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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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.
Nature Reviews Genetics thanks G. Konopka and the other, anonymous reviewer(s) for their contribution to the peer review of this work.
The authors declare no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
- 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). https://doi.org/10.1038/s41576-018-0066-2
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