Exonic Mosaic Mutations Contribute Risk for Autism Spectrum Disorder
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Abstract
Genetic risk factors for autism spectrum disorder (ASD) have yet to be fully elucidated. Postzygotic mosaic mutations (PMMs) have been implicated in several neurodevelopmental disorders and overgrowth syndromes. By leveraging whole-exome sequencing data on a large family-based ASD cohort, the Simons Simplex Collection, we systematically evaluated the potential role of PMMs in autism risk. Initial re-evaluation of published single-nucleotide variant (SNV) de novo mutations showed evidence consistent with putative PMMs for 11% of mutations. We developed a robust and sensitive SNV PMM calling approach integrating complementary callers, logistic regression modeling, and additional heuristics. In our high-confidence call set, we identified 470 PMMs in children, increasing the proportion of mosaic SNVs to 22%. Probands have a significant burden of synonymous PMMs and these mutations are enriched for computationally predicted impacts on splicing. Evidence of increased missense PMM burden was not seen in the full cohort. However, missense burden signal increased in subcohorts of families where probands lacked nonsynonymous germline mutations, especially in genes intolerant to mutations. Parental mosaic mutations that were transmitted account for 6.8% of the presumed de novo mutations in the children. PMMs were identified in previously implicated high-confidence neurodevelopmental disorder risk genes, such as CHD2, CTNNB1, SCN2A, and SYNGAP1, as well as candidate risk genes with predicted functions in chromatin remodeling or neurodevelopment, including ACTL6B, BAZ2B, COL5A3, SSRP1, and UNC79. We estimate that PMMs potentially contribute risk to 3%-4% of simplex ASD case subjects and future studies of PMMs in ASD and related disorders are warranted.
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Next-generation sequencing identified one intronic, two missense, and two nonsense variants in NCKAP1L in autism patients.
“Next-generation sequencing identified one intronic114, two missense133,134, and two nonsense variants in autism patients104,114, and the functional consequences of these variants remain to be established (Table 2u).”
From The WAVE complex in developmental and adulthood brain disorders (2025) · cites this paper as [134]
Mosaic mutation characteristics are similar to the Simons Simplex Collection despite different DNA sources, capture reagents, and sequencing instruments.
“Comparing these data to a similar mosaic set from the Simons Simplex Collection (SSC),23 we found similar mosaic mutation characteristics, despite the fact that different DNA sources, capture reagents, and sequencing instruments were used”
From Exome sequencing of 457 autism families recruited online provides evidence for autism risk genes (2019) · cites this paper as [23]
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Wilfert, A. B., Sulovari, A., Turner, T. N., Coe, B. P., & Eichler, E. E. (2017) · Genome Medicine · doi:10.1186/s13073-017-0498-x · Cited by 144 · see citing works
Selfish mutations dysregulating RAS-MAPK signaling are pervasive in aged human testes
Maher, G. J., Ralph, H. K., Ding, Z., Koelling, N., Mlcochova, H., Giannoulatou, E., Dhami, P., Paul, D. S., Stricker, S. H., Beck, S., et al. (2018) · Genome Research · doi:10.1101/gr.239186.118 · Cited by 85 · see citing works
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The Genetics of Autism Spectrum Disorders
Yuen, R. K. C., Szatmari, P., & Vorstman, J. A. S. (2019) · Autism and Pervasive Developmental Disorders · doi:10.1017/9781108297769.006 · Cited by 19 · see citing works
Chromatin remodeling dysfunction extends the etiological spectrum of schizophrenia: a case report
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The WAVE complex in developmental and adulthood brain disorders
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- Authors
- Krupp, D. R., Barnard, R. A., Duffourd, Y., Evans, S. A., Mulqueen, R. M., Bernier, R., Rivière, J.-B., Fombonne, E., & O’Roak, B. J.
- Affiliations
- Oregon Health & Science University (US)
- Université de Bourgogne (FR)
- University of Washington (US)
- McGill University (CA)
- Corresponding author
- O’Roak, Brian J.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2017-09
- Volume
- 101
- Issue
- 3
- Pages
- 369-390
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC5590950
- OpenAlex
- W2949076809
- Cited by
- 204
- References
- 74
- Citations by year
- 2026: 16 · 2025: 17 · 2024: 22 · 2023: 22 · 2022: 21 · 2021: 20 · 2020: 27 · 2019: 24 · 2018: 28 · 2017: 3 · 2016: 1 · 2014: 1
- FWCI
- 12.87
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Funders
- Simons Foundation (SFARI 305927)
- Agence Nationale de la Recherche (ANR-13-PDOC-0029)
- Klingenstein-Simons Fellow in Neurosciences
- Alfred P. Sloan Foundation Fellow in Neuroscience (FG-2015-65608)
- NARSAD Young Investigator Award (22935) from the Brain and Behavior Research Foundation
- 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 › Genomics and Rare Diseases
- Keywords
- autism spectrum disorder, de novo mutations, single nucleotide variants, Simons Simplex Collection, synonymous mutations, splicing, neurodevelopmental disorders, genetic risk factors, CHD2, CTNNB1, SCN2A, SYNGAP1, chromatin remodeling genes
- MeSH terms
- Autism Spectrum Disorder, Child, Exons, Female, Humans, Male, Mosaicism, Mutation, Genetic Variation, Zygote, Cohort Studies, Genetic Predisposition to Disease, Databases, Genetic
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