Nerve Cells

'Simplex' collection seeks to find origins of autism

In February 2005, more than a dozen leading scientists met for an unusual 'Autism Think Tank' in New York City. Over the course of two days, they brainstormed ways to enhance our understanding of autism through studies of genetics, brain imaging and neurophysiology.

Among other recommendations, these researchers emphasized the need to identify genetic risk factors for autism. The discussions led to our current effort to study "simplex" families in which one child (aged 4 to 15) has been determined to be on the autism spectrum but neither parent nor any other sibling is similarly affected.

The Simons Simplex Collection (SSC) is based, in large part, on the work of Michael Wigler and Jonathan Sebat and their colleagues at the Cold Spring Harbor Laboratory (CSHL). In a groundbreaking paper published in early 2007, the CSHL group reported that roughly ten percent of children with autism were found to have small deletions or duplications of DNA segments. Such Copy Number Variants (CNVs) were ten times more common in children with autism than in unaffected children. Strikingly, the CNVs were usually not present in the somatic cells (blood cells or other tissues) of either parent. They probably arise as new mutations in the germ cells of one or the other parent. Such "de novo" mutations are rare and they are usually not passed on from generation to generation. That is, they are not inherited. The authors predict that higher resolution genome scans for CNVs will show that most cases of autism arise in this manner.

The SSC is an unprecedented effort to study 2,000 families (8,000 individuals) with rigorous and uniformly applied phenotyping procedures. Precise phenotype descriptions are of paramount importance in our search for autism genetic risk factors.

Thirteen medical centers across North America are now involved. The selection of diagnostic instruments, and training in their use is under the direction of Catherine Lord, director of the University of Michigan Autism and Communication Disorders Center. In addition to the rigor of the initial phenotyping effort the SSC offers the opportunity to follow individuals over time. Standard instruments such as the Autism Diagnostic Observation Schedule (ADOS) and the Autism Diagnostic Interview - Revised (ADI-R) are supplemented with other measures of cognitive and emotional function, extensive medical histories, and teacher-interviews. Phenotype data will be correlated with genetic data obtained by analysis of DNA obtained from each participant in the study. Two groups funded by the Simons Foundation are poised to perform high-resolution genome scans for CNVs and to follow up with additional genetic analyses. The Wigler group at the CSHL lab will take one approach, and a group of geneticistsfrom SSC sites led by Matthew State at Yale will take a complementary approach. Data from these and all subsequent studies will be stored in a central database that is available on line to all researchers worldwide.

As Lord says, "We're all contributing to something that's bigger than what any of us could do as individuals."