Autism: Genetics Research to Learn Who, How and Why

Yale Medicine doctors are exploring genetics in the hope of developing treatments for the fast-growing disorder of autism.

The power of genetics

Discoveries in genetics offer tantalizing clues to the causes and development of autism. 

Abha Gupta, MD, PhD, is a top researcher into the connection between genetics and autism. But she says the patients keep her going in a field full of confounding mysteries. “When I go and interact with kids and their parents, I think, ‘Oh! This is why I do this,’” she says.

Dr. Gupta, an assistant professor of pediatrics and a researcher at the Yale Medicine Child Study Center, sees patients at Yale Medicine’s “Fast Track” autism clinic, where experts evaluate children from around the Northeast to determine whether they have autism.

In particular, Dr. Gupta remembers one mother and her severely impaired son. As she waited to see them in an examination room, she heard the mom sobbing outside the door. Once inside, the woman posed all the questions that parents in her situation have: What caused this? Can he grow out of it? Will he be able to have a job? What will happen to him when I’m gone? 

Dr. Gupta could offer no easy answers. “This frustration over not being able to provide more answers is what motivates me to persist in the lab, where I can make a contribution to understanding what causes autism, and hopefully develop treatments for the kids we see in the clinic.”

Autism is such a complex condition that even medical scientists and physicians struggle to come up with an apt definition. At present, clinicians define it as “a broad spectrum of developmental brain disorders characterized by difficulties in social interaction, verbal and nonverbal communication and repetitive behaviors.”

Autism is on the rise, startlingly so. About one out of every 2,000 children was diagnosed with autism in the 1970s and 1980s. Today the Centers for Disease Control estimates that among 8-year-olds in the United States one in 68 has an autism disorder.

Although behavioral therapies can help many children with autism to develop skills and improve their communication abilities, there is no cure for autism. And the cause of the disorder is elusive.

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‘Completely hooked’

Dr. Gupta never knew anyone with autism growing up, but she was drawn to the neuroscientific quandaries posed by the disorder.

“I came across a one-page article in Newsweek magazine on autism in 1995,” she says. “I was completely hooked and fascinated by it.”

After completing her residency in general pediatrics at the Children’s Hospital of Philadelphia (CHOP), she sought out a fellowship in developmental-behavioral pediatrics. “There was no basic science research in autism going on there at that time,” she says. “I was low on the totem pole, and people discouraged me. They thought I would stagnate.”

Then one day, Fred Volkmar, MD, former director of the Child Study Center, spoke at CHOP. “He presented a slide on their enormous autism research team,” Dr. Gupta says. “I remember running up to him afterwards to ask him a question as an excuse to meet him.”

In 2005, that encounter led Dr. Gupta to Yale Medicine, where she pursued a postdoctoral fellowship with Matthew State, MD, PhD, a child psychiatrist who was starting a lab in genetics.

“I’ve seen a complete transformation in the study of genetics of autism since then,” she says. “When I began, we spent two years looking at a single gene in families affected by autism. A few years later, we could look at all 20,000-plus genes in several individuals in one experiment.”

A devastating form of autism

Dr. Gupta eventually started her own lab. One of her major projects has been research into childhood disintegrative disorder—an extremely rare form of autism in which children develop normally until the age of 3 or 4 (in some cases, even later), then suddenly regress until they are severely impaired and barely communicative.

“We have a videotape of a child who was completely normal at 3,” Dr. Gupta says. “At 8 he experienced a dramatic regression in skills, and at 11 he was rocking back and forth, not talking at all.”

Yale Medicine has the world’s largest collection of DNA samples from patients with childhood disintegrative disorder, for which no group has published a comprehensive neurobiological study. Dr. Gupta collaborated with colleagues, including neuroimaging experts, to look for correlations between mutated genes and images of patients’ brains. She and her team also did eye-tracking studies to see where the children look when shown pictures of faces.

One finding was that while abnormalities in autism are often found in the brain’s neocortical regions, where higher-order thought processing occurs, childhood disintegrative disorder patients showed differences in the cerebellum, hippocampus and other “non-neocortical” regions, which control motor movements, memory and emotions.

Genetic analysis revealed that the mutated genes were most active in those same areas. “The results from two very different experimental techniques converged,” Dr. Gupta says.

While most kids with autism tend to look at people’s mouths instead of their eyes, these children looked at people’s eyes, perhaps because their period of normal development sealed that practice into their brain circuits. “Why they are so severely affected is still a mystery,” she says.

“Childhood disintegrative disorder lies at the intersection of autism, regression and intellectual disability,” says Dr. Gupta. “Since regression and intellectual disability affect many children with autism, we believe studying it will offer insights into a substantial proportion of the spectrum.”

Theory and practice

These discoveries offer tantalizing clues to the causes and development of autism. But they remain tiny spots of light breaking through a dense forest of mysteries.

“I want to link neuroscience to genetics, to see how gene mutations cause problems at the cellular level,” Dr. Gupta says. “What we know right now is that there are hundreds of genes implicated in autism. Yet genes that are highly associated with the disorder each account for, at the most, around 1 percent of cases.”

Dr. Gupta says she is most excited by techniques using so-called pluripotent stem cells. These are blood or skin cells that are put into a dish and programmed to turn into a variety of different cells. 

“We could take samples from a healthy person and introduce a mutation associated with autism, to see if that is sufficient to cause problems,” Dr. Gupta says. “We could also explore genome editing. If we take away an abnormality, was it necessary to cause dysfunction in the first place? The dream is that, eventually, we will screen new patients and identify targets for treatments related to their genetic profile.”

A collaborative environment

Dr. Gupta always imagined that she would live in Philadelphia, near where she grew up. But she was drawn to Yale Medicine’s “incredibly rich research environment.”

“We have an international reputation for autism care,” she says. “At Yale, so many people are attacking autism from so many different angles—from teaching social skills to genetic analysis. It’s very special to collaborate with these colleagues. And our patients are very motivated to contribute to the larger effort of research. They know if they donate blood it might not help their children, but it might help the next generation.”

Dr. Gupta is looking into combinations of environmental factors and genetics—which, metaphorically, is like adding thousands of trees to the forest she is exploring. “Genetics is hard enough. There are about 20,000 genes,” Dr. Gupta says. “Can you imagine all the environmental factors, and the possible interactions between the two?”

It’s a question that would scare off most people, but it energizes Dr. Gupta. As the number of children with autism has skyrocketed, the mission of finding viable treatments has become that much more vital.