Chromothripsis in Healthy Individuals Affects Multiple Protein-Coding Genes and Can Result in Severe Congenital Abnormalities in Offspring
0301 basic medicine
DNA Copy Number Variations
Research Support, Non-U.S. Gov't
Inheritance Patterns
Microarray Analysis
Translocation, Genetic
Congenital Abnormalities
COMPLEX CHROMOSOMAL REARRANGEMENTS
Open Reading Frames
03 medical and health sciences
Phenotype
GERMLINE
Journal Article
Genetics
Humans
Genetics(clinical)
DOI:
10.1016/j.ajhg.2015.02.005
Publication Date:
2015-03-29T16:40:53Z
AUTHORS (11)
ABSTRACT
Chromothripsis represents an extreme class of complex chromosome rearrangements (CCRs) with major effects on chromosomal architecture. Although recent studies have associated chromothripsis with congenital abnormalities, the incidence and pathogenic effects of this phenomenon require further investigation. Here, we analyzed the genomes of three families in which chromothripsis rearrangements were transmitted from a mother to her child. The chromothripsis in the mothers resulted in completely balanced rearrangements involving 8-23 breakpoint junctions across three to five chromosomes. Two mothers did not show any phenotypic abnormalities, although 3-13 protein-coding genes were affected by breakpoints. Unbalanced but stable transmission of a subset of the derivative chromosomes caused apparently de novo complex copy-number changes in two children. This resulted in gene-dosage changes, which are probably responsible for the severe congenital phenotypes of these two children. In contrast, the third child, who has a severe congenital disease, harbored all three chromothripsis chromosomes from his healthy mother, but one of the chromosomes acquired de novo rearrangements leading to copy-number changes. These results show that the human genome can tolerate extreme reshuffling of chromosomal architecture, including breakage of multiple protein-coding genes, without noticeable phenotypic effects. The presence of chromothripsis in healthy individuals affects reproduction and is expected to substantially increase the risk of miscarriages, abortions, and severe congenital disease.
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