A genome-wide search for autism genes in the Simons Simplex Collection
Matthew State, M.D., PhD.
Edwin Cook, Jr., M.D.
University of Illinois at Chicago
Bernard Devlin, Ph.D.
University of Pittsburgh
Daniel Geschwind, M.D., Ph.D.
University of California, Los Angeles
Christa Lese Martin, Ph.D.
Catherine Lord, Ph.D.
Weill Cornell Medical College
Eric Morrow, M.D., Ph.D.
James Sutcliffe, Ph.D.
Christopher Walsh, M.D., Ph.D.
Boston Children’s Hospital
Matthew State and his colleagues at 13 sites around the U.S. completed a comprehensive genomic analysis of the Simons Simplex Collection (SSC) using micro-array technology. (The SSC is a database of families that include one child with autism and unaffected parents and siblings.) The researchers then studied how small changes in chromosomal structure called copy number variants (CNVs) that arise spontaneously in the DNA of an individual — that is, are not present in either of that person’s parents — contribute to autism risk. These studies have narrowed in on specific regions of the genome and specific genes that contribute to autism.
Among the areas of the genome described by the researchers is a small section of chromosome 7. Having an extra copy of this region increases the risk for autism. It is the same chromosomal region that, when one copy is lost, leads to Williams syndrome, a rare developmental disorder characterized by intense interest in social interaction. Determining which gene or genes in this interval is modulating complex social behavior could offer important avenues for treating autism.
The researchers made several other findings. The group showed that deletions and duplications of chromosome 16p11.2 are the most common chromosomal change seen in individuals with autism. State and his multisite team of investigators also showed that girls with autism carry evidence of more profound genetic risks, suggesting that they are protected from autism when carrying less serious mutations that would lead to autism in boys.
The collaborative group of investigators conducted a series of other investigations using microarray data from the SSC. They found evidence that sequence changes common in the general population also carry risk for autism, though the individual effects are still too small to identify specific risk genes. They identified a possible new metabolic risk for autism through the identification of mutations in the gene THMLE. And the group showed that reports of increased head size in children with autism, and other specific mutations, need to be reevaluated, taking into account the head sizes of the parents. Lastly, they showed that recessive mutations, in addition to spontaneous mutations, play a role in autism risk.