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Genome-wide characteristics of de novo mutations in autism
Open accessAbstract
De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent–child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (P=4.2×10−10). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother (P=7.7×10−13), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated (P=2.4×10−24). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (P=8.0×10−9; odds ratio=1.84), of which 15.6% (P=4.3×10−3) and 22.5% (P=7.0×10−5) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.
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“individuals with ASD have a two- to three-fold increase in the number of rare copy number variations (CNVs) and de novo loss-of-function (nonsense, frameshift, and splice site) variants compared to their unaffected siblings11–14.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [14]
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Metadata
- Authors
- Yuen, R. K., Merico, D., Cao, H., Pellecchia, G., Alipanahi, B., Thiruvahindrapuram, B., Tong, X., Sun, Y., Cao, D., Zhang, T., Wu, X., Jin, X., Zhou, Z., Liu, X., Nalpathamkalam, T., Walker, S., Howe, J. L., Wang, Z., MacDonald, J. R., Chan, A. J., D’Abate, L., Deneault, E., Siu, M. T., Tammimies, K., Uddin, M., Zarrei, M., Wang, M., Li, Y., Wang, J., Wang, J., Yang, H., Bookman, M., Bingham, J., Gross, S. S., Loy, D., Pletcher, M., Marshall, C. R., Anagnostou, E., Zwaigenbaum, L., Weksberg, R., Fernandez, B. A., Roberts, W., Szatmari, P., Glazer, D., Frey, B. J., Ring, R. H., Xu, X., & Scherer, S. W.
- Affiliations
- Hospital for Sick Children (CA)
- BGI Group (China) (CN)
- University of Toronto (CA)
- Karolinska Institutet (SE)
- Google (United States) (US)
- Autism Speaks (US)
- University of Alberta (CA)
- Memorial University of Newfoundland (CA)
- Corresponding author
- Scherer, Stephen W
- ORCID
- Yuen, Ryan KC
- Merico, Daniele
- Cao, Hongzhi
- Pellecchia, Giovanna
- Alipanahi, Babak
- Thiruvahindrapuram, Bhooma
- Tong, Xin
- Sun, Yuhui
- Cao, Dandan
- Zhang, Tao
- Jin, Xin
- Liu, Xiaomin
- Nalpathamkalam, Thomas
- Walker, Susan
- Wang, Zhuozhi
- MacDonald, Jeffrey R
- D’Abate, Lia
- Tammimies, Kristiina
- Uddin, Mohammed
- Wang, Mingbang
- Li, Yingrui
- Wang, Jun
- Wang, Jian
- Yang, Huanming
- Marshall, Christian R
- Anagnostou, Evdokia
- Zwaigenbaum, Lonnie
- Weksberg, Rosanna
- Fernandez, Bridget A
- Glazer, David
- Ring, Robert H
- Xu, Xun
- Scherer, Stephen W
- Venue
- npj Genomic Medicine
- Published
- 2016-08-03
- Volume
- 1
- Issue
- 1
- Pages
- 160271-1602710
- ISSN
- 2056-7944 (ISSN-L)
- PMC
- PMC4980121
- OpenAlex
- W2484001856
- Cited by
- 216
- References
- 70
- Citations by year
- 2026: 9 · 2025: 6 · 2024: 7 · 2023: 13 · 2022: 28 · 2021: 23 · 2020: 30 · 2019: 33 · 2018: 32 · 2017: 33 · 2016: 2
- FWCI
- 21.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- npj Genomic Medicine (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Autism Speaks
- GlaxoSmithKline
- Genome Canada
- Ontario Brain Institute
- National Alliance for Research on Schizophrenia and Depression
- Stollery Children’s Hospital Foundation
- Children's Hospital Foundation
- Ontario Genomics
- Government of Ontario
- Ontario Genomics Institute
- Sick Kids Foundation
- University of Toronto
- Vetenskapsrådet
- Hospital for Sick Children
- U.S. Public Health Service (140849-1)
- Canadian Institutes of Health Research (140849_1)
- 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
- de novo mutations, autism spectrum disorder, germline mutations, somatic mutations, paternal age, clustered mutations, copy number variation, non-coding variants, untranslated regions, exon skipping, DNA methylation, DNMT3A, ADNP, mutation rate
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