title: Sequencing of a patient with balanced chromosome abnormalities and neurodevelopmental disease identifies disruption of multiple high risk loci by structural variation.
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.
authors.affiliation: Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Jonathon
authors.initials: J
authors.lastname: Blake
authors.affiliation: Flow Cytometry Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Andrew
authors.initials: A
authors.lastname: Riddell
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Theiss
authors.affiliation: Flow Cytometry Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Alexis Perez
authors.initials: AP
authors.lastname: Gonzalez
authors.affiliation: Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Haase
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Johannes W G
authors.initials: JW
authors.lastname: Janssen
authors.affiliation: Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany; CellNetworks Sequencing Core Facility, University of Heidelberg, Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Ibberson
authors.affiliation: Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Dinko
authors.initials: D
authors.lastname: Pavlinic
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Moog
authors.affiliation: Genomics Core Facility, EMBL Heidelberg, Heidelberg, Germany.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Benes
authors.affiliation: Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), University of Heidelberg/EMBL, Heidelberg, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Runz
mesh_terms: D001714:Bipolar Disorder / Q000235:genetics; D002675:Child, Preschool; D002869:Chromosome Aberrations; D003241:Consanguinity; D014644:Genetic Variation; D055106:Genome-Wide Association Study; D006801:Humans; D007361:Intelligence Tests; D007621:Karyotyping; D051741:Kruppel-Like Transcription Factors / Q000235:genetics; D007805:Language Development Disorders; D008279:Magnetic Resonance Imaging; D008297:Male; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics; D012559:Schizophrenia / Q000235:genetics; D017422:Sequence Analysis, DNA; D015534:Trans-Activators / Q000235:genetics
chemical_list: D051741:Kruppel-Like Transcription Factors; C109285:PSMD14 protein, human; D015534:Trans-Activators; C540527:ZNF804A protein, human; D046988:Proteasome Endopeptidase Complex