Identification of small exonic CNV from whole-exome sequence data and application to autism spectrum disorder
Open accessAbstract
Copy number variation (CNV) is an important determinant of human diversity and plays important roles in susceptibility to disease. Most studies of CNV carried out to date have made use of chromosome microarray and have had a lower size limit for detection of about 30 kilobases (kb). With the emergence of whole-exome sequencing studies, we asked whether such data could be used to reliably call rare exonic CNV in the size range of 1-30 kilobases (kb), making use of the eXome Hidden Markov Model (XHMM) program. By using both transmission information and validation by molecular methods, we confirmed that small CNV encompassing as few as three exons can be reliably called from whole-exome data. We applied this approach to an autism case-control sample (n = 811, mean per-target read depth = 161) and observed a significant increase in the burden of rare (MAF ≤1%) 1-30 kb CNV, 1-30 kb deletions, and 1-10 kb deletions in ASD. CNV in the 1-30 kb range frequently hit just a single gene, and we were therefore able to carry out enrichment and pathway analyses, where we observed enrichment for disruption of genes in cytoskeletal and autophagy pathways in ASD. In summary, our results showed that XHMM provided an effective means to assess small exonic CNV from whole-exome data, indicated that rare 1-30 kb exonic deletions could contribute to risk in up to 7% of individuals with ASD, and implicated a candidate pathway in developmental delay syndromes.
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A recent study identified ASD-associated exonic copy number variation mutations in genes coding for proteins involved in autophagic pathways.
“In support of a role for autophagy dysregulation in ASD etiology, a recent study identified ASD-associated exonic copy number variation mutations in genes coding for proteins involved in autophagic pathways (Poultney et al., 2013).”
From Loss of mTOR-Dependent Macroautophagy Causes Autistic-like Synaptic Pruning Deficits (2014) · cites this paper as Poultney et al., 2013
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- Authors
- Poultney, C. S., Goldberg, A. P., Drapeau, E., Kou, Y., Harony-Nicolas, H., Kajiwara, Y., De Rubeis, S., Durand, S., Stevens, C., Rehnström, K., Palotie, A., Daly, M. J., Ma’ayan, A., Fromer, M., & Buxbaum, J. D.
- Affiliations
- Icahn School of Medicine at Mount Sinai (US)
- Broad Institute (US)
- University of Helsinki (FI)
- Corresponding author
- Buxbaum, Joseph D.
- ORCID
- Venue
- The American Journal of Human Genetics
- Publisher
- Elsevier BV
- Published
- 2013-10
- Volume
- 93
- Issue
- 4
- Pages
- 607-619
- ISSN
- 0002-9297 (ISSN-L)
- PMC
- PMC3791269
- OpenAlex
- W2012352152
- Cited by
- 169
- References
- 51
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 4 · 2022: 8 · 2021: 14 · 2020: 11 · 2019: 10 · 2018: 13 · 2017: 20 · 2016: 21 · 2015: 23 · 2014: 24 · 2013: 1 · 2012: 1
- FWCI
- 15.26
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The American Journal of Human Genetics (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Mental Health (R01MH089025, MH100233, MH097849, R01MH097849, MH089025, R56MH097849, U01MH100233)
- National Institute of General Medical Sciences (R01GM098316)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomics and Rare Diseases
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Keywords
- copy number variation, exome sequencing, autism spectrum disorder, CNV burden, autophagy pathway, genetic risk
- MeSH terms
- Autophagy, Base Sequence, Child, Child Development Disorders, Pervasive, Exons, Humans, Molecular Sequence Data, Case-Control Studies, Gene Deletion, Sequence Analysis, DNA, Genetic Predisposition to Disease, DNA Copy Number Variations, Exome
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