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Cited by 113Advanced Neuroimaging Techniques and ApplicationsGenomic variations and chromosomal abnormalitiesGenetics and Neurodevelopmental Disorders

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Aberrant White Matter Microstructure in Children with 16p11.2 Deletions

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Owen, Julia P., Chang, Yi Shin, Pojman, Nicholas J., Bukshpun, Polina, Wakahiro, Mari L.J., Marco, Elysa J., Berman, Jeffrey I., Spiro, John E., Chung, Wendy K., Buckner, Randy L., Roberts, Timothy P.L., Nagarajan, Srikantan S., Sherr, Elliott H., Mukherjee, Pratik·2014·The Journal of Neuroscience
DOI 10.1523/jneurosci.4495-13.2014PMC PMC6608115
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Abstract

Copy number variants (CNVs) of the chromosomal locus 16p11.2, consisting of either deletions or duplications, have been implicated in autism, schizophrenia, epilepsy, and other neuropsychiatric disorders. Since abnormal white matter microstructure can be seen in these more broadly defined clinical disorders, we used diffusion magnetic resonance imaging and tract-based spatial statistics to investigate white matter microstructural integrity in human children with 16p11.2 deletions. We show that deletion carriers, compared with typically developing matched controls, have increased axial diffusivity (AD) in many major central white matter tracts, including the anterior corpus callosum as well as bilateral internal and external capsules. Higher AD correlated with lower nonverbal IQ in the deletion carriers, but not controls. Increases in fractional anisotropy and mean diffusivity were also found in some of the same tracts with elevated AD. Closer examination with neurite orientation dispersion and density imaging revealed that fiber orientation dispersion was decreased in some central white matter tracts. Notably, these alterations of white matter are unlike microstructural differences reported for any other neurodevelopmental disorders, including autism spectrum disorders that have phenotypic overlap with the deletion carriers. These findings suggest that deletion of the 16p11.2 locus is associated with a unique widespread pattern of aberrant white matter microstructure that may underlie the impaired cognition characteristic of this CNV.

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Crossref · 10.1523/jneurosci.4495-13.2014

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Figures

Figure 1 White matter regions with significantly increased FA (top), AD (middle), and MD (bottom) in 16p11.2 deletions carriers ( n = 23), comparedwiththehealthycontrols( n = 23), are displayed in red in a red-to-yellow color scale ( p < 0.025). The results reflect using NVIQ and site as nuisance regressors in the TBSS analysis.
Figure 1 White matter regions with significantly increased FA (top), AD (middle), and MD (bottom) in 16p11.2 deletions carriers ( n = 23), comparedwiththehealthycontrols( n = 23), are displayed in red in a red-to-yellow color scale ( p < 0.025). The results reflect using NVIQ and site as nuisance regressors in the TBSS analysis.CC-BY-NC-SA · From the PDF
Figure 2 White matter regions with increased AD in 16p11.2 deletion carriers ( n = 23), compared with the healthy controls ( n = 23), are displayed in red-to-yellow color scale ( p < 0.025). The results reflect using NVIQ, site, and STV as nuisance regressors in the TBSS analysis.
Figure 2 White matter regions with increased AD in 16p11.2 deletion carriers ( n = 23), compared with the healthy controls ( n = 23), are displayed in red-to-yellow color scale ( p < 0.025). The results reflect using NVIQ, site, and STV as nuisance regressors in the TBSS analysis.CC-BY-NC-SA · From the PDF
Figure 3 Post hoc tractographic measurements of FA and AD in four ROIs: the bilateral internal/external capsules. Top, Results for FA. Bottom, Results for AD. For all ROIs, deletions were significantly higher than the controls; one star denotes p < 0.05, two stars denote p < 0.01, and three stars denote p < 0.001.
Figure 3 Post hoc tractographic measurements of FA and AD in four ROIs: the bilateral internal/external capsules. Top, Results for FA. Bottom, Results for AD. For all ROIs, deletions were significantly higher than the controls; one star denotes p < 0.05, two stars denote p < 0.01, and three stars denote p < 0.001.CC-BY-NC-SA · From the PDF
Figure 4 Plots of mean FA in the eight most-affected tracts versus age for the deletion carriers (red) and controls (green) with linear trend lines.
Figure 4 Plots of mean FA in the eight most-affected tracts versus age for the deletion carriers (red) and controls (green) with linear trend lines.CC-BY-NC-SA · From the PDF
Figure 5 Plots of mean AD in the eight most-affected tracts versus age for the deletion carriers (red) and controls (green) with linear trend lines.
Figure 5 Plots of mean AD in the eight most-affected tracts versus age for the deletion carriers (red) and controls (green) with linear trend lines.CC-BY-NC-SA · From the PDF
Figure 6 Correlation between global AD and NVIQ for deletion carriers and for controls. The Pearson's correlation coefficient betweenglobalADandNVIQforthedeletioncarriersis -0.44with p < 0.05. There is no significant correlation between global AD and NVIQ for the controls.
Figure 6 Correlation between global AD and NVIQ for deletion carriers and for controls. The Pearson's correlation coefficient betweenglobalADandNVIQforthedeletioncarriersis -0.44with p < 0.05. There is no significant correlation between global AD and NVIQ for the controls.CC-BY-NC-SA · From the PDF
Figure7 Exampleaxialslicesoftheparametermaps:FA,ODI,FICV,andFISO.Theimagesare scaled from 0 to 1 with bright voxels being closest to 1.
Figure7 Exampleaxialslicesoftheparametermaps:FA,ODI,FICV,andFISO.Theimagesare scaled from 0 to 1 with bright voxels being closest to 1.CC-BY-NC-SA · From the PDF
Figure 8 White matter tracts with significantly decreased ODI in the 16p11.2 deletion carriers ( n = 21), compared with the healthy controls ( n = 21), are shown in blue color scale ( p < 0.025).
Figure 8 White matter tracts with significantly decreased ODI in the 16p11.2 deletion carriers ( n = 21), compared with the healthy controls ( n = 21), are shown in blue color scale ( p < 0.025).CC-BY-NC-SA · From the PDF

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Metadata

Authors
Owen, J. P., Chang, Y. S., Pojman, N. J., Bukshpun, P., Wakahiro, M. L. J., Marco, E. J., Berman, J. I., Spiro, J. E., Chung, W. K., Buckner, R. L., Roberts, T. P. L., Nagarajan, S. S., Sherr, E. H., & Mukherjee, P.
Affiliations
  • Children's Hospital of Philadelphia (US)
  • University of California, San Francisco (US)
  • Simons Foundation (US)
  • Columbia University Irving Medical Center (US)
  • Harvard University (US)
ORCID
Venue
The Journal of Neuroscience
Publisher
Society for Neuroscience
Published
2014-04-30
Volume
34
Issue
18
Pages
6214-6223
ISSN
  • 0270-6474 (ISSN-L)
  • 1529-2401
DOI
10.1523/jneurosci.4495-13.2014
PMC
PMC6608115
OpenAlex
W2049115342
Cited by
113
References
34
Citations by year
2025: 5 · 2024: 6 · 2023: 5 · 2022: 3 · 2021: 5 · 2020: 8 · 2019: 11 · 2018: 41 · 2017: 7 · 2016: 9 · 2015: 9 · 2014: 4
FWCI
7.56
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroscience (publishedVersion, cc-by-nc-sa)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-sa)
Funders
Simons Foundation Autism Research Initiative
Topics
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Advanced Neuroimaging Techniques and Applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genomic variations and chromosomal abnormalities
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords
16p11.2 deletion, copy number variation, white matter microstructure, axial diffusivity, fractional anisotropy, corpus callosum, internal capsule, external capsule, nonverbal intelligence, neurodevelopmental disorders, children
MeSH terms
Adolescent, Autistic Disorder, Biophysics, Brain, Child, Chromosome Deletion, Chromosomes, Human, Pair 16, Cognition Disorders, Female, Humans, Image Processing, Computer-Assisted, Male, Intellectual Disability, Models, Neurological, Nerve Fibers, Myelinated, Statistics as Topic, Case-Control Studies, Anisotropy, Chromosome Disorders, Diffusion Magnetic Resonance Imaging, Leukoencephalopathies

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