title: The strength of combined cytogenetic and mate-pair sequencing techniques illustrated by a germline chromothripsis rearrangement involving FOXP2.
abstract: Next-generation mate-pair sequencing (MPS) has revealed that many constitutional complex chromosomal rearrangements (CCRs) are associated with local shattering of chromosomal regions (chromothripsis). Although MPS promises to identify the molecular basis of the abnormal phenotypes associated with many CCRs, none of the reported mate-pair sequenced complex rearrangements have been simultaneously studied with state-of-the art molecular cytogenetic techniques. Here, we studied chromothripsis-associated CCR involving chromosomes 2, 5 and 7, associated with global developmental and psychomotor delay and severe speech disorder. We identified three truncated genes: CDH12, DGKB and FOXP2, confirming the role of FOXP2 in severe speech disorder, and suggestive roles of CDH12 and/or DGKB for the global developmental and psychomotor delay. Our study confirmes the power of MPS for detecting breakpoints and truncated genes at near nucleotide resolution in chromothripsis. However, only by combining MPS data with conventional G-banding and extensive fluorescence in situ hybridizations could we delineate the precise structure of the derivative chromosomes.
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lusine
authors.initials: L
authors.lastname: Nazaryan
authors.affiliation: Laboratory of Medical Genetics, Cytogenetics Unit, Department of Pediatrics, University General Hospital of Patras, Patras, Greece.
authors.forename: Eunice G
authors.initials: EG
authors.lastname: Stefanou
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Hansen
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Kosyakova
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Mads
authors.initials: M
authors.lastname: Bak
authors.affiliation: Department of Molecular Genetics, Western General Hospital, Edinburgh, UK.
authors.forename: Freddie H
authors.initials: FH
authors.lastname: Sharkey
authors.affiliation: Laboratory of General Biology, University of Ioannina, Ioannina, Greece.
authors.forename: Theodora
authors.initials: T
authors.lastname: Mantziou
authors.affiliation: Laboratory of General Biology, School of Medicine, University of Patras, Rio, Greece.
authors.forename: Anastasios D
authors.initials: AD
authors.lastname: Papanastasiou
authors.affiliation: Department of Genetics and Molecular Biology, 'Mitera' General Maternity/Gynecology and Children's Hospital, Hygeia Group, Athens, Greece.
authors.forename: Voula
authors.initials: V
authors.lastname: Velissariou
authors.affiliation: Institute of Human Genetics, Jena University Hospital, Friedrich Schiller University, Jena, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Liehr
authors.affiliation: Laboratory of General Biology, University of Ioannina, Ioannina, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Syrrou
authors.affiliation: Wilhelm Johannsen Centre for Functional Genome Research, Department of Cellular and Molecular Medicine, Faculty of Health Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Tommerup
mesh_terms: D002648:Child; D043171:Chromosomal Instability; D002889:Chromosomes, Human, Pair 2 / Q000235:genetics; D002895:Chromosomes, Human, Pair 5 / Q000235:genetics; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics; D020732:Cytogenetic Analysis; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008297:Male; D017422:Sequence Analysis, DNA; D013064:Speech Disorders / Q000175:diagnosis / Q000235:genetics*
chemical_list: C465448:FOXP2 protein, human; D051858:Forkhead Transcription Factors