Figure 1.
Autism heterogeneity in the context of common and rare genetic variation. Adapted from Reference 65 a with permission. (a) Susceptibility to autism spectrum disorder (ASD) may in some cases reflect the contribution of normal variation in heritable, potentially distinct core components of autism (endophenotypes). Normal variations in language, social, and repetitive restrictive behaviors are illustrated as overlapping but distinct functions, with the green and red demarcating the highest level of functioning and progressive abnormality, respectively. Under such a scheme, moderate abnormality in all three areas is necessary for a diagnosis of autism, but abnormality in one area, e.g., language, leads to a more circumscribed condition, such as specific language impairment. Patients with Asperger syndrome would have normal language but lie in the red zone for the other two components. Each of these heritable cognitive-behavioral components, or endophenotypes, although genetically complex, is likely to be less heterogeneous than the syndrome of autism. These endophenotypes can be studied separately to increase power to detect common genetic risk variants. (b) A simplified model of how a variety of risk variants, large and small, may contribute to ASDs in aggregate. The contribution of genetic or environmental factors is emphasized by the size or position of each representative weight. Mendelian mutations, such as de novo copy number variations, are depicted as a large ball because they are considered causal in many cases and would tip the balance, placing an individual essentially in the red in all categories shown in panel (a) (pleiotropy), resulting in autism. It is also likely that in some cases, common variation would modulate such major gene effects on phenotype.