Chromothripsis represents a novel phenomenon in the structural variation landscape of cancer genomes. Here, we analyze the genomes of ten patients with congenital disease who were preselected to carry complex chromosomal rearrangements with more than two breakpoints. The rearrangements displayed unanticipated complexity resembling chromothripsis. We find that eight of them contain hallmarks of multiple clustered double-stranded DNA breaks (DSBs) on one or more chromosomes. In addition, nucleotide resolution analysis of 98 breakpoint junctions indicates that break repair involves nonhomologous or microhomology-mediated end joining. We observed that these eight rearrangements are balanced or contain sporadic deletions ranging in size between a few hundred base pairs and several megabases. The two remaining complex rearrangements did not display signs of DSBs and contain duplications, indicative of rearrangement processes involving template switching. Our work provides detailed insight into the characteristics of chromothripsis and supports a role for clustered DSBs driving some constitutional chromothripsis rearrangements. Display omitted ► Constitutional complex chromosomal rearrangements display unanticipated complexity resembling chromothripsis ► Some chromothripsis rearrangements involve clustered double-stranded DNA breaks ► There exist distinct classes of chromothripsis rearrangements Complex genomic rearrangements are associated with birth defects and cancer development. Kloosterman, Cuppen, and colleagues use whole-genome sequencing analysis to unravel the precise structure of ten complex genomic rearrangements in patients with congenital malformations. Eight of the rearrangements are caused by chromosome shattering and nonhomologous DNA repair, while two rearrangements involve replicative repair processes. These rearrangements represent two different instances of chromothripsis. The authors show that chromosome shattering and repair may frequently underlie complex genomic rearrangements causing developmental defects.