Detection of Clinically Relevant Genetic Variants in Autism Spectrum Disorder by Whole-Genome Sequencing
Open accessAbstract
Autism Spectrum Disorder (ASD) demonstrates high heritability and familial clustering, yet the genetic causes remain only partially understood as a result of extensive clinical and genomic heterogeneity. Whole-genome sequencing (WGS) shows promise as a tool for identifying ASD risk genes as well as unreported mutations in known loci, but an assessment of its full utility in an ASD group has not been performed. We used WGS to examine 32 families with ASD to detect de novo or rare inherited genetic variants predicted to be deleterious (loss-of-function and damaging missense mutations). Among ASD probands, we identified deleterious de novo mutations in six of 32 (19%) families and X-linked or autosomal inherited alterations in ten of 32 (31%) families (some had combinations of mutations). The proportion of families identified with such putative mutations was larger than has been previously reported; this yield was in part due to the comprehensive and uniform coverage afforded by WGS. Deleterious variants were found in four unrecognized, nine known, and eight candidate ASD risk genes. Examples include CAPRIN1 and AFF2 (both linked to FMR1, which is involved in fragile X syndrome), VIP (involved in social-cognitive deficits), and other genes such as SCN2A and KCNQ2 (linked to epilepsy), NRXN1, and CHD7, which causes ASD-associated CHARGE syndrome. Taken together, these results suggest that WGS and thorough bioinformatic analyses for de novo and rare inherited mutations will improve the detection of genetic variants likely to be associated with ASD or its accompanying clinical symptoms.
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Genome sequencing leaves most ASD cases genetically unsolved.
“even its application leaves the majority of ASD cases “genetically unsolved”2,19–21.”
From Genome-wide detection of tandem DNA repeats that are expanded in autism (2020) · cites this paper as [20]
Exome and whole-genome sequencing studies estimate at least another ∼6% contribution to ASD risk.
“Exome and whole-genome sequencing studies have estimated at least another ∼6% contribution to ASD7–10,15”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [15]
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- Authors
- Jiang, Y.-H., Yuen, R. K. C., Jin, X., Wang, M., Chen, N., Wu, X., Ju, J., Mei, J., Shi, Y., He, M., Wang, G., Liang, J., Wang, Z., Cao, D., Carter, M. T., Chrysler, C., Drmic, I. E., Howe, J. L., Lau, L., Marshall, C. R., Merico, D., Nalpathamkalam, T., Thiruvahindrapuram, B., Thompson, A., Uddin, M., Walker, S., Luo, J., Anagnostou, E., Zwaigenbaum, L., Ring, R. H., Wang, J., Lajonchere, C., Wang, J., Shih, A., Szatmari, P., Yang, H., Dawson, G., Li, Y., & Scherer, S. W.
- Affiliations
- Duke University (US)
- Hospital for Sick Children (CA)
- BGI Group (China) (CN)
- University of Toronto (CA)
- McMaster University (CA)
- National Supercomputer Center in Tianjin (CN)
- University of Alberta (CA)
- Autism Speaks (US)
- Corresponding author
- Li, Yingrui
- Scherer, Stephen W.
- ORCID
- Jiang, Yong-hui
- Yuen, Ryan K.C.
- Jin, Xin
- Wang, Mingbang
- Mei, Junpu
- Shi, Yujian
- He, Mingze
- Wang, Guangbiao
- Wang, Zhe
- Cao, Dandan
- Carter, Melissa T.
- Drmic, Irene E.
- Lau, Lynette
- Marshall, Christian R.
- Merico, Daniele
- Nalpathamkalam, Thomas
- Thiruvahindrapuram, Bhooma
- Uddin, Mohammed
- Walker, Susan
- Anagnostou, Evdokia
- Zwaigenbaum, Lonnie
- Ring, Robert H.
- Wang, Jian
- Lajonchere, Clara
- Wang, Jun
- Shih, Andy
- Yang, Huanming
- Li, Yingrui
- Scherer, Stephen W.
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 93
- Issue
- 2
- Pages
- 249-263
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3738824
- OpenAlex
- W2040026415
- Semantic Scholar
- be9b3f0802ab52f423f80fdb7251e6d982924a63
- Cited by
- 474
- References
- 20
- Citations by year
- 2026: 8 · 2025: 13 · 2024: 17 · 2023: 18 · 2022: 27 · 2021: 41 · 2020: 38 · 2019: 39 · 2018: 38 · 2017: 53 · 2016: 64 · 2015: 54 · 2014: 54 · 2013: 10
- FWCI
- 33.14
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- UNC Libraries
- Funders
- Autism Speaks
- GlaxoSmithKline
- Sanofi
- Genome Canada
- European Bioinformatics Institute
- Ontario Genomics
- Government of Ontario
- Ontario Genomics Institute
- Sick Kids Foundation
- National Natural Science Foundation of China (30890032)
- Government of Jiangxi Province
- University of Toronto
- Hospital for Sick Children
- National Institutes of Health
- Canadian Institutes of Health Research
- National High-tech Research and Development Program (2012AA02A201)
- National Key Research and Development Program of China
- National Institute of Mental Health (R01MH098114)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (K12HD043494)
- 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, deleterious mutations, ASD risk genes, whole genome sequencing, FMR1 gene, fragile X syndrome, VIP, SCN2A, KCNQ2, NRXN1, CHD7, CHARGE syndrome, loss-of-function mutations, missense mutations
- MeSH terms
- Adult, Child, Child Development Disorders, Pervasive, Female, Humans, Male, Mutation, Pedigree, Genome, Genetic Heterogeneity, Genetic Predisposition to Disease, High-Throughput Nucleotide Sequencing
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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