The origin of unbalanced de novo chromosome translocations and inversions

The origin of de novo unbalanced translocations and unbalanced rearrangements mimicking a derivative from a pericentric inversion (herein called unbalanced inversions) is still enigmatic. We studied 43 of these de novo unbalanced rearrangements, two of them with more than one cell line, as detected in blood, including simple translocations (n=29), inv-dup del translocations (n=7), inversions (n=6), and inv-dup del inversions (n=1) in order to highlight their parental origin and mechanisms of formation. We also sequenced 19 breakpoint junctions between the derivative chromosome and the translocated portion of another chromosome or the same chromosome and detected a number of different motifs: 2 to 6 base pairs microhomologies (n=8), short insertions of 1 to 36 base pairs (n=8), LINE/L1-mediated non-allelic homologous recombination (n=2) and fork stalling and template switching (n=1). Parental origin was fully informative in 27 out of 43 cases, informative for only one imbalance (6 paternal and 3 maternal) in 9 cases, while in the remaining 8 cases no information was available. While all unbalanced inversions were of paternal origin, most simple translocations were of maternal origin (n=15), and two displayed bi-parental origin, showing that they originated post-zygotically. Only in one unbalanced translocation the duplicated portion showed three alleles, two of them of maternal origin, indicating that the zygote was possibly trisomic for that chromosome, as effect of maternal meiosis I non-disjunction. Thus, the translocation reflects the partial rescue by telomere capture of the supernumerary chromosome. This hypothesis is also supported by one case with three cell lines: a minor one with trisomy 9, a second line with unbalanced translocation t(9;14), and a third with normal karyotype. The inv-dup del translocations/inversions are likely the result of an original dicentric chromosome that after its breakage was stabilized by telomere capture Our findings suggest that partial rescue, through single- or multiple-step mechanisms, of an abnormal zygotic chromosome complement, consisting of either (i) a rearranged chromosome, such as a terminally deleted or dicentric “mirror” chromosome, or (ii) a whole supernumerary chromosome is the most likely mechanism leading to de novo unbalanced translocations/inversions. Accordingly, these de novo rearrangements do not imply any risk of recurrence in subsequent pregnancies.