The identification of multiple rare mutations has implicated numerous genes of diverse function in the aetiology of the ASDs. Although causality remains to be demonstrated in most cases, a substantial subset seems to be important in modulating disease risk. These de novo
mutations, together with those inherited in the context of a rare syndrome, each represent no more than 1–2% of cases individually, but account for at least 10–20% of the ASDs (; Supplementary information S1 (table)
). The proportion of ASDs that might eventually come to be explained in terms of such major gene effects (as opposed to multigene interactions) should be clarified within the next year or two.
Given variable expressivity and incomplete penetrance among individuals carrying the same rare mutation, understanding the manner by which these rare variants interact with common alleles remains important. Similarly, the normal distribution of ASD-like features in populations62
as well as the elevated frequency of the broader autism phenotypes in close relatives of probands9,10
argues for an important role of common variation. That several common variants have now been independently shown to modulate risk and/or presentation is also evidence of important progress. A significant challenge here, however, is a continued focus on categorical measures (such as whether an individual is affected or not). Instead, quantitative endophenotypes will be necessary to properly identify risk alleles and understand the manner by which variation contributes to pathology. From a biological perspective, common variants are likely to have much greater salience when studied with regards to more specific phenotypes, including measures of gene expression, brain structure and quantitative aspects of social behaviour or communication. Use of quantitative end-points will also allow evaluation of whether genes that modulate ASD risk can contribute to aspects of normal phenotypic variation. For example, the association of variation in CNTNAP2
with language onset raises the possibility that variation in this gene might also modulate language-related cognitive phenotypes in both the general population and other clinically distinct, but related, disorders.
Also important, and immediately tractable, is the question of whether ASDs of different etiologies share common molecular mechanisms or pathways, and, if they do, whether the relationship between the underlying genes be understood83,84
. Given the observed heterogeneity, an understanding of how risk factors interact functionally is an important step towards therapeutic interventions. Although this etiological heterogeneity will complicate substantially the translation of genetic findings from the laboratory to the clinic, it might prove useful in the identification of common targets for clinical intervention (BOX 2
). Related to the heterogeneity in the ASDs, and discussed above, is the absence of clarity surrounding the specifics of the relationship between the ASDs, MR and other neuropsychiatric conditions. Although each can appear together, that they are also seen independently provides an opportunity to understand the overlap between MR and autism at the level of brain structure and function. Other co-morbid disorders observed in families with ASD probands also provide an important entry-point for exploring the genetic and biological boundaries of these conditions. For example, some of the language deficits observed in the ASDs are also seen in other disorders such as specific language impairment. Similarly, aspects of frontal executive and social dysfunction seem to overlap with other childhood neurodevelopmental conditions such as attention deficit hyperactivity disorder. These concepts reinforce the idea that current clinical notions of boundaries between neuropsychiatric disorders need not be representative of the underlying genetic or biological etiologies. At a practical level, these data support evaluation of putative ASD-linked variants in unaffected family members, typically developing controls and cohorts with other neurodevelopmental disorders (for example, nonspecific MR, schizophrenia and bipolar disorder). Also helpful here could be the use of rare disease subtypes to define the relationships between ASDs, as well as links to clinically distinct disorders with overlapping features.
Finally, we must aim to integrate existing and emerging genetic candidates into our understanding of human brain function. Such efforts are likely to provide important insights not only into ASD but also into related disorders in which behaviour is compromised through impaired function of overlapping regions and circuits. Because genes modulate behaviour through complex temporal and positional expression, analyses of candidate genes both through development41
and in patient material (for example, the Autism Tissue Program
) will be important. Advances in systems biology should provide an important platform on which to integrate the modulatory effects of multiple interacting genes with functional data compiled from many levels of analysis83,84
From the dominance of psychodynamic theories of autism as recently as 1970 to the awareness of upwards of 20 bona fide risk genes today, it must be concluded that substantial progress has been made in a relatively short time. That the identification of virtually every ASD-related gene and syndrome occurred within the last 5–10 years is particularly telling. Linkage studies have not found ‘the autism gene’ but have unequivocally demonstrated that more sophisticated solutions will be required to explain this group of disorders. The availability of new technology — particularly the ability to engage families in research through the internet — will permit the initiation of population-based strategies that are likely to provide more satisfying answers. Despite the immense amount of work implied in this agenda, the landscape for the future study of the ASDs is coming into view and has never looked as promising.
|Frontal executive||Frontal executive function describes broad aspects of higher cognition (for example, attention, working memory and relational reasoning) that are mediated by the frontal lobe and interconnected subcortical circuitry.|