Abstract
Though extensively characterized clinically, the causes of autism spectrum disorder (ASD) remain a mystery. ASD is known to have a strong genetic basis, but it is genetically very heterogeneous. Recent studies have estimated that de novo disruptive mutations in hundreds of genes may contribute to ASD. However, it is unclear how it is possible for mutations in so many different genes to contribute to ASD. Recent findings suggest that many of the mutations disrupt genes involved in transcription regulation that are expressed prenatally in the developing brain. De novo disruptive mutations are also more frequent in girls with ASD, despite the fact that ASD is more prevalent in boys. In this paper, we hypothesize that loss of robustness may contribute to ASD. Loss of phenotypic robustness may be caused by mutations that disrupt capacitors that operate in the developing brain. This may lead to the release of cryptic genetic variation that contributes to ASD. Reduced robustness is consistent with the observed variability in expressivity and incomplete penetrance. It is also consistent with the hypothesis that the development of the female brain is more robust, and it may explain the higher rate and severity of disruptive de novo mutations in girls with ASD.
Highlights
The genetic architecture of autism spectrum disorder (ASD) is very complex and hard to dissect
Based on this model, genetic variation associated with ASD could be divided to two types: (1) genetic variation, mainly rare mutations, that reduce the phenotypic robustness of the brain, and (2) genetic variation, such as common variants, that influence brain functions involved with social cognition
SUMMARY The classical genetic view of ASD and many other neuropsychiatric disorders is focused on genes that code for neural components that are essential for brain function
Summary
The genetic architecture of ASD is very complex and hard to dissect. Recently, there have been several breakthroughs in our understanding of this heterogeneous disease, including increased appreciation of the importance of de novo mutations (Sebat et al, 2007). The power of enrichment analyses based on CNVs is limited by their large size, which in many cases encompasses a large number of genes In such analyses gene size may be an important confounding factor, especially when dealing with disorders of the brain (Raychaudhuri et al, 2010). Another approach was to study genes with single base mutations; including mutations that lead to ASD associated genetic syndromes
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