Autism spectrum disorders are heritable, and chromosomal defects are thought to play a role in their development. In a 2008 study, a group of researchers, including James F. Gusella of Massachusetts General Hospital, discovered that a stretch of DNA containing several genes is missing from chromosome 16 in about one percent of people affected or suspected to be affected with autism. The researchers hope to identify the specific genes located in this chromosomal region that play a role in causing autism.

The defect in chromosome 16 is extremely rare in the general population, and the fact that it spontaneously originates in the individual diagnosed with autism — rather than being inherited from unaffected parents — suggests that the defect drives the development of the disorder. In the same study, the researchers noticed that a duplication, rather than a deletion, of the same stretch of DNA might also predispose individuals to developing autism, albeit in an inherited and less consistent manner. This further piqued the researchers’ interest in this region of chromosome 16 and supported their hypothesis that a defective gene in that region leads to the faulty brain development underlying autism. Subsequent work has revealed that copy-number alterations of this segment do not themselves guarantee a diagnosis of autism, but are also associated with other phenotypes, such as schizophrenia and obesity.

To test their hypothesis, Gusella and colleagues are using gene sequencing and bioinformatics technology to determine which of the genes affected by the deletion or duplication of chromosome 16 contribute to autism. They have sequenced each of the genes in a large number of individuals with autism spectrum disorder from the Autism Genetic Resource Exchange and followed up the initial findings with sequencing of select genes in the Simons Simplex Collection. A number of putative functional variants were identified and are being analyzed, but as yet, a specific gene associated with autism has not been identified definitively. In parallel with these analyses, the researchers are using cutting-edge methods to generate stem cells from subjects with the 16p deletion and convert them into neurons and other types of cells, which will then be used as precise tools to test the effects of the autism-linked genes. Besides uncovering the role of particular genes, the researchers hope these stem cells can be used in studies of other autism-linked genes to shed light on the molecular basis for the development of autism.