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Autism spectrum disorder: insights into convergent mechanisms from transcriptomics


Heredity has a major role in autism spectrum disorder (ASD), yet underlying causal genetic variants have been defined only in a fairly small subset of cases. The enormous genetic heterogeneity associated with ASD emphasizes the importance of identifying convergent pathways and molecular mechanisms that are responsible for this disorder. We review how recent transcriptomic analyses have transformed our understanding of pathway convergence in ASD. In particular, deep RNA sequencing coupled with downstream investigations has revealed that a substantial fraction of autistic brains possess distinct transcriptomic signatures. These signatures are in part a consequence of altered neuronal activity and have a particular impact on pre-mRNA alternative splicing patterns.

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Fig. 1: Major cellular pathways underlying ASD are interconnected through neuronal activity.
Fig. 2: Using transcriptomics to assess molecular changes underlying ASD.
Fig. 3: Cortical organoids grown in vitro to model human brain development reveal an excitatory-to-inhibitory imbalance in ASD.
Fig. 4: Splicing changes in ASD.
Fig. 5: Misregulated RNA processing is a central component of ASD aetiology.


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This work was supported by Canadian Institutes of Health Research (CIHR) grants to S.P.C. and B.J.B. and by a Simons Foundation grant to B.J.B. M.Q.-V. was supported by a CIHR scholarship and an Ontario Graduate Scholarship. B.J.B. holds the University of Toronto Banbury Chair in Medical Research.

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Nature Reviews Genetics thanks G. Konopka and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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All authors researched data for the article, provided substantial contribution to discussions of the content and reviewed or edited the manuscript before submission. M.Q.-V., S.P.C. and B.J.B. wrote the article.

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Correspondence to Mathieu Quesnel-Vallières, Sabine P. Cordes or Benjamin J. Blencowe.

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Glutamate signalling

Molecular pathway that includes the excitatory neurotransmitter glutamate and its synaptic receptors; largely responsible for driving neuronal activity.

Excitatory-to-inhibitory imbalance

Change in the ratio between excitatory (primarily glutamate) and inhibitory (primarily GABA) synaptic transmission that regulates normal brain activity and behaviour.

Glutamatergic neurons

Glutamate-expressing neurons that potentiate neuronal activity.

GABAergic neurons

GABA-expressing neurons that act as inhibitors of neuronal activity.


Process during which neural stem cells proliferate and differentiate into glial cells and neurons to generate the cortex during brain development.


GABAergic interneurons are a type of inhibitory neuron that filters neuronal activity and maintains the excitatory-to-inhibitory balance.

Cerebral organoids

Tissues grown in vitro from embryonic stem cells or induced pluripotent stem cells under conditions that promote the generation of differentiated, cortex-like structures (including neurons) to model brain development.

Cortical layering

Anatomical distribution of neurons into six molecularly distinct layers in the cortex during brain development; this layering is conserved in mammals.

Cassette exons

Exons that can be skipped or included in mRNA transcripts through alternative splicing.

Splicing quantitative trait loci

Genomic regions that are associated with variations in splicing patterns.

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Quesnel-Vallières, M., Weatheritt, R.J., Cordes, S.P. et al. Autism spectrum disorder: insights into convergent mechanisms from transcriptomics. Nat Rev Genet 20, 51–63 (2019).

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