A germline chromothripsis event stably segregating in 11 individuals through three generations

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

“…Remarkably, chromothripsis was detected in a wide range of cancer entities and recognized to be the hallmarks of those with a poor prognosis (Notta et al, ; Rode, Maass, Willmund, Lichter, & Ernst, ). Thereafter its discovery in cancerous tissues, a very similar pattern was also observed in germline chromosomal rearrangements both at the balanced and at the unbalanced state although, in general, with a minor number of chromosomal breaks than observed in cancers (Bertelsen et al, ; Chiang et al, ; Kloosterman et al, ; Kloosterman, Guryev, et al, ; Kloosterman, Hoogstraat, et al, ).…”

“…In the recent years, a few cases had been reported of balanced chromothripsis in healthy or mildly affected persons whose children, more severely affected, were with recombinant genomic imbalances or even with apparently the same rearrangement present in the parent. In some of these cases, the parental karyotype was initially interpreted as a balanced two‐way simple translocation (Bertelsen et al, ; de Pagter et al, ). In this study, we illustrate two cases in which we demonstrated that the genomic imbalance present in the index case was derived by parental recombination events between the chromothriptic chromosomes and their normal homologs, although the presence of the parental complex rearrangement was far from predictable in both of them.…”

Defining the diverse spectrum of inversions, complex structural variation, and chromothripsis in the morbid human genome

“…To summarize existing knowledge of chromoanagenesis and contextualize the findings from this study, we conducted a literature review of published reports of germline chromoanagenesis at sequence resolution, almost all of which arose de novo in affected individuals. The results of this review are consolidated in Table 1 and Additional file 2: Table S6 [9, 10, 13, 17–23, 76–78]. Based on this knowledge, and separate from the genome-wide SV analysis of the 686 SSC participants described above, we performed liWGS on an additional three unrelated participants (participants TL010, UTR22, and TL009) with developmental anomalies and large de novo translocational insertions identified by clinical karyotyping, which we suspected may represent more complex rearrangements.…”

“…While still rare, our data confirm that non-tumorigenic chromoanagenesis exists as both constitutional and somatic variation and that cytogenetically detected de novo interchromosomal insertions may hallmark such extreme rearrangements, though larger collections of samples are warranted to further investigate this phenomenon. The review of chromoanagenesis literature performed herein [10, 13, 17–23, 76–78] (Table 1 and Additional file 2: Table S6) supports three conclusions: (1) constitutional chromoanagenesis is frequently balanced, possibly due to embryonic selection against loss of genes intolerant to haploinsufficiency [79–81]; (2) extreme genomic rearrangements can be tolerated in the developing germline [77, 78], although cases of unbalanced extreme chromoanagenesis have mostly been reported in cancer; and (3) at least 2/55 of these rearrangements appeared to be the product of multiple compounding mutational events [23] and another 4/55 rearrangements were observed to acquire additional rearrangements de novo upon unstable transmission from parent to child [23, 77], suggesting it is unlikely that such catastrophic rearrangements always arise in a single mutational event. This latter conclusion draws a key parallel between the two prevailing proposed mechanisms of cancer chromoanagenesis, wherein some rearrangements likely arise from DNA shattering in missegregated micronuclei during mitosis [12, 54, 82–85], yet others acquire additional breakpoints over punctuated tumor evolution [14, 79, 86], not unlike the six constitutional rearrangements with some degree of evidence against a singular mutational event [23, 77].…”

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.…”