Cited by 127Autism Spectrum Disorder ResearchGenetics and Neurodevelopmental DisordersAlzheimer's disease research and treatments

Lost in Translation: Traversing the Complex Path from Genomics to Therapeutics in Autism Spectrum Disorder

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Sestan, Nenad, State, Matthew W.·2018·Neuron

Abstract

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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Crossref · 10.1016/j.neuron.2018.10.015

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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 measured
  • 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.

    “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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Authors
Sestan, N., & State, M. W.
Affiliations
QB3 (US)
Corresponding author
State, Matthew W.
Venue
Neuron
Publisher
Elsevier BV
Published
2018-10
Volume
100
Issue
2
Pages
406-423
ISSN
0896-6273 (ISSN-L)
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
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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