Endophenotypes in Autism Spectrum Disorders

Autism Spectrum Disorder (ASD) is a complex disease with onset during early childhood and typically a life-long course. Genetic liability plays a prominent role in ASD, as siblings of affected individuals display on average 25-fold higher autism risk rates compared to the general population. However, genetic contributions fit in most cases with complex, “multiple-hit”, oligogenic/polygenic models encompassing several loci and also gene-environment interactions. Furthermore, ASD should be viewed as the extreme end of a set of continuous dimensions pertaining to the realms of human socialization, language development and behaviour, rather than as a “black or white” medical condition. This complexity spurs interest into the heuristic potential of “endophenotypes” in ASD, as originally applied by Gottesman and Shields (1973) to the realm of psychiatry. Endophenotypes can be defined as familial, heritable and quantitative traits associated with a complex disease. Occupying an intermediate position between genotype and behaviour, these traits offer the potential to bridge the gap between complex disease phenotypes, such as autism, and the underlying genetic mechanisms. The most reliable endophenotypes in ASD can be grouped into seven categories: biochemical, morphological, hormonal, immunological, neurophysiological/neuroanatomical, neuropsychological and behavioural. Their use holds promise to foster advances not only toward more reliable genotype-phenotype correlations in autism research, but also in dissecting clinical subgroups of ASD patients with relatively homogeneous pathophysiological underpinnings, aiding clinicians in early diagnosis once incorporated into broader biomarker panels, and predicting developmental trajectories and treatment response.