With a database of about 600 families and counting, Cure Autism Now's Autism Genetic Resource Exchange is providing scientists with the information they need to uncover autism's genetic secrets

by Ela Schwartz

Meet the Robb family: Dara, Doug, and their five beautiful children. There’s Taylor, the oldest at age ten, a high-achiever and superb athlete who enjoys reading and writing. Dougie, age seven, is a creative thinker, a master at video games, affectionate, and as Dad puts it, "loves Mom more than anything in the world." Five-year-old Jaxon also loves video games as well as music and is looking forward to piano lessons. Peyton, a bright four-year-old, is into dolls and dress-up and loves to sing and dance. Mia Grace, two, may be the baby of the family and a girly-girl like her sister but is showing a strong-mindedness that will surely make her a force to reckon with.

But the Robb family is not as typical as they appear. Both Jaxon and Dougie are on the autism spectrum: Dougie has been diagnosed with PDD/NOS and ADHD and Jaxon is autistic with limited speech and many self-stim behaviors.

For Doug and Dara, this has meant finding appropriate therapies and programs for the boys, fighting the school district for services and moving to a community with a good ABA program for Jaxon. For the girls, it's meant adjusting to the fact that there is not just one, but two children who need extra attention from mom and dad.

"We have struggled for so long," says Dara. "Why us? Why have we been given these circumstances, not only once, but twice?"

The Robbs are not alone. Just as autism has become more prevalent, so have families with more than one affected child. Research has shown that if one child in a family has autism, there’s a 5 percent chance that another child will also be affected, a statistically significant increase over the general population.

There clearly appears to be a genetic component at work, but it’s not that simple. Although some forms of autism, such as Fragile X syndrome, can be traced to a single gene, in most cases, autism is idiopathic, meaning there is no identifiable cause. In these cases, scientists say it’s more likely that multiple genes are involved, and piecing together this elusive puzzle is the holy grail researchers are searching for.

Thanks to a unique program formed by Cure Autism Now called the Autism Genetic Resource Exchange (AGRE, pronounced "agree"), these multiplex families (those with more than one member with autism) can help researchers on their quest by donating not money but a gift just as precious—their DNA.

"With two boys diagnosed, I thought about my daughters," explains Dara Robb regarding her decision to enroll in AGRE. "What happens when they get married and want to have kids? They're at risk if there's a genetic predisposition to autism. We thought about the future children of the world and how much higher the rate of autism could become. We decided to turn around our despair, anger and grief and use it to help others as well as our boys."

Marianne Toedtman, registered nurse, outreach and resource manager for AGRE and the mother of an autistic child, says that approximately 600 families have joined with AGRE so far, and the program is continuing to reach out to more. "Families feel this is the right thing to do," she says. "I think they recognize that this research is unlikely to benefit their children, but that this is something important they can contribute to."

AGRE is a project born from other parents' pain channeled into productive action. John Shestack and Portia Iverson, the founders of Cure Autism Now and parents of a child with autism, found that only a few universities had collections of no more than 100 multiplex families, and none shared information with outside researchers. CAN decided to create a resource that would actively recruit families and share the data, and AGRE was launched in 1997.

"CAN saw that the best way to hurry science and promote collaboration and sharing was to create a resource that would take recruitment and data collection out of the hands of the researchers," says Clara Lajonchere, program director for AGRE. "By providing clinical information and genetic material on a large number of well-characterized families, we facilitate science by getting researchers to do what they do best…research."

Lajonchere, who has a Ph.D. in experimental psychology with concentrations in neuroscience and psychopathology, joined AGRE as program director in 2003. Though not the parent or relative of an individual with autism, she is driven by her compassion for children along with an intellectual curiosity about the workings of the brain and a desire to see the mystery of autism solved.

"At the close of 2004, there were 19 papers that cited the AGRE resource," says Lajonchere. "We have found all these findings to be incredibly important because each provides a piece of the puzzle. As we lay down each piece, the puzzle starts to come together and researchers are able to ask the right questions."

Funding is provided primarily through a grant from the National Institute of Mental Health (NIMH) to Dr. Daniel Geschwind, AGRE’s chief scientific advisor.

AGRE in Action

How does AGRE work? Families first complete and sign a Family Contact Form. Once a family is approved, the AGRE staff makes three home visits.

First, a diagnostician conducts a parent interview and performs an assessment on each affected child. This may be followed up by another visit or phone interview.

Then an AGRE pediatric neurologist comes to perform physical exams on affected individuals and collect family medical information and histories that look for traits and hereditary syndromes that may predispose individuals and families to autism.

Lajonchere says that family members who have not been diagnosed with autism may still demonstrate impairment in some of the autism symptom categories. "For example, some adults may have had delayed speech or difficulty with spelling and reading as children," she says. "Some individuals may have difficulty in social situations and others may exhibit some obsessive or compulsive tendencies. For genetic purposes, it turns out that those family members who may not reach the strict threshold for Autistic Disorder according to our diagnostic tools, are still incredibly powerful for research."

Finally, a phlebotomist draws blood from all participating family members.

Families are assured confidentiality: All family data, DNA samples and other identifying information collected are coded by an identification number to protect the identities of participating families.

Parents might be apprehensive about the process. How will the kids react to strangers coming into the home? Will the doctor or phlebotomist be annoyed that the children aren't cooperating?

Not to worry, says Toedtman, who reassures families that all AGRE staff are skilled in working with autistic children. "We use top-notch, high-quality staff," she says, adding that the vast majority of families who complete surveys evaluating their experiences say they were pleased with the AGRE team and the process.

The Robbs have been through the first step, the home interview, and are looking forward to completing the process. "The AGRE staff has been wonderful so far," says Robb. "We heard from other families that they're very professional and that you feel very comfortable having them in your home."

In return, participating families receive the AGRE newsletter. Parents who once felt they were suffering alone can read about the experiences and struggles of others like themselves and be given hope by learning about the exciting research being conducted by scientists—research that would not be possible without their participation.

Achieving Immortality

Each family’s DNA contribution becomes a gift that keeps giving to the research community. After the blood draw, samples are packaged, labeled with a confidential ID number, and shipped to the Rutgers University Cell and DNA Repository (RUCDR) in New Jersey. Here, according to Jay A. Tischfield, Ph.D., scientific director of RUCDR, samples are immortalized, a process that involves removing the white cells from the blood and treating them with a virus that causes the cells to divide at a rapid rate for an indefinite period. Staff can grow large numbers of these cells, typically over a billion for each subject.

"Once the DNA is available, the transformed cells are cryopreserved (frozen) and stored in a state of 'suspended animation' in large tanks containing liquid nitrogen," Tischfield says, "which can be 'defrosted' to yield more living cells." Thus, the RUCDR can supply DNA and cells to qualified researchers throughout the world, who may test for as many as a thousand genetic markers.

Tischfield explains that the data is entered into computer databases, which are then analyzed by statistical geneticists, who point out regions on chromosomes that could contain susceptibility genes. Molecular geneticists then intensely dissect these regions in an effort to identify genes important in autism. "While the entire process of finding genes may take many years, it has been dramatically successful with many of the simpler genetic diseases," Tischfield states.

After being approved by the AGRE Steering Committee, researchers can access data on the "approved researchers" section of the Web site or order biomaterials for analysis.

Researchers laud AGRE as providing a valuable resource, without which their work would not be possible.

Rita Cantor, professor of human genetics at UCLA School of Medicine, has used the AGRE data for a number of gene mapping studies for autism and quantitative traits that measure features of autism. "This data was critical, as it is the only publicly available data set for a genetic disorder that is constantly updated and can easily be downloaded from the Web," she says. "It is truly a unique resource that has helped researchers make important progress in understanding the genetic basis of autism. Most other researchers who are focusing on the genetics of autism are including the AGRE data with their own to conduct more powerful statistical tests in their gene finding efforts."

James S. Sutcliffe, Ph.D., assistant professor of molecular physiology and biophysics at Vanderbilt Kennedy Center (for Research on Human Development) at Vanderbilt University, concurs that AGRE is an "invaluable resource" that has been critical to his work.

Sutcliffe has used AGRE data for genome wide linkage analysis and application of novel approaches to detect clinically, or genetically, relevant interactions between potential autism risk loci. "We have also used data and samples from the AGRE resource to analyze linkage related to clinical subsets, as well as to test for potential involvement of specific candidate genes, like the serotonin transporter," he says.

"It requires enormous effort, time, highly-trained people, and resources to ascertain, recruit and perform detailed clinical characterization on a large number of families with any disease, and certainly for autism," he continues. "That this resource is made available to investigators who may then use biomaterials (like DNA) or genetic data to perform novel studies, to apply novel statistical techniques in what is a rapidly evolving field of studying complex genetic disease is of incalculable value. Many of us are interested in teasing out genetic risk factors in disorders, like autism, that have a substantial genetic component, but one which exhibits a complex architecture. Therefore, the availability of this wonderful resource will clearly have a vital role to play in facilitating the more rapid identification of genetic factors that contribute to risk of a child developing autism."

A.H. M. Mahbubul Huq, M.D., Ph.D., assistant professor in the department of neurology at Wayne State University in Detroit, won the Cure Autism Now 2003 Pilot Grant Award for research on candidate genes for autism on chromosome 7q. He has also published five scientific publications using AGRE data over the last two years.

"Without the samples from AGRE, we would not have been able to carry out our studies," he says. "Offering DNA samples from well characterized families is incredibly helpful and a very effective way of stimulating research."

Huq and other researchers say those family interviews—termed phenotypic data—is equally helpful. It enables researchers to essentially specialize by seeking out genes that contribute to particular autistic traits and then hone in on possible genetic causes.

Dr. T. Conrad Gilliam, director of the Columbia Genome Center at Columbia University College of Physicians and Surgeons and a member of the AGRE Steering Committee, says that using genotypic and phenotypic information is the way psychiatric genetics is going. "It may be that autism alone is too complicated, composed of too many genetic factors. And we may have to break it down into things like, for example, language acquisition, or any of those phenotypic aspects, to get concrete results."

However, Lajonchere says that autism cannot be pinned entirely on genes. "Many researchers believe that certain individuals have a genetic fragility or predisposition to autism that could be influenced by factors in the environment," she says. Possible causes could include exposures from chemicals used in the industrial processes, consumer products, prenatal or postnatal illnesses, medications, vaccinations and diet.

Thimerosal, a mercury-based preservative used in vaccines, is one suspected, and still controversial, culprit. "There is evidence both for and against the thimerosal theory," Lajonchere says. "Unfortunately, the jury is still out on this very crucial question. CAN realizes that this is a very important issue and is committed to supporting further work in this area."

From Cause to Cure

Once a cause is found, research can focus on finding a cure. "When the underlying neurobiological deficits are understood, there could be very basic neurobiological targets for new treatments," Lajonchere says. "Our hope is that with the help of Cure Autism Now and AGRE, researchers will develop therapeutic treatments that target some of the more debilitating symptoms of the disorder."

With more families and more research being done, Lajonchere is optimistic that a cure for autism will be discovered. "Our goal, and the goal of our board members, is to be out of business in ten years. We're not going to stop until we're all collecting unemployment."

The Robbs, meanwhile, are moving forward on their own journey. Dougie and Jaxon are progressing, and although the girls have had to sacrifice for the boys, there are advantages to having a big family. "Peyton has been instrumental in helping Dougie develop his play skills and his ability to interact," says Dara, "and I feel Mia will be able to connect with Jaxon at some point just like Peyton has done with Dougie."

After attending CAN's Walk Now in Philadelphia, they are becoming active not only with AGRE but with CAN's New Jersey chapter. And Dara has found an inner strength she didn't know she had. "You need strength to deal with these circumstances on a daily basis," she says. "Until someone pointed out how strong I was, I never would have thought or believed it. But they were right. That same strength is helping me to step out and become a voice, to help make a difference in any way I can. I love my boys, and I will fight the fight for them until it is done!"

Reprinted from Spectrum magazine, April/May 2005. Copyright© all text 2005 by Ela Schwartz