title: Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring.
abstract: Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across three to five chromosomes. Two mothers did not show any phenotypic abnormalities, although 3-13 protein-coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy-number changes in two children. This resulted in gene-dosage changes, which are probably responsible for the severe congenital phenotypes of these two children. In contrast, the third child, who has a severe congenital disease, harbored all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy-number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein-coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals affects reproduction and is expected to substantially increase the risk of miscarriages, abortions, and severe congenital disease.
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Mirjam S
authors: MS
authors: de Pagter
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Markus J
authors: MJ
authors: van Roosmalen
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Annette F
authors: AF
authors: Baas
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Ivo
authors: I
authors: Renkens
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Karen J
authors: KJ
authors: Duran
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Ellen
authors: E
authors: van Binsbergen
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Masoumeh
authors: M
authors: Tavakoli-Yaraki
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Ron
authors: R
authors: Hochstenbach
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands.
authors: Lars T
authors: LT
authors: van der Veken
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands; Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht 3584 CT, the Netherlands.
authors: Edwin
authors: E
authors: Cuppen
authors: Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht 3584 CG, the Netherlands. Electronic address: w.kloosterman@umcutrecht.nl.
authors: Wigard P
authors: WP
authors: Kloosterman
mesh_terms: D000013:Congenital Abnormalities / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics; D006801:Humans; D040582:Inheritance Patterns / Q000235:genetics*; D046228:Microarray Analysis; D016366:Open Reading Frames / Q000235:genetics*; D010641:Phenotype; D014178:Translocation, Genetic / Q000235:genetics*