Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder
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Recent progress in the genomics of non-syndromic autism spectrum disorder (nsASD) highlights rare, large-effect, germline, heterozygous de novo coding mutations. This distinguishes nsASD from later-onset psychiatric disorders where gene discovery efforts have predominantly yielded common alleles of small effect. These differences point to distinctive opportunities for clarifying the neurobiology of nsASD and developing novel treatments. We argue that the path ahead also presents key challenges, including distinguishing human pathophysiology from the potentially pleiotropic neurobiology mediated by established risk genes. We present our view of some of the conceptual limitations of traditional studies of model organisms, suggest a strategy focused on investigating the convergence of multiple nsASD genes, and propose that the detailed characterization of the molecular and cellular landscapes of developing human brain is essential to illuminate disease mechanisms. Finally, we address how recent advances are leading to novel strategies for therapeutics that target various points along the path from genes to behavior.
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The well-established sexual dimorphism of social disability adds another dimension to the search space between risk gene and human behaviour.
“In addition, the wellestablished sexual dimorphism of social disability adds yet another dimension to the expansive search space that exists between risk gene and human behaviour 48 .”
From Autism spectrum disorder (2020) · cites this paper as [48]
In “The Challenges of Clarifying nsASD Pathophysiology,” the paper says that male predominance in ASD prevalence suggests sexual dimorphism adds complexity to connecting risk genes with human social disability. It does not establish sexual dimorphism of social disability itself; it calls the male predominance unexplained. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlthough the study of ASD risk genes in model systems has revealed a great deal about general biology, how these findings relate to the pathophysiology of ASD is less clear.
“Although the study of ASD risk genes in model systems has revealed a great deal about general biology, how these findings relate to the pathophysiology of ASD is less clear 48,49 .”
From Autism spectrum disorder (2020) · cites this paper as [48]
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Lord, C., Brugha, T. S., Charman, T., Cusack, J., Dumas, G., Frazier, T., Jones, E. J. H., Jones, R. M., Pickles, A., State, M. W., et al. (2020) · Nature Reviews Disease Primers · doi:10.1038/s41572-019-0138-4 · Cited by 1,859 · see citing works
Self-citationAutism spectrum heterogeneity: fact or artifact?
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Mechanisms Underlying Circuit Dysfunction in Neurodevelopmental Disorders
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- Authors
- Sestan, N., & State, M. W.
- Affiliations
- QB3 (US)
- Corresponding author
- State, Matthew W.
- ORCID
- State, Matthew W.
- Venue
- Neuron
- Publisher
- Elsevier BV
- Published
- 2018-10
- Volume
- 100
- Issue
- 2
- Pages
- 406-423
- ISSN
- 0896-6273 (ISSN-L)
- PMC
- PMC6989093
- OpenAlex
- W2898312868
- Cited by
- 127
- References
- 163
- Citations by year
- 2026: 6 · 2025: 15 · 2024: 12 · 2023: 19 · 2022: 16 · 2021: 22 · 2020: 27 · 2019: 10
- FWCI
- 1.97
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Neuron (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- NIH (MH106934, MH106874, MH109904, MH109901, MH110926, MH110928, MH116487, MH116488, MH102342, MH111662, MH105575, MH115747)
- Overlook International Foundation
- Simons Foundation
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- de novo mutations, germline mutations, gene discovery, neurobiology of autism, pleiotropy, model organisms, human brain development, risk genes
- MeSH terms
- Autism Spectrum Disorder, Brain, Humans, Mutation, Genetic Therapy, Genomics
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