Unraveling the complex genetics of autism

To unravel the genetic mutations linked with ASDs, two separate research groups searched for "copy number variants" (CNVs), duplications or deletions of one or more sections of DNA, in genetic samples from over 1000 ASD families that were recruited as part of the Simons Simplex Collection project. The authors compared DNA from affected and unaffected siblings using distinct versions of a sensitive and powerful genetic screening technique which, combined with the large sample size, allowed discovery of CNVs on a finer scale than was previously possible.

"We observed a higher incidence of de novo (new) CNVs in children with ASD than their unaffected siblings," explains Dr. Michael Wigler from Cold Spring Harbor Laboratory who led one of the studies. "The functions of the genes in the regions of de novo variation point to a great diversity of genetic causes, but also suggest functional convergence. In addition, our results show that, relative to males, females have a greater resistance to autism from genetic causes, which raises the question of the fate of female carriers." In a companion study led by Dr. Dennis Vitkup from Columbia University, the CNVs identified in Dr. Wigler's study were analyzed using a new method which revealed that the affected genes are part of a large network involved in the development of synapses, key sites of communication between neurons.

A separate collaborative and multi-site study led by Dr. Matthew W. State from Yale University identified six rare recurrent de novo CNVs and, along with Dr. Wigler's group, found a significant association of ASD with de novo duplications of a chromosomal region that, when deleted, causes Williams-Beuren syndrome, a rare neurodevelopmental disorder which is associated with a highly social personality. "Finding strong evidence that at one position in the genome increases in the genetic material lead to ASD, while losses at precisely the same region lead to a highly social personality, was particularly exciting. This relatively small genomic interval clearly holds important clues to understanding the social brain," explains Dr. State.

Taken together, results from these studies highlight the importance of diverse rare genetic variations in autism. "The diversity implies that a treatment for one form of autism may have no value for the majority," says Dr. Wigler. "Once the specific genes mutated in ASDs are known with confidence, we can begin to think with clarity about problems specific to individuals within categories of causation rather than attempting to manage a conglomerate disorder." Dr. State adds, "These studies represent a significant step forward in understanding the genomic architecture of ASDs and provide important new points of traction in elaborating the molecular mechanisms and developmental neurobiology underlying ASDs. This type of knowledge is a critical first step in developing novel treatment approaches."