Chromothripsis and Human Genetic Disease

Abstract Chromothripsis (CTH) is a newly discovered mutational mechanism, which in a single catastrophic event results in localised complex structural rearrangements confined to one or a few chromosomes. After an initial shattering or clustered fragmentation of a chromosomal region, the fragments join together in random order and orientation. During this process some of the generated fragments may be lost. It is not entirely clear which factors trigger the localised fragmentation; however, several mechanisms have been proposed, such as ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei, LINE1‐endonucleases, etc. CTH may disrupt multiple genes and/or regulatory regions. When it is incompatible with cell survival, the result should be apoptosis. However, if a cell escapes apoptosis, the extensive genomic rearrangements may have different phenotypic outcomes: cancer (somatic), congenital and developmental disorders (germline), neutral or even beneficial effects. Key Concepts Chromothripsis is a phenomenon where multiple localised double‐stranded DNA breaks result in complex genomic rearrangements. Chromothripsis occurs within a single cell cycle. Ionising radiation, aborted apoptosis, isolation of chromosome(s) in micronuclei and LINE1‐endonucleases are proposed to have a role in chromothripsis. Chromothripsis in somatic cells may trigger cancer development. Chromothripsis in the germline may result in congenital and developmental disorders.