotypical human forebrain. Cells are labeled in green for neurons and red for astrocytes. (Courtesy of Dr. George Chen | UCLA Health)

The organoids, floating in a Petri dish, are tiny and beige – “not particularly exciting,” according to George Chen, PhD, an assistant project scientist in Dr. Geschwind’s research group. But their lack of visual appeal belies the enormous information they convey about brain development.

Dr. Chen explained that the study will focus on the organoids’ first 200 days, analogous to a brain developing in utero. Studying the role of NR4A2 will add to the understanding of how each risk gene contributes to neurodevelopment.

“That can give us a better picture of what genes are critical at which time points to lead to a neurotypical phenotype, or lead to a deleterious phenotype,” said Dr. Chen.

He and his colleagues can assess changes in individual cells as well as their interactions with other cells, to provide a detailed look at the mutation’s effects.

Dr. Geschwind, who is also a faculty member in the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA, cautioned that any understanding of NR4A2-related neurodevelopmental disorder cannot rely on studying one patient alone, but requires at least three, and preferably more.

Using his networks as a parent-advocate, Joe has introduced the research group to other families who may participate. He has also linked them with other investigators studying the gene.

Dr. Geschwind, who is also director of the UCLA Institute for Precision Health, will share with them the stem cell patient lines, each of which costs $5,000 to set up.

Certainly, it was the shared passion of the Geschwind Lab and families that ushered the study of autism to a greater understanding of its genetic basis. But it was the crucial support of both federal and private funds that has propelled it forward for the last three decades.

“The reason we were able to work with Mr. Henry is because we had philanthropic support that allows us to take patient samples and create patient lines,” said Dr. Geschwind, “as well as 27 years of infrastructure that's been built by NIH grants.”

Future treatments

The Geschwind Lab’s study of NR4A2 is only just beginning, with the ultimate aim of developing a therapeutic treatment.

But for Joe, getting involved in research was not so much about finding a cure for Franklin.

“I love my kid how he is. My enthusiasm is to just help out the greater cause.”

He points to NR4A2 as a gene of interest not only in his son’s condition but also for its associations with a range of other diseases, including Parkinson’s and Alzheimer’s.

“This particular genetic research is a drop in the bucket,” he said. “My son’s legacy may be that he's helped to stop those diseases in their tracks.”

The research on risk genes may be sped up with a developing initiative, Dr. Geschwind said, to study many rare mutations in parallel, instead of one at a time.

“We're in an unbelievably exciting time in biomedical research, where we can actually model brain diseases in a dish,” said Dr. Geschwind. “We're on the precipice of these extraordinary opportunities.

“I have hope that in my career, we'll be able to develop therapies for brain disorders, especially neurodevelopmental and neurodegenerative disorders.”