Chromothripsis: potential origin in gametogenesis and preimplantation cell divisions. A review

Objective: To review the discovery of chromothripsis and analyze its impact on human reproduction.

Design: Database and literature analysis.

Setting: University hospital.

Patient(s): Carriers of massive and complex chromosomal rearrangements.

Intervention(s): Cytogenetic analysis and molecular testing (fluorescence in situ hybridization, microarray, whole-genome sequencing).

Main outcome measure(s): Chromothripsis occurrence in human gametes and preimplantation embryos, with regard to the potential causative mechanisms described in literature.

Result(s): Databases were searched for the literature published up to March 2014. Chromothripsis is characterized by the shattering of one (or a few) chromosome segments followed by a haphazard reassembly of the fragments generated, arising through a single initial catastrophic event. Several mechanisms involving abortive apoptosis, telomere erosion, mitotic errors, micronuclei formation, and p53 inactivation might cause chromothripsis. The remarkable point is that all these plausible mechanisms have been identified in the field of human reproduction as causal factors for reproductive failures and the genesis of chromosomal abnormalities. Specific features of gametogenesis and early embryonic development such as the weakness of cell cycle and mitosis checkpoints and the rapid kinetics of division in germ cells and early cleavage embryos may contribute to the emergence of chromothripsis.

Conclusion(s): The discovery of this new class of massive chromosomal rearrangement has deeply modified our understanding on the genesis of complex genomic rearrangements. Data presented in this review support the assumption that chromothripsis could operate in human germlines and during early embryonic development. Chromothripsis might arise more frequently than previously thought in both gametogenesis and early human embryogenesis.