Blake, Jonathon Riddell, Andrew Theiss, Susanne Perez Gonzalez, Alexis Haase, Bettina Jauch, Anna W. G. Janssen, Johannes Ibberson, David Pavlinic, Dinko Moog, Ute Benes, Vladimir Runz, Heiko Sequencing of a Patient with Balanced Chromosome Abnormalities and Neurodevelopmental Disease Identifies Disruption of Multiple High Risk Loci by Structural Variation <div><p>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 <i>de novo</i> BCAs at the karyotype level. Nucleotide-level characterization of the clinically described BCA breakpoints revealed disruption of at least three NDD candidate genes (<i>LINC00299</i>, <i>NUP205</i>, <i>PSMD14</i>) 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 <i>ZNF804A</i> 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 <i>ZNF804A</i> 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.</p></div> Computational biology;genomics;Genome sequencing;genetics;Genetic mutation;Mutation types;Human genetics;Chromosomal disorders;cytogenetics;Genetics of disease;Genomic medicine;genetic testing;neuroscience;Developmental neuroscience;Clinical genetics;neurology;Developmental and pediatric neurology;pediatrics;chromosome;abnormalities;neurodevelopmental;identifies;disruption;loci 2014-03-13
    https://plos.figshare.com/articles/dataset/_Sequencing_of_a_Patient_with_Balanced_Chromosome_Abnormalities_and_Neurodevelopmental_Disease_Identifies_Disruption_of_Multiple_High_Risk_Loci_by_Structural_Variation_/960636
10.1371/journal.pone.0090894