Jenn Drohan remembers being so thrilled when her son Max developed normally: He smiled, sat up, and crawled. Then he walked. He babbled. Then he talked. Jenn and her husband, John, had an older son, Sam, who showed signs of having autism. The couple hoped that maybe Max would avoid the hallmark problems of people on the autism “spectrum”: difficulty interacting socially, difficulty communicating, and repetitive behaviors. As a toddler, Max was sunny and social.
At 17 months old, Max began to change. He stopped making eye contact with people. He seemed to lose interest in the world around him. He started talking less. Then, he stopped talking altogether. He became increasingly anxious. His behavior became more unpredictable and disruptive. After their older son, Sam, was officially diagnosed with autism, the couple, who lives just north of Boston, had Max evaluated for the disorder. Just like Sam, Max received a diagnosis of autism.
Seven years ago, not long after Max’s diagnosis, the family got the chance to have their genomes, their complete set of genes, analyzed by a team at the Children’s Hospital of Boston. The Boston Autism Consortium conducted a study, which also used data from a database called the Autism Genetic Research Exchange (AGRE), and compared “phenotypes” — the observed individual characteristics of Jenn, her husband, and her sons — with “genotypes,” their full genetic sequence.
The study found that Jenn and Sam, the couple’s older son, shared an abnormality on one chromosome. They were told this shared genetic glitch, known as a 18q22.3 deletion, may have resulted in Sam’s autism. In addition, the researchers found that John and Max, their younger son, also shared a chromosomal abnormality. This shared glitch, a 15q11.2 microdeletion, affected Max, but not John.
With the results, the Drohans became one of the first families to learn of at least some of the possible genetic factors that resulted in the autistic issues of their sons, now age 9 and 11. While it is far from a complete genetic explanation of the family’s unusual situation, the Drohans found it comforting.
“It made me feel validated,” explains Jenn Drohan. “I wasn’t just being hypervigilant because I had an older son with autism. This genetic result let me know that, yes, this is definitely autism.”
In the few years since the Drohans got that genetic report, there has been a revolution in the scientific understanding of the genetic architecture of autism, a disorder that has been increasing steadily for nearly two decades. Today about 1 in 68 children has been identified with autism spectrum disorder (ASD), according to recent estimates from the Centers for Disease Control and Prevention. Some attribute these apparently rising autism rates to an increased awareness of the disorder and broader diagnostic definitions. Others feel the rise is due to environmental exposure to certain risk factors.
Scientists now theorize that about 50 to 60 percent of ASD cases may be traced to genetics. Researchers have identified about a hundred genes that may play a part in autism and have begun to figure out which particular genes may be the most important and how many of these genes there are. They’re collecting genomic data in gigantic, open-source databases unimaginable even a decade ago.
The progress is both incredibly fast and frustratingly slow: Researchers have discovered that rare genetic changes can play a key part in this difficult, and increasingly common, disorder. However, they have yet to make complete sense of these genetic changes or to develop ways to turn this new knowledge into better diagnostics or medications. They’re beginning to visualize how these mutations interact, where they might be clustered in the genetic code, and how these changes might affect brain development and the connections between nerve cells. So far, attempts to turn these advances into actual treatments have failed, but experts say they expect progress on that front in the next decade or two. And already, some researchers say, clinical genomic analysis is making it possible for individual families to gain insight into their particular experience, just as the Drohan family did.
“The new understanding is that autism is a collection of many different disorders, but they have common features,” explains Jonathan Sebat, the chief of the Beyster Center for Molecular Genomics of Neuropsychiatric Diseases at the University of California, San Diego.
“From a purely scientific standpoint, in 10 years, the progress is breathtaking: We’ve gone from no traction at all to systemic gene and point mutation discovery, sequencing the whole exome,” says Matthew State, a professor and the chair of the psychiatry department at the University of California, San Francisco (UCSF) and a researcher in the field of genetics for nearly 20 years. “But the families of our patients are understandably impatient. For them, 10 years is a long time. Both things are true.”
Leo Kanner, a physician who pioneered pediatric psychiatry at Johns Hopkins University in Baltimore first described “early infantile autism” in 1943, naming it after the “autistic aloneness” that he observed in some of his patients. Most people on the autism spectrum have problems with communication and social interaction. Yet the number and variety of symptoms in those who receive a diagnosis of autism spectrum disorder is vast: intellectual disability, repetitive behaviors, a narrow range of interests, gastrointestinal problems, anxiety, learning differences, and many more.
As parents of autistic children like to say, “If you’ve met one child with autism, then you’ve met one child with autism.” Cases vary widely and are so individual that it’s no wonder researchers have trouble making sense of it all.
All sorts of things have been blamed for autism such as “cold mothering,” infection, fevers during pregnancy, and inflammation. More than a decade ago, a study seemed to point to the measles, mumps, and rubella (MMR) vaccine as a cause. Though that study has been scientifically disproven many times, the idea that immunizations cause autism fuels controversies to this day.
Since the early 1970s, researchers have studied twins and families to pinpoint genetic links to the disease. In 1995, a groundbreaking study of twins confirmed that autism has genetic roots.
Scientists quickly realized that the genetic side of the ASD story was terrifically complex. In some inherited genetic disorders, children exhibit symptoms and behaviors similar to autism. About 1 in 3 children diagnosed with Fragile X syndrome, which produces cognitive disabilities, also meets diagnostic criteria for ASD, and 25 to 50 percent of people with tuberous sclerosis complex, a condition that causes noncancerous tumors to form in the brain and other vital organs, fulfills autism diagnostic criteria. Other research on twins and families has established that ASD could be inherited, but no clear pattern of inheritance, such as dominant inheritance, was apparent.
Scientists began by using approaches that had worked well in investigating other genetic disorders like cystic fibrosis, a condition that causes the buildup of thick mucus in the lungs. Some ran studies that looked for shared genetic markers in families that had more than one autistic member, a technique called linkage. These failed to find more than a few genes that were consistently detected in multiple studies and could be clearly linked to autism.
“Finding clear genetic linkage from generation to generation turned out to be the exception rather than the rule,” says Stephan Sanders, an assistant professor of psychiatry at UCSF.
Others tried to find out if common genetic changes, known as single nucleotide polymorphisms (SNPs), which are simple single letter changes in the DNA code, might be associated with autism. The data seemed to yield some evidence for the involvement of genes on every chromosome in the human genome. Many of these changes seemed to confer only small effects. But scientists began to believe that many cases of autism might be due to the buildup of many common genetic mutations that together caused ASD in an individual. A recent study in Nature Genetics suggests that most of the genetic basis of ASD in the general population may be of this type.
Unfortunately, “It’s a little bit everywhere” doesn’t make for a useful scientific insight when you are trying to find better ways to diagnose or to treat ASD. Another part of the problem was that, until recently, researchers didn’t have the technological firepower to try different approaches. All that would change with the advent of whole genome sequencing, a laboratory technique that makes it possible to describe the DNA of an entire genome all at once.
With this new technological firepower, scientists were able to find some rare single letter genetic changes that lead to ASD. But while these findings make for good diagnostic tests — find the rare gene, make the diagnosis — they explain only a few cases.
Over the course of 2007 and 2008, a series of academic papers built the case that an important part of the autism story could be found in larger genetic variants, called structural variants, in which instead of a single letter change, a particular stretch or segment of DNA is either deleted or duplicated. Sometimes these rare variations could involve an inversion, or flipping, of the DNA segment. In other cases, a stretch of DNA might cut from its usual location and paste somewhere else, thus changing the structure of the gene. Until then, researchers didn’t have the tools to see these structural changes in the genetic code.
But the even more astounding finding to emerge from those studies was that a lot of the copy or cut-and-paste mistakes seemed to be new, or “de novo.” This means that the genetic mutation could be found in the child with autism, but not in the parents. These mutations originate in the sperm or egg, and thus are present in the newborn. So, while the changes are in fact genetic, they are not inherited.
“We had suddenly honed in on spontaneous mutations as the key culprit,” explains Sebat, who wrote a 2007 paper in Nature about these de novo mutations. “That’s where the strongest genetic signal lies.”
Most researchers agree that if we’re going to make sense of all this genetic information, we’re going to have to figure out how these genetic changes interact with one another and environmental factors to produce the group of symptoms we call ASD. If hundreds of genes are involved in autism, which ones seem to be the most important?
“Now the problem is, what do these genes do?” says Ivan Iossifov, an assistant professor at the Cold Spring Harbor Laboratory in Cold Spring Harbor, New York. Iossifov’s 2014 Nature paper suggested that de novo mutations might contribute to 30 percent of ASD diagnoses in simplex cases, where only one family member is diagnosed. The study also found that there’s an overlap between the genes that seem to have a role in ASD and those that play a role in other neurological disorders such as schizophrenia and intellectual delays.
A 2007 Nature study on mice was able to link certain genetic changes to specific behaviors such as reduced social interaction, repetitive behaviors, inflexibility, and anxiety. Other teams, including the Wall Lab at Stanford University, are working on ways to visualize these genetic connections with methods like computer modeling.
“We don’t understand the physiology,” explains Mike Wigler, a professor at the Cold Spring Harbor Laboratory who, with Sebat, is also an author of the de novo variations study. “We might be able to treat one class of kids one way, and another class in a different way. But we don’t really understand all these genes and pathways yet.”
Of course, that’s exactly what the families of kids with autism want to have: an understanding of the genetics in their kids and how that might guide diagnosis and treatment. Only a tiny fraction of patients with ASD get genetic testing, but experts say that clinical tests available now may help to explain the cases of as many as 20 percent of patients with ASD. One company, Seaside Therapeutics, near Boston, tried to target a neurotransmitter with a drug it hoped would help improve social behavior and reduce irritability in patients with ASD. Unfortunately, that trial didn’t succeed, but researchers remain hopeful.
“We already have a sizable list of autism genes, and this will continue to grow,” says Sebat. “We need to begin to recognize which of these genes point to a therapeutic pathway. The treatments will come slowly, but they will come.”
The Nature paper by Wigler and Iossifov also articulated hope for treatments. Because everyone has two copies of all genes, and sometimes it takes only one corrupt copy of a gene to cause autism, Wigler said they theorized that if they could strengthen the remaining normal gene, it could be possible to restore proper function. “In our view, the long-term prognosis for treating ASD is positive,” the paper concludes.
“We’re always searching for answers,” says mom Jenn Drohan. “Why did this happen? What can we do about it? Different medications work very differently in my two sons. It would be great if someday we could look at somebody’s genetics and say, ‘This will work. This won’t.’”
Other parents have become frustrated waiting for genetic answers. “I think genetics is part of it,” says Raj Batra, a cancer researcher at the University of California, Los Angeles, and a father of three boys, two of whom have ASD. However, Batra has begun to focus simply on how to deal with his two autistic children, rather than waiting for a genetic explanation. He says it is entirely speculative that identifying genomic markers will lead to precision medicine. He is strongly in favor of jointly pursuing experimental treatment strategies that seek to change observed behavioral deficits, he says, as opposed to being wholly dependent on pharmacogenomics, which studies how genes affect a patient’s response to drugs in order to guide drug strategies. He points out that the vast majority of effective treatments for autism are based on behavioral interventions.
“I think it’s going to be difficult to look at autism from the bottom up — it’s so varied,” Batra says. “We need to be talking about systems biology, and with autism, we’re just not there yet.”
Leading researchers generally agree with Batra’s take, but they’re much more hopeful that we will eventually explain autism from the bottom up, from gene to physiology to behavior.
“We have come up with many high-effect mutations,” says State, of UCSF. “The fields of developmental neurobiology and systems biology are converging in a way that will really empower the next generation of studies. This will not be a list of genes; it will be that we will be able to understand autism in the same [systemic] way that we have begun to understand cancer and autoimmune disease.