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The genetic and neurobiologic compass points toward common signaling dysfunctions in autism spectrum disorders
Open accessAbstract
Autism spectrum disorder (ASD) is a common neurodevelopmental disorder with high heritability. Here, we discuss data supporting the view that there are at least two distinct genetic etiologies for ASD: rare, private (de novo) single gene mutations that may have a large effect in causing ASD; and inherited, common functional variants of a combination of genes, each having a small to moderate effect in increasing ASD risk. It also is possible that a combination of the two mechanisms may occur in some individuals with ASD. We further discuss evidence from individuals with a number of different neurodevelopmental syndromes, in which there is a high prevalence of ASD, that some private mutations and common variants converge on dysfunctional ERK and PI3K signaling, which negatively impacts neurodevelopmental events regulated by some receptor tyrosine kinases.
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“Later pregnancy and early postnatal life are additionally implicated by accumulating molecular and pathological evidence pointing to altered neuronal connectivity and a resultant perturbation in signaling pathways, systems under intense development in these periods.25,26”
From Environmental Chemical Exposures and Autism Spectrum Disorders: A Review of the Epidemiological Evidence (2014) · cites this paper as [26]
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“Evidence supporting environmental contributions to ASD risk include observations of incomplete concordance for autism among monozygotic twins and incomplete penetrance within individuals expressing a given ASD-linked gene mutation, whereby a significant percentage of carriers do not express autistic phenotypes [ 14 , 19 , 22 ].”
From DNA methylation: a mechanism linking environmental chemical exposures to risk of autism spectrum disorders? (2016) · cites this paper as [19]
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Metadata
- Authors
- Levitt, P., & Campbell, D. B.
- Affiliations
- Vanderbilt University (US)
- Corresponding author
- Levitt, Pat
- ORCID
- Levitt, Pat
- Venue
- Journal of Clinical Investigation
- Published
- 2009-04-01
- Volume
- 119
- Issue
- 4
- Pages
- 747-754
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2662567
- OpenAlex
- W2018736722
- Cited by
- 234
- References
- 115
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 7 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 7 · 2019: 5 · 2018: 6 · 2017: 18 · 2016: 13 · 2015: 14 · 2014: 27 · 2013: 16 · 2012: 26
- FWCI
- 1.91
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Neuroscience › Developmental Neuroscience › Williams Syndrome Research
- Keywords
- autism spectrum disorder, genetic etiology, de novo mutations, common genetic variants, ERK signaling, PI3K signaling, receptor tyrosine kinase, neurodevelopmental syndrome, neurodevelopmental disorders
- MeSH terms
- Alleles, Autistic Disorder, Child, Female, Humans, Male, Models, Genetic, Models, Neurological, Mutation, Proto-Oncogene Proteins, Genetic Variation, Signal Transduction, Receptors, Growth Factor, Proto-Oncogene Proteins c-met, Phosphatidylinositol 3-Kinases, Genetic Predisposition to Disease, MAP Kinase Signaling System, Genome-Wide Association Study
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