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). This simplified model (A) depicts how a variety of risk variants, large and small, may contribute to ASD in aggregate (B). The notion of hetereogeneous genetic mechanisms acting in different patients is captured by three individual examples depicted by circles (C).
(A) Normal variations in language, social behavior, and repetitive-restrictive behavior are illustrated as overlapping but with distinct functions (blue and orange demarcate the highest level of functioning and progressive abnormality, respectively). In this scheme, moderate abnormality in all three areas is necessary to be diagnosed with autism, but abnormality in one area, for example language, leads to a more circumscribed condition, such as specific language impairment. Patients with Asperger’s syndrome would have normal language but would lie in the orange zone for the other two components. Each of these heritable cognitive-behavioral components (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) The contribution of genetic or environmental factors is emphasized by size or position of each representative weight. Mendelian mutations, such as de novo CNVs, are depicted by a large ball because they are considered causal in many cases and would tip the balance, placing an individual essentially into the orange zone in all categories shown in (A) (pleiotropy), resulting in autism.
The reality, however, is that there are few mutations that act alone or are fully causal (green circle in C.) Many mutations, including those that are recurrent, are not fully penetrant, and some patients have more than one de novo CNV. Similarly, most mutations, even rare mutations such as those in the gene encoding neuroligin 4, or recurrent mutations such as del (16p), show variable expressivity, resulting in developmental delay or mental retardation in some individuals and autism in others. So, the environment or other common variants that might modulate social behavior or language could be tipping the balance toward autism in a child who would otherwise have had mild or moderate mental retardation (blue circle in C). In other cases, multiple common variants, each with a small effect and related to different components, would push an individual toward the right of the distribution and along with environmental or epigenetic factors would result in an individual with ASD (multicolored circle in C). Each of these scenarios, or a combination of the three, may be acting in a given individual with autism. Defining the extent to which each contributes on a population level to ASD is a goal of current genetic research.