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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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Molecular cloning of the 5;15 translocation in case 1.A, magnified view of the chromosome 5 breakpoint boundary detected by array-CGH using a 244 K oligonucleotide-based whole-genome microarray. The shaded area indicates a loss in DNA copy number (deletion) detected by three oligonucleotide probes (green dots). Black dots represent probes with no changes in copy number (non-deleted region). B, whole chromosome view (left) and magnified view (right) of the chromosome 15 breakpoint boundaries detected by custom oligonucleotide-based 15q11-q13 microarray. The shaded areas indicate a deletion (majority of green dots) and a gain in DNA copy number (duplication) detected by red dots (see arrow). The area containing few widely spaced probes represents BP3, a large region containing paralogous sequences. The last deleted oligomer is at 26,210,153 bp within HERC2, corresponding to BP3; the duplicated region is between 26,996,914 (first duplicated) and 27,106,557 bp (last duplicated) with first normal oligomer at 27,108,882 bp just distal to BP3, within the APBA2 gene. An arrowhead points to the two black spots possibly indicating a single copy region between the deletion and the duplication. C, schematic representation of the rearrangement showing the two chromosomes involved, the position and orientation of the duplicated region, and the location of the two junctions (arrows). D, DNA sequences spanning the chromosome 5 deletion/15 duplication junction (Jc1) aligned with the reference sequences. E, dot-plot diagram, made with PipMaker software [45], showing the relative location of the inverted chromosome 15 duplication boundaries (Jc1 and Jc2, arrows) and of the GOLGA8E-associated inverted low copy repeat. The duplicated portion is represented by an orange arrow box.
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pone-0039180-g001: Molecular cloning of the 5;15 translocation in case 1.A, magnified view of the chromosome 5 breakpoint boundary detected by array-CGH using a 244 K oligonucleotide-based whole-genome microarray. The shaded area indicates a loss in DNA copy number (deletion) detected by three oligonucleotide probes (green dots). Black dots represent probes with no changes in copy number (non-deleted region). B, whole chromosome view (left) and magnified view (right) of the chromosome 15 breakpoint boundaries detected by custom oligonucleotide-based 15q11-q13 microarray. The shaded areas indicate a deletion (majority of green dots) and a gain in DNA copy number (duplication) detected by red dots (see arrow). The area containing few widely spaced probes represents BP3, a large region containing paralogous sequences. The last deleted oligomer is at 26,210,153 bp within HERC2, corresponding to BP3; the duplicated region is between 26,996,914 (first duplicated) and 27,106,557 bp (last duplicated) with first normal oligomer at 27,108,882 bp just distal to BP3, within the APBA2 gene. An arrowhead points to the two black spots possibly indicating a single copy region between the deletion and the duplication. C, schematic representation of the rearrangement showing the two chromosomes involved, the position and orientation of the duplicated region, and the location of the two junctions (arrows). D, DNA sequences spanning the chromosome 5 deletion/15 duplication junction (Jc1) aligned with the reference sequences. E, dot-plot diagram, made with PipMaker software [45], showing the relative location of the inverted chromosome 15 duplication boundaries (Jc1 and Jc2, arrows) and of the GOLGA8E-associated inverted low copy repeat. The duplicated portion is represented by an orange arrow box.

Mentions: In case 1 (Case 2 in [11]), array-CGH analysis identified a 5q deletion of about 240 kb (fig. 1a), as well as a 100 kb duplication contiguous to the 15q deletion (fig. 1b). Using qPCR, we restricted the location of the chromosome 15 duplication breakpoints proximally to a 14 kb region inside the BP3 segmental duplication and distally to a 2 kb sequence (Table 1). We also restricted the chromosome 5 breakpoint to a 600 bp region. We successfully amplified the 5; distal 15 junction (Jc1) by LR-PCR (fig. 1d), demonstrating that the duplicated portion of chromosome 15 is inverted, as in most inv dup del rearrangements [12]. A 300 kb inverted repeat partially overlapping the duplicated region (fig. 1e) may be responsible for the genesis and location of the rearrangement. The chromosome 15 breakpoint is inside a LINE repeat and the junction shows a 2-bp microhomology. The proximal chromosome 15 breakpoint is contained inside the BP3 segmental duplication. The complex organization of this region did not allow us to fully characterize the junction (Jc2) and confirm the existence of the single-copy region suggested by array-CGH data (Fig. 1b, arrowhead). The duplication is not present in the database of genomic variants (http://projects.tcag.ca/variation/) and its de novo/inherited occurrence remains unknown because we did not have enough material from the parents to perform an array investigation.


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)

Molecular cloning of the 5;15 translocation in case 1.A, magnified view of the chromosome 5 breakpoint boundary detected by array-CGH using a 244 K oligonucleotide-based whole-genome microarray. The shaded area indicates a loss in DNA copy number (deletion) detected by three oligonucleotide probes (green dots). Black dots represent probes with no changes in copy number (non-deleted region). B, whole chromosome view (left) and magnified view (right) of the chromosome 15 breakpoint boundaries detected by custom oligonucleotide-based 15q11-q13 microarray. The shaded areas indicate a deletion (majority of green dots) and a gain in DNA copy number (duplication) detected by red dots (see arrow). The area containing few widely spaced probes represents BP3, a large region containing paralogous sequences. The last deleted oligomer is at 26,210,153 bp within HERC2, corresponding to BP3; the duplicated region is between 26,996,914 (first duplicated) and 27,106,557 bp (last duplicated) with first normal oligomer at 27,108,882 bp just distal to BP3, within the APBA2 gene. An arrowhead points to the two black spots possibly indicating a single copy region between the deletion and the duplication. C, schematic representation of the rearrangement showing the two chromosomes involved, the position and orientation of the duplicated region, and the location of the two junctions (arrows). D, DNA sequences spanning the chromosome 5 deletion/15 duplication junction (Jc1) aligned with the reference sequences. E, dot-plot diagram, made with PipMaker software [45], showing the relative location of the inverted chromosome 15 duplication boundaries (Jc1 and Jc2, arrows) and of the GOLGA8E-associated inverted low copy repeat. The duplicated portion is represented by an orange arrow box.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3375265&req=5

pone-0039180-g001: Molecular cloning of the 5;15 translocation in case 1.A, magnified view of the chromosome 5 breakpoint boundary detected by array-CGH using a 244 K oligonucleotide-based whole-genome microarray. The shaded area indicates a loss in DNA copy number (deletion) detected by three oligonucleotide probes (green dots). Black dots represent probes with no changes in copy number (non-deleted region). B, whole chromosome view (left) and magnified view (right) of the chromosome 15 breakpoint boundaries detected by custom oligonucleotide-based 15q11-q13 microarray. The shaded areas indicate a deletion (majority of green dots) and a gain in DNA copy number (duplication) detected by red dots (see arrow). The area containing few widely spaced probes represents BP3, a large region containing paralogous sequences. The last deleted oligomer is at 26,210,153 bp within HERC2, corresponding to BP3; the duplicated region is between 26,996,914 (first duplicated) and 27,106,557 bp (last duplicated) with first normal oligomer at 27,108,882 bp just distal to BP3, within the APBA2 gene. An arrowhead points to the two black spots possibly indicating a single copy region between the deletion and the duplication. C, schematic representation of the rearrangement showing the two chromosomes involved, the position and orientation of the duplicated region, and the location of the two junctions (arrows). D, DNA sequences spanning the chromosome 5 deletion/15 duplication junction (Jc1) aligned with the reference sequences. E, dot-plot diagram, made with PipMaker software [45], showing the relative location of the inverted chromosome 15 duplication boundaries (Jc1 and Jc2, arrows) and of the GOLGA8E-associated inverted low copy repeat. The duplicated portion is represented by an orange arrow box.
Mentions: In case 1 (Case 2 in [11]), array-CGH analysis identified a 5q deletion of about 240 kb (fig. 1a), as well as a 100 kb duplication contiguous to the 15q deletion (fig. 1b). Using qPCR, we restricted the location of the chromosome 15 duplication breakpoints proximally to a 14 kb region inside the BP3 segmental duplication and distally to a 2 kb sequence (Table 1). We also restricted the chromosome 5 breakpoint to a 600 bp region. We successfully amplified the 5; distal 15 junction (Jc1) by LR-PCR (fig. 1d), demonstrating that the duplicated portion of chromosome 15 is inverted, as in most inv dup del rearrangements [12]. A 300 kb inverted repeat partially overlapping the duplicated region (fig. 1e) may be responsible for the genesis and location of the rearrangement. The chromosome 15 breakpoint is inside a LINE repeat and the junction shows a 2-bp microhomology. The proximal chromosome 15 breakpoint is contained inside the BP3 segmental duplication. The complex organization of this region did not allow us to fully characterize the junction (Jc2) and confirm the existence of the single-copy region suggested by array-CGH data (Fig. 1b, arrowhead). The duplication is not present in the database of genomic variants (http://projects.tcag.ca/variation/) and its de novo/inherited occurrence remains unknown because we did not have enough material from the parents to perform an array investigation.

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