The ongoing dissection of the genetic architecture of autistic spectrum disorder

Autistic spectrum disorders (ASD) are a group of neurodevelopmental disorders clinically characterized by deficits in three core domains termed the phenotypic triad: impairments in social interaction; impairments in communication; and restricted interests and repetitive behavior. The group consists of Asperger's syndrome (AS), pervasive developmental disorder not otherwise specified (PDD-NOS) and the prototypical autistic disorder (AD). They all share a similar age of onset of approximately 12 to 36 months, which corresponds to the developmental time period when spatial and temporal transcriptional cascades lead to remodeling and elaboration of neuronal circuitry [1,2]. The prevalence of ASD is between 10 in 10,000 and 60 to 70 in 10,000, depending on the precise definition used [3]. Evidence from family studies implies that ASD has a strong genetic basis: the concordance rate in monozygotic (MZ) twins ranges from 70 to 90%, whereas dizygotic (DZ) twin concordance varies from 0 to 10% [4,5]. Familial aggregation studies have shown that the relative risk of developing autism in first-degree relatives of an autistic patient is 3 to 7%, which is ten-fold higher than the prevalence in the general population. Although these lines of evidence suggest that the disorder is primarily of genetic origin, the genetic susceptibility factors responsible for ASD have remained largely elusive, despite several recent advancements in the field.Despite the seemingly precise definition of ASD above, it must be understood that ASD is not necessarily a simple binary diagnosis. ASD is a grouping of childhood developmental disorders that reflect the difficulties in categorizing psychiatric disorders on the background of a shifting landscape of child development, neuroplasticity and historical nosology, which do not necessarily reflect a homogenous grouping of phenotypes with shared genetic characters on the underlying biological level. ASD has a wide clinical spectrum, with some individual