Autism is a neurodevelopmental disorder defined by three categories of deficits: 1) abnormal development or impairment of social interaction, 2) abnormal development or impairment of communication skills, and 3) stereotypic and repetitive behaviors [1
]. Autism is part of a larger family of neurodevelopmental disorders categorized by the Diagnostic and Statistical Manual IV-R under the term Pervasive Developmental Disorders (PDD) [1
]. PDD includes Asperger Syndrome (AS), where language appears normal, and pervasive developmental disorder not otherwise specified (PDD-NOS) in which children meet some but not all criteria for autism. Collectively, these disorders are known as the autism spectrum disorders (ASD) [1
]. Rett syndrome and Childhood Disintegrative Disorder also are classified as a PDD, but are exclusionary for a diagnosis of autism.
Hypothesized by Kanner to be an innate or inborn disorder in his original description, autism was not formally determined to be a genetic disorder until Folstein and Rutter demonstrated a greater than 50% concordance for monozygotic, versus 0% for dizygotic twins. More recent twin studies have observed as high as 90% trait heritability for monozygotic twins [2
], and family studies suggest a 22 fold increased risk over the general population for first-degree relatives [3
], although this does not use the current CDC prevalence estimate of 1/152 for ASD [4
]. Taken together, these studies indicate a high genetic liability, while leaving some room for environmental factors that may influence the penetrance or expressivity of these disorders with respect to genetic risk factors.
Although ASD is highly heritable, the identification of candidate genes has been hindered by the heterogeneity of the syndrome and insufficient numbers of participants, as compared to whole genome association studies in other complex genetic disorder. The establishment of collaborative groups, such as the International Molecular Genetic Study of Autism Consortium (IMGSAC) and Autism Genome Project Consortium [5
], and shared resources, such as the Autism Genetic Resource Exchange Consortium (AGRE) [7
], were therefore important steps in facilitating the identification of candidate genes. Linkage peaks on chromosomes 7q22–32 [5
] and chromosome 17q21 [9
] have been replicated. However most linkage signals have not been replicated, despite large increases in sample size, consistent with significant genetic heterogeneity [6
]. Recently, a whole genome association study involving over 1500 cases and controls combined from different cohorts has identified and replicated at least one locus at genome-wide significance [13
]. This demonstrates the promise of this approach, while at the same time, suggesting that very large sample sizes will be needed to identify additional genetic risk due to common alleles. Currently, there are over 25 different loci that may be considered autism susceptibility candidate genes (ASCG) and many more implicated loci are under investigation [12
]. Most of these are rare, Mendelian mutations, including copy number variation (CNV) or syndromic forms of autism, and only a few are due to common genetic variation. In this brief overview, we will try to highlight some of the major advances in the study of autism, as well as discuss what the known ASCG can tell us about the neurodevelopmental mechanisms that may be causative.