Using large clinical data sets to infer pathogenicity for rare copy number variants in autism cohorts
Open accessAbstract
Copy number variants (CNVs) have a major role in the etiology of autism spectrum disorders (ASD), and several of these have reached statistical significance in case-control analyses. Nevertheless, current ASD cohorts are not large enough to detect very rare CNVs that may be causative or contributory (that is, risk alleles). Here, we use a tiered approach, in which clinically significant CNVs are first identified in large clinical cohorts of neurodevelopmental disorders (including but not specific to ASD), after which these CNVs are then systematically identified within well-characterized ASD cohorts. We focused our initial analysis on 48 recurrent CNVs (segmental duplication-mediated 'hotspots') from 24 loci in 31 516 published clinical cases with neurodevelopmental disorders and 13 696 published controls, which yielded a total of 19 deletion CNVs and 11 duplication CNVs that reached statistical significance. We then investigated the overlap of these 30 CNVs in a combined sample of 3955 well-characterized ASD cases from three published studies. We identified 73 deleterious recurrent CNVs, including 36 deletions from 11 loci and 37 duplications from seven loci, for a frequency of 1 in 54; had we considered the ASD cohorts alone, only 58 CNVs from eight loci (24 deletions from three loci and 34 duplications from five loci) would have reached statistical significance. In conclusion, until there are sufficiently large ASD research cohorts with enough power to detect very rare causative or contributory CNVs, data from larger clinical cohorts can be used to infer the likely clinical significance of CNVs in ASD.
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De novo or transmitted CNVs at 15q11.2-q13, 16p11.2, and the X-linked PTCHD1-PTCHD1AS locus contribute to ASD risk.
“De novo or transmitted CNVs, such as 15q11.2–q13 duplications of the affected region in Prader-Willi syndrome (PWS [MIM 176270]) and Angelman syndrome (AS [MIM 105830]), 16p11.2 deletion (MIM 611913), 16p11.2 duplication (MIM 614671), and X-linked deletions including the PTCHD1-PTCHD1AS locus (MIM 300828), have also been found to contribute to risk.6,13,14”
From Convergence of genes and cellular pathways dysregulated in autism spectrum disorders (2014) · cites this paper as [13]
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Self-citation
- Authors
- Moreno-De-Luca, D., Sanders, S. J., Willsey, A. J., Mulle, J. G., Lowe, J. K., Geschwind, D. H., State, M. W., Martin, C. L., & Ledbetter, D. H.
- Affiliations
- Yale University (US)
- Emory University (US)
- University of California, Los Angeles (US)
- Geisinger Health System (US)
- Corresponding author
- Ledbetter, D H
- Venue
- Molecular Psychiatry
- Published
- 2012-10-09
- Volume
- 18
- Issue
- 10
- Pages
- 1090-1095
- ISSN
- 1359-4184 (ISSN-L)
- 1476-5578
- PMC
- PMC3720840
- OpenAlex
- W2080984518
- Cited by
- 161
- References
- 33
- Citations by year
- 2026: 6 · 2025: 3 · 2024: 9 · 2023: 11 · 2022: 8 · 2021: 16 · 2020: 11 · 2019: 15 · 2018: 7 · 2017: 14 · 2016: 12 · 2015: 16 · 2014: 20 · 2013: 13
- FWCI
- 9.41
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- cc-by-nc-nd
- www.springer.com/tdm (unspecified)
- Locations
- Molecular Psychiatry (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institute of Mental Health (U24MH081810, MH074090, MH081754, R01MH081754, U54MH068172, R01MH074090)
- 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
- copy number variation, autism spectrum disorder, rare variants, recurrent CNVs, segmental duplication, neurodevelopmental disorders, clinical cohort, risk alleles, genetic etiology
- MeSH terms
- Congenital Abnormalities, Autistic Disorder, Developmental Disabilities, Child Development Disorders, Pervasive, Humans, Causality, Prevalence, Gene Deletion, Sample Size, Gene Dosage, Genetic Heterogeneity, Genetic Predisposition to Disease, Gene Duplication, Genetic Association Studies, Data Mining, Homologous Recombination
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