Frequency and complexity of de novo structural mutation in autism
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Abstract
Genetic studies of autism spectrum disorder (ASD) have established that de novo duplications and deletions contribute to risk. However, ascertainment of structural variants (SVs) has been restricted by the coarse resolution of current approaches. By applying a custom pipeline for SV discovery, genotyping, and de novo assembly to genome sequencing of 235 subjects (71 affected individuals, 26 healthy siblings, and their parents), we compiled an atlas of 29,719 SV loci (5,213/genome), comprising 11 different classes. We found a high diversity of de novo mutations, the majority of which were undetectable by previous methods. In addition, we observed complex mutation clusters where combinations of de novo SVs, nucleotide substitutions, and indels occurred as a single event. We estimate a high rate of structural mutation in humans (20%) and propose that genetic risk for ASD is attributable to an elevated frequency of gene-disrupting de novo SVs, but not an elevated rate of genome rearrangement.
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De novo structural variants and protein-altering point mutations contribute to ASD risk.
“Early studies established that de novo structural variants (SVs) (Brandler et al., 2016; Sebat et al., 2007) and protein-altering point mutations (Iossifov et al., 2012; Neale et al., 2012; O’Roak et al., 2012; Sanders et al., 2012) contribute to risk for ASD.”
From Getting to the cores of autism (2019) · cites this paper as Brandler et al., 2016
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“De Novo Mutations Early studies established that de novo structural variants (SVs) (Brandler et al., 2016; Sebat et al., 2007) and protein-altering point mutations (Iossifov et al.”
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Self-citation
- Authors
- Brandler, W. M., Antaki, D., Gujral, M., Noor, A., Rosanio, G., Chapman, T. R., Barrera, D. J., Lin, G. N., Malhotra, D., Watts, A. C., Wong, L. C., Estabillo, J. A., Gadomski, T. E., Hong, O., Fajardo, K. V. F., Bhandari, A., Owen, R., Baughn, M., Yuan, J., Solomon, T., Moyzis, A. G., Maile, M. S., Sanders, S. J., Reiner, G. E., Vaux, K. K., Strom, C. M., Zhang, K., Muotri, A. R., Akshoomoff, N., Leal, S. M., Pierce, K., Courchesne, E., Iakoucheva, L. M., Corsello, C., & Sebat, J.
- Affiliations
- University of California San Diego (US)
- Rady Children's Hospital-San Diego (US)
- Quest Diagnostics (United States) (US)
- University of California, San Francisco (US)
- Baylor College of Medicine (US)
- Corresponding author
- Sebat, Jonathan
- ORCID
- Brandler, William M.
- Antaki, Danny
- Gujral, Madhusudan
- Noor, Amina
- Barrera, Daniel J.
- Lin, Guan Ning
- Malhotra, Dheeraj
- Estabillo, Jasper A.
- Gadomski, Therese E.
- Hong, Oanh
- Bhandari, Abhishek
- Owen, Renius
- Baughn, Michael
- Yuan, Jeffrey
- Solomon, Terry
- Moyzis, Alexandra G.
- Maile, Michelle S.
- Sanders, Stephan J.
- Reiner, Gail E.
- Vaux, Keith K.
- Zhang, Kang
- Muotri, Alysson R.
- Akshoomoff, Natacha
- Leal, Suzanne M.
- Pierce, Karen
- Iakoucheva, Lilia M.
- Corsello, Christina
- Sebat, Jonathan
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2016-04
- Volume
- 98
- Issue
- 4
- Pages
- 667-679
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC4833290
- OpenAlex
- W2951164835
- Cited by
- 104
- References
- 45
- Citations by year
- 2026: 4 · 2025: 5 · 2024: 8 · 2023: 9 · 2022: 17 · 2021: 8 · 2020: 7 · 2019: 16 · 2018: 16 · 2017: 11 · 2016: 3
- FWCI
- 12.37
- 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, cc-by-nc-nd)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- Simons Foundation (275724)
- Autism Science Foundation
- Simons Foundation Autism Research Initiative
- National Institutes of Health (HG007497)
- National Institute of Mental Health (R01MH109885, MH104766, R21MH104766, MH076431, MH105524, R01MH105524, R01MH076431)
- National Human Genome Research Institute (U41HG007497, HG007497, U24HG007497)
- National Institute of General Medical Sciences (T32GM008666, T32GM145427)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD065288, R01HD065288)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- autism spectrum disorder, de novo structural variants, structural mutations, de novo duplication, de novo deletion, de novo assembly, genetic risk, genome rearrangement
- MeSH terms
- Autism Spectrum Disorder, Alleles, Amino Acid Sequence, Base Sequence, Child, Female, Gene Frequency, Humans, Male, Molecular Sequence Data, Pedigree, Sensitivity and Specificity, Reproducibility of Results, Gene Rearrangement, Genome, Human, Case-Control Studies, Gene Deletion, Gene Duplication, Microarray Analysis, INDEL Mutation, Genetic Loci, DNA Copy Number Variations, Genotyping Techniques
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