Chromothripsis in healthy individuals affects multiple protein-coding genes and can result in severe congenital abnormalities in offspring

MS de Pagter, Markus J. van Roosmalen, AF Baas, Ivo Renkens, KJ Duran, E van Binsbergen, Masoumeh Tavakoli-Yaraki, PFR Hochstenbach, LTJN van der Veken, EPJG Cuppen, WP Kloosterman

Research output: Contribution to conferenceAbstractOther research output


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 3-5 chromosomes. Two mothers did not show any phenotypic malformations, 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 likely responsible for their severe congenital phenotypes. In contrast, one child with 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, spontaneous abortions and severe congenital disease.
Original languageEnglish
Publication statusPublished - 8 Jun 2015
EventThe European Human Genetics Conference 2015 - SECC, Glasgow, United Kingdom
Duration: 6 Jun 20159 Jun 2015


ConferenceThe European Human Genetics Conference 2015
Abbreviated titleESHG 2015
Country/TerritoryUnited Kingdom
Internet address


  • Chromothripsis
  • Congenital Abnormalities
  • Healthy carriers


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