Epigenetics of Autism-related Impairment: Copy Number Variation and Maternal Infection
Open accessAbstract
OBJECTIVE: Epidemiological data have suggested maternal infection and fever to be associated with increased risk of autism spectrum disorder (ASD). Animal studies show that gestational infections perturb fetal brain development and result in offspring with the core features of autism and have demonstrated that behavioral effects of maternal immune activation are dependent on genetic susceptibility. The goal of this study was to explore the impact of ASD-associated copy number variants (CNVs) and prenatal maternal infection on clinical severity of ASD within a dataset of prenatal history and complete genetic and phenotypic findings. METHODS: We analyzed data from the Simons Simplex Collection sample including 1971 children with a diagnosis of ASD aged 4 to 18 years who underwent array comparative genomic hybridization screening. Information on infection and febrile episodes during pregnancy was collected through parent interview. ASD severity was clinically measured through parent-reported interview and questionnaires. RESULTS: We found significant interactive effects between the presence of CNVs and maternal infection during pregnancy on autistic symptomatology, such that individuals with CNVs and history of maternal infection demonstrated increased rates of social communicative impairments and repetitive/restricted behaviors. In contrast, no significant interactions were found between presence of CNVs and prenatal infections on cognitive and adaptive functioning of individuals with ASD. CONCLUSIONS: Our findings support a gene-environment interaction model of autism impairment, in that individuals with ASD-associated CNVs are more susceptible to the effects of maternal infection and febrile episodes in pregnancy on behavioral outcomes and suggest that these effects are specific to ASD rather than to global neurodevelopment.
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Prior work provides some evidence in support of MIA-gene interactions, such as co-occurrence of MIA with TSC2 haploinsuffiency, rare de novo CNVs and PTEN mutations.
“Prior work provides some evidence in support of such MIA-gene interactions, such as co-occurrence of MIA with TSC2 haploinsuffiency,92 rare de novo CNVs93 and PTEN mutations.39”
From Maternal immune activation dysregulation of the fetal brain transcriptome and relevance to the pathophysiology of autism spectrum disorder (2018) · cites this paper as [93]
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- Authors
- Mazina, V., Gerdts, J., Trinh, S., Ankenman, K., Ward, T., Dennis, M. Y., Girirajan, S., Eichler, E. E., & Bernier, R.
- Affiliations
- Pennsylvania State University (US)
- University of Washington (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Mazina, Varvara
- ORCID
- Venue
- Journal of Developmental & Behavioral Pediatrics
- Published
- 2015-02
- Volume
- 36
- Issue
- 2
- Pages
- 61-67
- ISSN
- 0196-206X (ISSN-L)
- PMC
- PMC4318761
- OpenAlex
- W2033984965
- Cited by
- 101
- References
- 25
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 6 · 2023: 5 · 2022: 12 · 2021: 10 · 2020: 11 · 2019: 10 · 2018: 11 · 2017: 9 · 2016: 16 · 2015: 8
- FWCI
- 8.83
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Journal of Developmental & Behavioral Pediatrics (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institute of Mental Health (R01MH101221)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (U54HD083091)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Keywords
- autism spectrum disorder, copy number variation, maternal infection, prenatal infection, maternal fever, gene-environment interaction, ASD severity, social communication deficits, restricted and repetitive behaviors, fetal brain development, Simons Simplex Collection, adaptive behavior
- MeSH terms
- Autism Spectrum Disorder, Child, Child, Preschool, Female, Fever, Humans, Male, Pregnancy, Pregnancy Complications, Infectious, Registries, Severity of Illness Index, Genetic Predisposition to Disease, Epigenesis, Genetic, DNA Copy Number Variations, Gene-Environment Interaction
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