Flanking complex copy number variants in the same family formed through unequal crossing-over during meiosis

Abstract

Two phenomena that have been described in germline complex genomic rearrangements (CGRs) formation are chromothripsis and chromoanasynthesis, characterized by distinct features such as the orientation and copy number of the involved fragments. Herein we present different CGRs on chromosome 5p in a mother and her daughter that through unequal crossing-over during meiosis has evolved from a chromothriptic rearrangement in the mother into another complex rearrangement in her daughter involving both deletions and duplications. Initially, both rearrangements were classified as simple copy number variants, but follow-up studies using whole-genome sequencing revealed a much more complex nature of both rearrangements and enabled us to decipher the biological process involved in the formation of the rearrangement found in the daughter.In conclusion, these two cases highlight the need of analyzing the inheritance patterns of CGRs, and provide an example of a disease-causing CGR formed through multiple genetic events.