Chromothripsis in Healthy Individuals Affects Multiple Protein-Coding Genes and Can Result in Severe Congenital Abnormalities in Offspring

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.

Unbalanced translocations arise from diverse mutational mechanisms including chromothripsis

“…Though most germline translocations involve only two chromosomes, some are the product of many breakpoints on three to five different chromosomes. Originally seen in cancer (Stephens et al 2011), chromosome shattering or chromothripsis is now recognized as a cause of some germline translocations (Kloosterman et al 2011(Kloosterman et al , 2012Chiang et al 2012;Nazaryan et al 2014;Pellestor et al 2014;de Pagter et al 2015). …”

Chromothripsis in Oncology: Literature Review and Case Report

“…Кроме того, этот феномен был недавно обнаружен у больных хроническим лимфолейкозом (ХЛЛ) [1,3,6, 17], множественной миеломой (ММ) [5], острыми лейкозами [18], миелодиспластическим синдромом (МДС) [4], лимфомами [3,16] и даже у здоровых лиц [19].…”

Germline mutation contribution to chromosomal instability

“…Chromothripsis is characterized by small-scale DNA copy number changes and extensive intrachromosomal rearrangements confined to single chromosome or chromosome arm and has been featured in human cancers (Crasta et al 2012, Zhang et al 2015. Germline chromothripsis is associated with congenital abnormalities as well as developmental disorders (de Pagter et al 2015, Anderson et al 2016, Bertelsen et al 2016. Parent-to-child transmission of chromothripsis has been associated with de novo complex copy number changes and severe congenital abnormalities in the child (de Pagter et al 2015), suggesting that germline chromothripsis may lead to further CIN and potentially, predisposition to cancers.…”