title: A Distinct Class of Chromoanagenesis Events Characterized by Focal Copy Number Gains.
abstract: Chromoanagenesis is the process by which a single catastrophic event creates complex rearrangements confined to a single or a few chromosomes. It is usually characterized by the presence of multiple deletions and/or duplications, as well as by copy neutral rearrangements. In contrast, an array CGH screen of patients with developmental anomalies revealed three patients in which a single chromosome carries from 8 to 11 large copy number gains confined to a single chromosome or chromosomal arm, but the absence of deletions. Subsequent fluorescence in situ hybiridization and massive parallel sequencing revealed the duplicons to be clustered together in distinct locations across the altered chromosomes. Breakpoint junction sequences showed both microhomology and non-templated insertions of up to 40 bp. Hence, these patients each demonstrate a single altered chromosome of clustered insertional duplications, no deletions, and breakpoint junction sequences showing microhomology and/or non-templated insertions. These observations are difficult to reconcile with current mechanistic descriptions of chromothripsis and chromoanasynthesis. Therefore, we hypothesize those rearrangements to be of a mechanistically different origin. In addition, we suggest that large untemplated insertional sequences observed at breakpoints are driven by a non-canonical non-homologous end joining mechanism.
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Heleen
authors.initials: H
authors.lastname: Masset
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Matthew S
authors.initials: MS
authors.lastname: Hestand
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Hilde
authors.initials: H
authors.lastname: Van Esch
authors.affiliation: Laboratoire Cerba, Département de Génétique Humaine, Saint-Ouen l'Aumône, France.
authors.forename: Pascale
authors.initials: P
authors.lastname: Kleinfinger
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, CHU Toulouse, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Plaisancié
authors.affiliation: APHP, Hôpital Armand-Trousseau, Service de Génétique Clinique, Paris, France.|APHP, Hôpital Armand-Trousseau, Service de Neuropédiatrie, Paris, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Afenjar
authors.affiliation: Laboratoire de Biologie Clinique, Clinique Saint Jean Languedoc, Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Molignier
authors.affiliation: Laboratoire de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, France.|Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, UCBL, Lyon, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Schluth-Bolard
authors.affiliation: Laboratoire de Cytogénétique Constitutionnelle, Hospices Civils de Lyon, France.|Lyon Neuroscience Research Center, CNRS UMR5292, INSERM U1028, UCBL, Lyon, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Sanlaville
authors.affiliation: Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: Joris R
authors.initials: JR
authors.lastname: Vermeesch
mesh_terms: D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D002658:Developmental Disabilities / Q000235:genetics*; D005260:Female; D015894:Genome, Human; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D046228:Microarray Analysis; D017422:Sequence Analysis, DNA
keywords: chromoanagenesis; chromoanasynthesis; chromothripsis; polymerase theta