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Cited by 437Genomic variations and chromosomal abnormalitiesGenomics and Rare DiseasesGenome Rearrangement Algorithms

An evidence-based approach to establish the functional and clinical significance of copy number variants in intellectual and developmental disabilities

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Kaminsky, Erin B, Kaul, Vineith, Paschall, Justin, Church, Deanna M, Bunke, Brian, Kunig, Dawn, Moreno-De-Luca, Daniel, Moreno-De-Luca, Andres +26 more·2011·Genetics in Medicine
DOI 10.1097/gim.0b013e31822c79f9PMC PMC3661946
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Abstract

Purpose Copy number variants have emerged as a major cause of human disease such as autism and intellectual disabilities. Because copy number variants are common in normal individuals, determining the functional and clinical significance of rare copy number variants in patients remains challenging. The adoption of whole-genome chromosomal microarray analysis as a first-tier diagnostic test for individuals with unexplained developmental disabilities provides a unique opportunity to obtain large copy number variant datasets generated through routine patient care. Methods A consortium of diagnostic laboratories was established (the International Standards for Cytogenomic Arrays consortium) to share copy number variant and phenotypic data in a central, public database. We present the largest copy number variant case-control study to date comprising 15,749 International Standards for Cytogenomic Arrays cases and 10,118 published controls, focusing our initial analysis on recurrent deletions and duplications involving 14 copy number variant regions. Results Compared with controls, 14 deletions and seven duplications were significantly overrepresented in cases, providing a clinical diagnosis as pathogenic. Conclusion Given the rapid expansion of clinical chromosomal microarray analysis testing, very large datasets will be available to determine the functional significance of increasingly rare copy number variants. This data will provide an evidence-based guide to clinicians across many disciplines involved in the diagnosis, management, and care of these patients and their families.

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  • An extended search in CNV databases revealed a single individual with heterozygous 1.1Mb deletion with isolated Arnold-Chiari malformation.

    “An extended search in copy number variation (CNV) databases regarding human phenotypes associated with CNVs involving the MIR140 gene revealed a single individual with heterozygous 1.1Mb deletion with isolated Arnold-Chiari malformation41.”

    From Gain-of-function mutation of microRNA-140 in human skeletal dysplasia (2019) · cites this paper as [41]

    The Results section (CNV Characterization; page unavailable) describes aggregate CNV findings, not an individual with the claimed phenotype. Searches of our copy for MIR140, a 1.1 Mb deletion, and Arnold-Chiari malformation found no passage addressing the claimed case. (LLM, conf=0.76)

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Authors
Kaminsky, E. B., Kaul, V., Paschall, J., Church, D. M., Bunke, B., Kunig, D., Moreno-De-Luca, D., Moreno-De-Luca, A., Mulle, J. G., Warren, S. T., Richard, G., Compton, J. G., Fuller, A. E., Gliem, T. J., Huang, S., Collinson, M. N., Beal, S. J., Ackley, T., Pickering, D. L., Golden, D. M., Aston, E., Whitby, H., Shetty, S., Rossi, M. R., Rudd, M. K., South, S. T., Brothman, A. R., Sanger, W. G., Iyer, R. K., Crolla, J. A., Thorland, E. C., Aradhya, S., Ledbetter, D. H., & Martin, C. L.
Affiliations
  • Emory University (US)
  • National Center for Biotechnology Information (US)
  • Mayo Clinic (US)
  • Salisbury District Hospital (GB)
  • Michigan Medicine (US)
  • University of Nebraska Medical Center (US)
  • University of Utah (US)
Corresponding author
  • Ledbetter, David H
  • Martin, Christa L
ORCID
Venue
Genetics in Medicine
Publisher
Elsevier BV
Published
2011-09
Volume
13
Issue
9
Pages
777-784
ISSN
1098-3600 (ISSN-L)
DOI
10.1097/gim.0b013e31822c79f9
PMC
PMC3661946
OpenAlex
W2110105653
Cited by
437
References
10
Citations by year
2026: 13 · 2025: 13 · 2024: 11 · 2023: 13 · 2022: 23 · 2021: 33 · 2020: 29 · 2019: 31 · 2018: 25 · 2017: 42 · 2016: 44 · 2015: 36 · 2014: 42 · 2013: 38 · 2012: 38
FWCI
22.72
Type
journal article
Language
en
Open access
Licence
Locations
  • Genetics in Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • ePrints Soton (University of Southampton) (submittedVersion)
Funders
  • National Institutes of Health
  • National Institute of Mental Health (MH080129, R01MH092902, MH074090, R01MH080129, R01MH083722, MH083722, R01MH074090)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD064525, RC2HD064525)
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 › Biochemistry, Genetics and Molecular Biology › Genetics › Genome Rearrangement Algorithms
Keywords
copy number variation, intellectual disability, developmental disabilities, chromosomal microarray analysis, recurrent deletions, duplication, pathogenicity, case-control study, phenotypic data, public databases, autism spectrum disorder
MeSH terms
Developmental Disabilities, Humans, Intellectual Disability, Genome, Human, Gene Dosage, Evidence-Based Medicine, Cytogenetic Analysis, DNA Copy Number Variations

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