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De novo unbalanced translocations in Prader-Willi and Angelman syndrome might be the reciprocal product of inv dup(15)s.

Rossi E, Giorda R, Bonaglia MC, Candia SD, Grechi E, Franzese A, Soli F, Rivieri F, Patricelli MG, Saccilotto D, Bonfante A, Giglio S, Beri S, Rocchi M, Zuffardi O - PLoS ONE (2012)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Pavia, Pavia, Italy.

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.

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Related in: MedlinePlus

Physical map of the 15q11.2-q14 region.The six segmental duplication sites responsible for specific recurrent rearrangements in this region, known as BP1-6, are represented by black boxes. All genes in the region are shown. The position of the chromosome 15 breakpoints of the five translocation cases we have examined are represented by thin arrows. The positions of the eight translocation cases (MR1-8) described by Mignon-Ravix [10] are indicated by thick arrows.
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pone-0039180-g002: Physical map of the 15q11.2-q14 region.The six segmental duplication sites responsible for specific recurrent rearrangements in this region, known as BP1-6, are represented by black boxes. All genes in the region are shown. The position of the chromosome 15 breakpoints of the five translocation cases we have examined are represented by thin arrows. The positions of the eight translocation cases (MR1-8) described by Mignon-Ravix [10] are indicated by thick arrows.

Mentions: Our data indicate that the 15q breakpoints of our unbalanced translocations fall within one of the segmental duplications in the region only in case 1 and that breakpoint locations were different in all cases. A map of the 15q11-q14 region, with the breakpoints of our cases and of cases with similar type of rearrangements studied by Mignon-Ravix et al [10], is shown in Fig. 2. In a total of 13 unbalanced translocations there is no breakpoint clustering, at least between BP2 and BP5. In the four cases reported by Mignon-Ravix et al [10] the claimed clustering at BP6 consisted of a 460 kb interval simply defined by FISH, and in any case outside the 15q segmental duplications.


De novo unbalanced translocations in Prader-Willi and Angelman syndrome might be the reciprocal product of inv dup(15)s.

Rossi E, Giorda R, Bonaglia MC, Candia SD, Grechi E, Franzese A, Soli F, Rivieri F, Patricelli MG, Saccilotto D, Bonfante A, Giglio S, Beri S, Rocchi M, Zuffardi O - PLoS ONE (2012)

Physical map of the 15q11.2-q14 region.The six segmental duplication sites responsible for specific recurrent rearrangements in this region, known as BP1-6, are represented by black boxes. All genes in the region are shown. The position of the chromosome 15 breakpoints of the five translocation cases we have examined are represented by thin arrows. The positions of the eight translocation cases (MR1-8) described by Mignon-Ravix [10] are indicated by thick arrows.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3375265&req=5

pone-0039180-g002: Physical map of the 15q11.2-q14 region.The six segmental duplication sites responsible for specific recurrent rearrangements in this region, known as BP1-6, are represented by black boxes. All genes in the region are shown. The position of the chromosome 15 breakpoints of the five translocation cases we have examined are represented by thin arrows. The positions of the eight translocation cases (MR1-8) described by Mignon-Ravix [10] are indicated by thick arrows.
Mentions: Our data indicate that the 15q breakpoints of our unbalanced translocations fall within one of the segmental duplications in the region only in case 1 and that breakpoint locations were different in all cases. A map of the 15q11-q14 region, with the breakpoints of our cases and of cases with similar type of rearrangements studied by Mignon-Ravix et al [10], is shown in Fig. 2. In a total of 13 unbalanced translocations there is no breakpoint clustering, at least between BP2 and BP5. In the four cases reported by Mignon-Ravix et al [10] the claimed clustering at BP6 consisted of a 460 kb interval simply defined by FISH, and in any case outside the 15q segmental duplications.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Medical Genetics, University of Pavia, Pavia, Italy.

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.

Show MeSH
Related in: MedlinePlus