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    Sequencing of a Patient with Balanced Chromosome Abnormalities and Neurodevelopmental Disease Identifies Disruption of Multiple High Risk Loci by Structural Variation

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    16
    Author
    Blake, J; Riddell, A; Theiss, S; Gonzalez, AP; Haase, B; Jauch, A; Janssen, JWG; Ibberson, D; Pavlinic, D; Moog, U; ...
    Date
    2014-03-13
    Source Title
    PLoS One
    Publisher
    PUBLIC LIBRARY SCIENCE
    University of Melbourne Author/s
    Gonzalez, Alexis Perez
    Affiliation
    Melbourne Dental School
    Metadata
    Show full item record
    Document Type
    Journal Article
    Citations
    Blake, J., Riddell, A., Theiss, S., Gonzalez, A. P., Haase, B., Jauch, A., Janssen, J. W. G., Ibberson, D., Pavlinic, D., Moog, U., Benes, V. & Runz, H. (2014). Sequencing of a Patient with Balanced Chromosome Abnormalities and Neurodevelopmental Disease Identifies Disruption of Multiple High Risk Loci by Structural Variation. PLOS ONE, 9 (3), https://doi.org/10.1371/journal.pone.0090894.
    Access Status
    Open Access
    URI
    http://hdl.handle.net/11343/260305
    DOI
    10.1371/journal.pone.0090894
    Abstract
    Balanced chromosome abnormalities (BCAs) occur at a high frequency in healthy and diseased individuals, but cost-efficient strategies to identify BCAs and evaluate whether they contribute to a phenotype have not yet become widespread. Here we apply genome-wide mate-pair library sequencing to characterize structural variation in a patient with unclear neurodevelopmental disease (NDD) and complex de novo BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (LINC00299, NUP205, PSMD14) that gave rise to abnormal mRNAs and could be assumed as disease-causing. However, unbiased genome-wide analysis of the sequencing data for cryptic structural variation was key to reveal an additional submicroscopic inversion that truncates the schizophrenia- and bipolar disorder-associated brain transcription factor ZNF804A as an equally likely NDD-driving gene. Deep sequencing of fluorescent-sorted wild-type and derivative chromosomes confirmed the clinically undetected BCA. Moreover, deep sequencing further validated a high accuracy of mate-pair library sequencing to detect structural variants larger than 10 kB, proposing that this approach is powerful for clinical-grade genome-wide structural variant detection. Our study supports previous evidence for a role of ZNF804A in NDD and highlights the need for a more comprehensive assessment of structural variation in karyotypically abnormal individuals and patients with neurocognitive disease to avoid diagnostic deception.

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