Abstract
The development of robust, non-hypothesis based case/control studies has led to a large push forward towards identifying common genetic variants that contribute to complex traits. However, despite many attempts, the search for common disease-predisposing variants in childhood developmental disorders has largely failed. Recently, a role for rare causal variants and de novo mutations is emerging in the genetic architecture of some of these disorders, particularly those that incur a large degree of selection against the phenotype. In this paper, we examine these data and use classic genetic epidemiological approaches to gain insights into the genetic architecture of ASD. Future studies using next generation sequencing should elucidate the precise role de novo mutations play in disorders traditionally thought to have resulted from polygenic or common disease, common variants inheritance.
Highlights
Autistic spectrum disorders (ASD) are a group of neurodevelopmental disorders clinically characterized by deficits in three core domains termed the phenotypic triad: impairments in social interaction; impairments in communication; and restricted interests and repetitive behavior
Given the diverse nature of the ASD phenotype, it would be foolhardy to attempt to provide an absolute cause for the disorder, whether from the perspective of neuroscience, psychology or genetics
ASD represents a continuum on the phenotypic level, this does not necessarily imply the presence of a continuum at the genetic level
Summary
Autistic spectrum disorders (ASD) are a group of neurodevelopmental disorders clinically characterized by deficits in three core domains termed the phenotypic triad: impairments in social interaction; impairments in communication; and restricted interests and repetitive behavior. This would posit that under a polygenic model, the allelic variants that produce the ASD phenotype must have combined more frequently to produce individuals that would be modernly diagnosed as autistic In order for these variants to have remained globally at a similar frequency, there could not have been any selection acting against them, or any fixation by genetic drift during small population migrations and settlements, otherwise an uneven disease distribution would be presently observed. Considering the low transmission of the ASD-conferring allelic variants, it is very unlikely that the remaining cases of idiopathic ASD could explain an even disease distribution around the globe Analyzing this observed feature under the genetic architecture of idiopathic ASD dominated by de novo mutations, an even disease distribution would be predicted, as mutation rates should not be considerably different between any specific global populations. The mechanism that leads to a phenotype with variable expressivity at most loci is unknown; it is possible that other genetic variants and environmental factors may influence the ASD phenotype when such a gene is mutated
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