The Simons Simplex Collection aims to gather samples from
2,000 families in which a single child is affected with autism.

In June 2003, more than a dozen of the country’s leading autism experts met for an unusual ‘Autism Think Tank’ in New York City. Over two days, they sat at one large table, brainstorming research ideas in genetics, brain imaging, neurophysiology — anything that might help propel the field toward a cure.

On the genetics front, the Autism Genetic Resource Exchange (AGRE) had for the previous six years been populating a gene bank of blood samples from autistic children and their families across the country.

In what managing director Clara Lajonchere calls a “swat team approach,” the California-based AGRE group sends medical teams directly to the children’s homes for cognitive tests and blood samples. AGRE then makes that data available to any reputable researcher.

But the massive effort — the group has sampled 1,717 families to date — has a few drawbacks.

“What we can do in the home is limited,” Lajonchere says. AGRE, which is funded by the nonprofit Autism Speaks, can’t do imaging tests, for instance, or long-term follow-ups on behavioral or language skills.

What’s more, the researchers collect samples mostly from “multiplex” families — those that have more than one family member diagnosed with an Autism Spectrum Disorder (ASD) — leaving out the large group of ‘simplex’ families that have just one autistic child.

These shortcomings were central to the animated discussions at the think tank and in follow-up meetings in 2005.

“We agreed that the AGRE collection was going to be a great resource of multiplex, but that simplex kids might be different genetically and might be different clinically,” recalls Emory University geneticist David Ledbetter, who sits on AGRE’s scientific advisory board. “We thought [a simplex project] would be an important one to take on.”

The discussions led to the Simons Simplex Collection, which aims to catalog the genetic makeup, medical histories, and behavioral patterns of 2,000 autistic children aged 5 to 15 from simplex families.

In August 2006, the University of Michigan’s Autism and Communication Disorders Center, led by clinical psychologist Cathy Lord, became the pilot clinic for the project.

As of February 2008, the SSC has grown to 13 sites, which together have collected samples from 78 simplex families.

With rigorous and uniform phenotyping procedures, and a novel web-based database system, the SSC is set to identify many of the genetic changes that characterize autism and unite the research field. “We’re all contributing to something that’s bigger than what any of us could do as individuals,” Lord says.

Multiple causes

When AGRE began in 1997, its goal was to find causal genes for autism. Because the researchers knew they had limited funds, they recruited families that have more than one member diagnosed with autism. “They figured they’d get the most bang for their buck if they focused on families where there was some kind of known genetic component,” Lajonchere says.

But those families only account for a subset of cases of autism, notes Gerald Fischbach, director of the Simons Foundation Autism Research Initiative. “Most cases arise seemingly out of nowhere, where normal parents have a child who is autistic,” Fischbach says.

The prevalence of these simplex cases suggests that autism might arise not from the presence of a causal gene, but from specific changes to the chromosome in the seconds, days or months after conception.

“We’re in the camp that thinks a significant proportion of autism will be from mutations in single genes, or chromosomal deletions and duplications,” says Ledbetter.

If all autistic children were genetically tested, he says, about 15 percent would have a known chromosomal abnormality. As genetic technologies improves, he adds, “that percentage is likely to go up significantly.”

A segment of 25 genes on chromosome 16, for instance, was found in January to be deleted or duplicated in about one percent of children with autism. Fragile X syndrome accounts for one to two percent of all autism cases, and a duplication on chromosome 15 accounts for another one to two percent. “Many of these small one-percent groups, when combined, account for most cases of autism,” Ledbetter says.

Rigorous tests

Perhaps the most notable aspect of the SSC is the meticulous phenotyping protocols each of the 13 centers follows. This has been a focus of Lord’s clinic since 1989, when she and others developed the Autism Diagnostic Observation Schedule (ADOS), the gold standard for accurately describing the behavioral and language deficits in kids with autism.

“For kids of different ages, there are different sets of toys and activities, and we watch them playing and then code different aspects of their behavior,” Lord explains. Extensive medical histories and parent- and teacher-interviews supplement the behavioral, psychological and language tests.

Accurate phenotypic descriptions are crucial because there are no specific biomarkers for autism and the disorder’s behavioral symptoms often resemble those of other neuro-developmental diseases.

Researchers from each SSC site are individually trained at Lord’s clinic in the study protocols, allowing researchers from all of the sites to combine their samples. With access to larger groups of kids with particular — and rare — subtypes, “We can better address the heterogeneity of the disorder,” Lord explains.

The phenotyping data will eventually be paired with genetic data from the blood samples. “This collection is going to be very, very powerful in terms of detective work,” says clinical geneticist Donna Martin, the genetics principal investigator at the University of Michigan site. “Once we get the gene mutations, we’ll be able to go back and pinpoint specific features that were present in their phenotype.”

Each of the sites will send blood samples — collected from the autistic child, as well as from parents and unaffected siblings — to the Rutgers University Cell and DNA Repository in Piscataway, New Jersey, where a team of researchers and robots will process the samples into cell lines and store them for later use.

With the DNA from these samples, two centers — the Yale Center of Excellence in Genomic Science and the Cold Spring Harbor Laboratory in New York — will perform comprehensive genomic analyses.

Each center plans to use a different kind DNA microarray that breaks the genome up into millions of small pieces to look for abnormalities. "The idea is that the two methodologies will be complementary: one would catch things that the other misses," explains the Rutgers repository’s director Jay Tischfield.

Matched with the phenotyping information from the individual clinics, that genetic data will be stored on a central database designed for the SSC that all participating researchers can access online.

Like the AGRE collection, the SSC data will also eventually be opened up to any reputable researcher.

“We're going to have two extremely large datasets that will be freely available to all researchers," adds Lajonchere. “When you consider how much work there is to do, it's really divide and conquer."