Abstract
We investigated 52 cases of de novo unbalanced translocations, consisting in a terminally deleted or inverted-duplicated deleted (inv-dup del) 46th chromosome to which the distal portion of another chromosome or its opposite end was transposed. Array CGH, whole-genome sequencing, qPCR, FISH, and trio genotyping were applied. A biparental origin of the deletion and duplication was detected in 6 cases, whereas in 46, both imbalances have the same parental origin. Moreover, the duplicated region was of maternal origin in more than half of the cases, with 25% of them showing two maternal and one paternal haplotype. In all these cases, maternal age was increased. These findings indicate that the primary driver for the occurrence of the de novo unbalanced translocations is a maternal meiotic non-disjunction, followed by partial trisomy rescue of the supernumerary chromosome present in the trisomic zygote. In contrast, asymmetric breakage of a dicentric chromosome, originated either at the meiosis or postzygotically, in which the two resulting chromosomes, one being deleted and the other one inv-dup del, are repaired by telomere capture, appears at the basis of all inv-dup del translocations. Notably, this mechanism also fits with the origin of some simple translocations in which the duplicated region was of paternal origin. In all cases, the signature at the translocation junctions was that of non-homologous end joining (NHEJ) rather than non-allelic homologous recombination (NAHR). Our data imply that there is no risk of recurrence in the following pregnancies for any of the de novo unbalanced translocations we discuss here.
Highlights
Unbalanced translocations leading to monosomy and trisomy for the distal parts of two different chromosomes account for about 0,1% of chromosomal imbalances detected at amniocentesis in cases mainly ascertained for advanced maternal age or ultrasound abnormalities (Chang et al 2013), and for Electronic supplementary material The online version of this article contains supplementary material, which is available to authorized users.Extended author information available on the last page of the article about 1% in subjects with developmental delay and intellectual disability (Robberecht et al 2013; Weckselblatt et al 2015)
Class D: Inv-dup del unbalanced inversion (n = 1) showing an inv-dup del chromosome ending with the distal portion of the opposite arm of the same chromosome (Online Resource 2: Figure S7)
A meiotic recombination proximal to or at the translocation breakpoint must have preceded a non-disjunction in maternal meiosis II
Summary
The de novo unbalanced chromosome mimicks a recombinant from a parental pericentric inversion (Rivera et al 2013) in which the deleted arm ends with the distal portion of the opposite arm. The frequency of this type of translocation, to which we will refer as “de novo unbalanced inversion”, is unknown.
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