Abstract
OBJECTIVE: The observed heterogeneity of autism spectrum disorder (ASD)-and the diversity of rare germline mutations with which it has been associated-has been difficult to reconcile with knowledge of its pronounced heritability in the population. METHODS: This article reviews and synthesizes recent family and developmental studies incorporating behavioral indices of inherited risk for ASD. RESULTS: Autism may arise from critical combinations of early inherited neurobehavioral susceptibilities-some specific to autism, some not-each of which may be traceable to partially-independent sets of genetic variation. These susceptibilities and their respective genetic origins may not relate to the characterizing symptoms of autism (after it develops) in a straightforward way, and may account for "missing heritability" in molecular genetic studies. CONCLUSIONS: Within-individual aggregations of a finite set of early inherited neurobehavioral susceptibilities-each individually common in the population-may account for a significant share of the heritability of ASD. Comprehensive identification of these underlying traits my help elucidate specific early intervention targets in individual patients, especially if autism represents a developmental consequence of earlier-interacting susceptibilities. Scientific understanding of the early ontogeny of autism will benefit from epidemiologically-rigorous, genetically-informative studies of robust endophenotypic candidates whose inter-relationships in infancy are mapped and normed.