Abstract
The 15q11-q13 region is characterized by high instability, caused by the presence of several paralogous segmental duplications. Although most mechanisms dealing with cryptic deletions and amplifications have been at least partly characterized, little is known about the rare translocations involving this region. We characterized at the molecular level five unbalanced translocations, including a jumping one, having most of 15q transposed to the end of another chromosome, whereas the der(15)(pter->q11-q13) was missing. Imbalances were associated either with Prader-Willi or Angelman syndrome. Array-CGH demonstrated the absence of any copy number changes in the recipient chromosome in three cases, while one carried a cryptic terminal deletion and another a large terminal deletion, already diagnosed by classical cytogenetics. We cloned the breakpoint junctions in two cases, whereas cloning was impaired by complex regional genomic architecture and mosaicism in the others. Our results strongly indicate that some of our translocations originated through a prezygotic/postzygotic two-hit mechanism starting with the formation of an acentric 15qter->q1::q1->qter representing the reciprocal product of the inv dup(15) supernumerary marker chromosome. An embryo with such an acentric chromosome plus a normal chromosome 15 inherited from the other parent could survive only if partial trisomy 15 rescue would occur through elimination of part of the acentric chromosome, stabilization of the remaining portion with telomere capture, and formation of a derivative chromosome. All these events likely do not happen concurrently in a single cell but are rather the result of successive stabilization attempts occurring in different cells of which only the fittest will finally survive. Accordingly, jumping translocations might represent successful rescue attempts in different cells rather than transfer of the same 15q portion to different chromosomes. We also hypothesize that neocentromerization of the original acentric chromosome during early embryogenesis may be required to avoid its loss before cell survival is finally assured.
Highlights
A variety of different structural rearrangements involving the proximal 15q have breakpoints mapping to the segmental duplication blocks (BP1-BP5) [1,2] present in this genomic region
In the four cases reported by MignonRavix et al [10] the claimed clustering at BP6 consisted of a 460 kb interval defined by FISH, and in any case outside the 15q segmental duplications
Considering the production of an inv dup(15) by non allelic homologous recombination (NAHR), it seems likely that it will be complemented by the formation of a reciprocal 15qter-.q1::q1.qter acentric product (Fig. 3B). This mechanism is well accepted for other recurrent rearrangements, such as the inv dup(8p)s where we demonstrated that NAHR between two segmental duplications at 8p23 produces a dicentric mirror chromosome 8qter-.p23::p23-.qter and its reciprocal acentric product 8pter-.p23::p23-.pter [25], the theoretical formation of a reciprocal acentric chromosome for the inv dup(15)s has never been taken into consideration
Summary
A variety of different structural rearrangements involving the proximal 15q have breakpoints mapping to the segmental duplication blocks (BP1-BP5) [1,2] present in this genomic region. In 2007, Mignon-Ravix et al [10] demonstrated, by FISH analysis, that in four of eight patients with this type of translocations, either de novo or inherited, breakpoints clustered in an interval of about 460 kb at 15q14, distal to BP5, between BACs RP11-64O3 and RP11-150L8. They suggested this region could be a specific hotspot for unbalanced translocations involving the proximal 15q region. In order to obtain new insight in the mechanisms generating de novo unbalanced translocations involving the 15q1 region, we investigated whether the breakpoints of these translocations, usually associated with PWS or AS phenotype, depending on their parental origin, occurred as a consequence of the specific genomic architecture of this region
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