There is overwhelming evidence that ASDs are genetic disorders, but the genetic mechanisms are varied, involving both inherited and de novo changes, as well as mutations, trinucleotide repeats, CNVs, and larger chromosomal abnormalities. An increasing proportion of ASD is being recognized as being the result of RVs associated with high ORs.
summarizes estimates the prevalence of some genetic variants in subjects ascertained for ASDs. Note that an additional 5% to 10% of cases have been identified with CNVs that are not recurrent but are likely pathogenic (based on size, de novo origin, etc). This suggests that, even with our current knowledge, 20% to 30% of ASDs can be given an etiological diagnosis using standard clinical genetic methods, including high-resolution karyotyping, array comparative genomic hybridization (array CGH), and MECP2
sequencing in girls,70,71
as well as PTEN
sequencing in individuals with extreme macrocephaly68
and the examination of methyl ation and gene dosage abnormalities in 15q.72
It is of interest that synaptic and neuronal cell adhesion molecules (CAMs) are appearing in RVs in ASDs. It is also of interest that cytoplasmic proteins that bind to synaptic CAMs are also being identified. These findings will lead to evidence-based hypotheses as to the molecular and cellular deficits underlying ASDs with differing etiologies. Of particular interest is the replicated finding of SHANKS deficits, which directly implicates glutamatergic synapse dysfunction in both autism and Asperger syndrome. This finding is supported by the replicated findings with NRXN1 and NLGNS/4,which can also play a role in excitatory synapse formation, maintenance, and plasticity.
As the technology for detecting smaller and smaller deletions and duplications improves and as people take advantage of the newest technologies of ultradeep sequencing, the search for RVs in ASDs will enter a new phase. In this context, a useful model for the genetic and genomic architecture of ASD might be that of MR. In MR several hundred genes have been found and the evidence is strong that there are more genes to be found. Not only are some of the MR genes associated with ASDs, but as we discover more and more rare variants in autism, it is becoming increasingly clear that the architecture of MR could represent a good model as to what we will find in ASDs.
There is empirical evidence that ASD can, in some cases, respond to intensive behavioral interventions.73
Thus, identifying individuals with greater risks of ASD at an earlier age will have important clinical and practical implications. It will require the simultaneous analysis of multiple genetic and genomic mechanisms before effective tools for the molecular assessment of ASD etiology, used in conjunction with behavioral assessment, can be applied in a widespread manner.
As ASD loci continue to be identified, animal models that recapitulate the genetic changc(s) can be developed. These models can clarify the function of the gene products in vivo, and will ultimately be useful to evaluate novel pharmaceutical interventions. An exciting development which will serve as a useful model going forward is the elaboration of the mGluR theory of FXS.74
This in turn has led to the initiation of a recent large-scale clinical trial in FXS in which a reverse agonist of mGlu5 is being assessed in FXS. As additional RVs associated with ASDs are identified, novel therapeutic approaches will arise, some which may be specific to a given RV (“personalized medicine”) and some that might prove effective across ASDs with differing etiologies.