title: Genomic and functional overlap between somatic and germline chromosomal rearrangements.
abstract: Genomic rearrangements are a common cause of human congenital abnormalities. However, their origin and consequences are poorly understood. We performed molecular analysis of two patients with congenital disease who carried de novo genomic rearrangements. We found that the rearrangements in both patients hit genes that are recurrently rearranged in cancer (ETV1, FOXP1, and microRNA cluster C19MC) and drive formation of fusion genes similar to those described in cancer. Subsequent analysis of a large set of 552 de novo germline genomic rearrangements underlying congenital disorders revealed enrichment for genes rearranged in cancer and overlap with somatic cancer breakpoints. Breakpoints of common (inherited) germline structural variations also overlap with cancer breakpoints but are depleted for cancer genes. We propose that the same genomic positions are prone to genomic rearrangements in germline and soma but that timing and context of breakage determines whether developmental defects or cancer are promoted.
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Sebastiaan
authors.initials: S
authors.lastname: van Heesch
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Marieke
authors.initials: M
authors.lastname: Simonis
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Markus J
authors.initials: MJ
authors.lastname: van Roosmalen
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Vamsee
authors.initials: V
authors.lastname: Pillalamarri
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Harrison
authors.initials: H
authors.lastname: Brand
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Ewart W
authors.initials: EW
authors.lastname: Kuijk
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Kim L
authors.initials: KL
authors.lastname: de Luca
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Nico
authors.initials: N
authors.lastname: Lansu
authors.affiliation: Department of Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.
authors.forename: A Koen
authors.initials: AK
authors.lastname: Braat
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Androniki
authors.initials: A
authors.lastname: Menelaou
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Wensi
authors.initials: W
authors.lastname: Hao
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Korving
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Snijder
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Lars T
authors.initials: LT
authors.lastname: van der Veken
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Ron
authors.initials: R
authors.lastname: Hochstenbach
authors.affiliation: Department of Clinical Genetics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, the Netherlands.
authors.forename: Alida C
authors.initials: AC
authors.lastname: Knegt
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Karen
authors.initials: K
authors.lastname: Duran
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Ivo
authors.initials: I
authors.lastname: Renkens
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Najla
authors.initials: N
authors.lastname: Alekozai
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Myrthe
authors.initials: M
authors.lastname: Jager
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Sarah
authors.initials: S
authors.lastname: Vergult
authors.affiliation: Center for Medical Genetics, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Björn
authors.initials: B
authors.lastname: Menten
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Ewart
authors.initials: E
authors.lastname: de Bruijn
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Boymans
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Elly
authors.initials: E
authors.lastname: Ippel
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: van Binsbergen
authors.affiliation: Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Talkowski
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands.
authors.forename: Klaske
authors.initials: K
authors.lastname: Lichtenbelt
authors.affiliation: Hubrecht Institute-KNAW and University Medical Center Utrecht, Uppsalalaan 8, 3584 CT Utrecht, the Netherlands; Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address: e.cuppen@hubrecht.eu.
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.affiliation: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Universiteitsweg 100, 3584 CG Utrecht, the Netherlands. Electronic address: w.kloosterman@umcutrecht.nl.
authors.forename: Wigard P
authors.initials: WP
authors.lastname: Kloosterman
mesh_terms: D000818:Animals; D002869:Chromosome Aberrations; D056905:Chromosome Breakpoints; D002877:Chromosomes, Human / Q000235:genetics*; D000013:Congenital Abnormalities / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D051858:Forkhead Transcription Factors / Q000235:genetics; D015321:Gene Rearrangement; D015894:Genome, Human; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics; D015027:Zebrafish
chemical_list: D004268:DNA-Binding Proteins; C095239:ETV1 protein, human; C486626:FOXP1 protein, human; D051858:Forkhead Transcription Factors; D035683:MicroRNAs; D012097:Repressor Proteins; D014157:Transcription Factors