Genomic and Functional Overlap between Somatic and Germline Chromosomal Rearrangements

Sebastiaan van Heesch, Marieke Simonis, Markus J van Roosmalen, Vamsee Pillalamarri, Harrison Brand, Ewart W Kuijk, Kim L de Luca, Nico Lansu, A Koen Braat, Androniki Menelaou, Wensi Hao, Jeroen Korving, Simone Snijder, Lars T van der Veken, Ron Hochstenbach, Alida C Knegt, Karen Duran, Ivo Renkens, Najla Alekozai, Myrthe JagerSarah Vergult, Björn Menten, Ewart de Bruijn, Sander Boymans, Elly Ippel, Ellen van Binsbergen, Michael E Talkowski, Klaske Lichtenbelt, Edwin Cuppen, Wigard P Kloosterman

Research output: Contribution to journal/periodicalArticleScientificpeer-review

20 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)2001-10
Number of pages10
JournalCell Reports
Issue number6
Publication statusPublished - 24 Dec 2014


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