Unraveling the Mystery of Autism, One Person at a Time

Matthew Kolen (L), who was diagnosed with Asperger's syndrome at age eight, hugs his brother Russell after blowing out the candles on his 13th birthday cake at his house in Long Island, New York, on June 4, 2012. Matthew's diagnosis was dropped in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders and was subsumed into the broader category of autism spectrum disorder. Shannon Stapleton/Reuters

Updated | If you've seen one person with autism, you've seen one person with autism. It's a common refrain among doctors who treat the neurodevelopmental disorder, which manifests differently in almost every case, even among the most closely related individuals.

People with autism engage in repetitive or obsessive actions and interests, struggle to communicate and have difficulty relating to others and to the world around them. But the exact features of the disorder, as well as its severity, can vary significantly. That's why autism, now diagnosed in one in every 68 children in the United States, is no longer considered one condition but rather a spectrum of related but distinct disorders.

At one end of the autism spectrum is 26-year-old Taylor Newsum. He has difficulty picking up on certain social cues, but even so, each day he takes the train from his parents' home in Brooklyn to midtown Manhattan, where he works as an administrative assistant in a psychologist's office. He plans to become a social worker. At the other end of the spectrum is his sister, Savannah Newsum. Compared with Taylor, Savannah, 21, has much more limited verbal skills and social skills, and it is difficult for her to maneuver through the world without assistance.

"Taylor is very independent, highly functioning and will one day live on his own. Savannah will always require someone in her life to help her get through her day," says their mother, Darnell Newsum.

That no single feature is present in all—or even a majority of—people with autism is a major roadblock not only in meeting the many different needs of those on the autism spectrum but also in understanding why the disorder develops in the first place. Now scientists are turning to families like the Newsums to search for clues where it begins: in our DNA.

A new study called SPARK—Simons Foundation Powering Autism Research for Knowledge—seeks to pinpoint genetics and other risk factors of autism by studying 50,000 individuals with autism and their family members. It's the largest study of the disorder to date, built on an effort to sequence the exome—the sliver of the genome that accounts for almost 85 percent of the glitches known to cause human diseases—and dig through patient medical histories to identify certain genetic underpinnings of autism.

In the short term, this will allow researchers to begin to identify genetically defined subtypes of autism. Grouping and comparing individuals with similar genetic changes could yield clues about a person's future prognosis and the health complications, such as seizures, gastrointestinal problems and schizophrenia, that are associated with certain subtypes. In the longer term, says the study's leader, Wendy Chung, director of Columbia University's clinical genetics program, SPARK's findings could lead to individualized treatment options, from medicines to behavioral interventions, that take into account the disorder's genetics.

"Do I need to keep seizures on my radar for any one patient? Can we predict what challenges families might need to prepare for down the road? Answering these types of questions will make a big difference for patients because we will better understand how to help them," Chung says.

Teasing Out the Genetic Roots

A long history of studying families affected by autism has confirmed its strong genetic basis. In families with one child with autism, for example, the risk of a second child having the condition can be as high as 20 percent; in families with more than one child with autism, the risk jumps even higher. And identical twins, who share the same genome, or complete set of genes, and fraternal twins, who share about half of their genetic code, are far more likely to develop autism than are different-aged siblings.

Genome sequencing has already ferreted out mutations in 65 genes that increase the risk of developing autism, and hundreds of others will likely be implicated as well. Some are passed from the DNA of the mother, the father or, sometimes, from both parents to the child. Others arise spontaneously, meaning they aren't present in either parent's genetic makeup.

To date, genetic causes have been pinpointed in only about 20 percent of autism cases, usually those that are associated with certain rare diseases, such as Fragile X syndrome or Phelan-McDermid syndrome. But there's no smoking gun for the remaining cases. It's still largely unknown which genes drive the development of the disorder. The number of genetic mutations that contribute to autism is manifold, on the order of several hundreds, perhaps even a thousand. That means the likelihood that any two patients will have a mutation in the same gene is very low. In fact, the most commonly mutated gene in autism—a gene called CHD8—is so rare it's seen in only about 0.1 percent of people with the disorder.

And, Chung points out, even among those who do share the same genetic mutations, it's not unusual for their outcomes to be wildly divergent. In some cases, the same change can cause severe disabilities in one individual but only mild behavioral problems in another. "In a way, you're looking at many, many rare disorders," Chung says.

Of course, genes alone aren't to blame. The same family studies that demonstrate autism's genetic basis also confirm that factors other than genetics, collectively referred to as "the environment," play a role. "If genetics were the only factor that determined whether a child develops autism, two identical twins, who share the exact same DNA, would always either both have autism or both not have autism," says Raphael Bernier, an associate professor of psychiatry at the University of Washington in Seattle. He says autism is caused by a combination of genetics and a "vast array" of environmental factors—from a child's exposure to certain toxins to overweight parents.

"Our best guess is that in many individuals, autism is caused by genes interacting with not only other genes but with an unknown number of potential environmental factors too," says Bernier, whose clinic is participating in SPARK. But which environmental factors actually contribute to autism and by how much remain a hotly debated question SPARK hopes to answer.

The study's success hinges on its ability to amass an army of patients and family members to capture not only the full breadth of autism's genetic diversity but also the different and unique challenges of each individual with autism. A data set of this massive caliber is also necessary, says Bernier, to see patterns they may not otherwise see in a small group of patients. "A genetic mutation that only occurs in one in every 500 patients could easily be overlooked; in 50,000 patients, that same mutation would crop up 100 times," he says.

"Imagine that all families in SPARK report on the nature of their child's communication struggles, and then we aggregate these reports and cross-reference them with genetic profiles. Finding genetic commonalities in experiences and how different families manage specific challenges could lead to real improvements," says Pamela Feliciano, scientific director of SPARK and the mother of a child with autism.

Only about 5 percent of children with autism participate in clinical trials, compared with more than 90 percent of children with cancer, for example. In an effort to make study enrollment as easy as possible, SPARK investigators designed the study to enable people with autism and their families to enroll online via a smartphone, tablet or computer, in addition to enrolling study participants at a doctor's office or clinic. The Newsums—Taylor, Savannah and their parents—were among the first to raise their hand as study volunteers. Each contributed a small vial of saliva to the research project and filled out a medical questionnaire. Eventually, SPARK will return sequencing data and any actionable findings to health care providers of participants who want such information.

The project's success will rely on crowdsourcing the painstaking task of analyzing the tsunami of data that's starting to come in. Investigators from 21 medical schools and autism research centers across the U.S. have already joined the project, and de-identified data will be made available via a web-based portal to qualified researchers from the scientific community at large. "There could be a brilliant mathematician who has the ability to see patterns and associations that others don't," says Chung. "We don't presume that only investigators who happen to call themselves autism researchers are the only ones who have something to teach us about autism."

SPARK is not the only study that is examining genomic data for a large number of patients with autism. MSSNG—named for the "missing" information about autism—was launched in 2014 by the research and advocacy organization Autism Speaks, in partnership with Google and the Hospital for Sick Children in Toronto. The project aims to mine the DNA of 10,000 people with autism and their family members, and it's on pace to reach that goal later this summer. MSSNG goes beyond SPARK's plan of sequencing the exome—it will look at all 3.2 billion letters of genetic code in the human genome to get a more "holistic" view of the genetic underpinnings of autism, says Mathew Pletcher, interim chief scientific officer at Autism Speaks.

With more than 5,000 genomes already fully sequenced, the MSSNG data set has allowed scientists to discover new parts of the genome involved in autism that were previously missed, using techniques that look at only parts of the DNA. "It also revealed that the disorder's genetic underpinnings are way more complex than previously thought," Pletcher says.

Using MSSNG data, a team at the Hospital for Sick Children sequenced, in their entirety, the genomes of 340 people from 85 families, each of which had at least two children diagnosed with autism. The research showed that most siblings who have the disorder have little to no overlap in the same autism-associated genes, turning on its head the long-held belief that siblings with autism had inherited the same autism-predisposing genes from their parents. "In many cases, they have different 'forms' of autism, which begins to explain why siblings with autism so often have such different features and why they require distinct approaches to help them manage the disorder," says Pletcher.

Once complete, MSSNG will host its data, along with a suite of data analysis tools, on the Google Cloud platform, Pletcher says, where it will be accessible to "anyone, anywhere."

"The goal is to ask and answer as many questions as possible, make as many discoveries as possible and help people on the autism spectrum do a lot better," he says.

Updated: This story has been updated to reflect that the genetic cause of autism has not been associated with Williams syndrome.

This story has been updated to reflect that Pamela Feliciano, scientific director of SPARK, is the mother of a child with autism—not an adult child with autism.