A Palindrome-Mediated Recurrent Translocation with 3:1 Meiotic Nondisjunction: The t(8;22)(q24.13;q11.21)

The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 08/2010; 87(2):209-18. DOI: 10.1016/j.ajhg.2010.07.002
Source: PubMed


Palindrome-mediated genomic instability has been associated with chromosomal translocations, including the recurrent t(11;22)(q23;q11). We report a syndrome characterized by extremity anomalies, mild dysmorphia, and intellectual impairment caused by 3:1 meiotic segregation of a previously unrecognized recurrent palindrome-mediated rearrangement, the t(8;22)(q24.13;q11.21). There are at least ten prior reports of this translocation, and nearly identical PATRR8 and PATRR22 breakpoints were validated in several of these published cases. PCR analysis of sperm DNA from healthy males indicates that the t(8;22) arises de novo during gametogenesis in some, but not all, individuals. Furthermore, demonstration that de novo PATRR8-to-PATRR11 translocations occur in sperm suggests that palindrome-mediated translocation is a universal mechanism producing chromosomal rearrangements.

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    • "(PATRR22), respectively [Edelmann et al., 2001; Kurahashi and Emanuel, 2001a; Tapia-Paez et al., 2001]. PA- TRR22 also mediates additional translocations with four other PA- TRRs, suggesting PATRR-mediated translocations as one of the universal pathways for chromosomal rearrangements [Kehrer-Sawatzki et al., 1997; Kurahashi et al., 2003; Nimmakayalu et al., 2003; Gotter et al., 2004; Gotter et al., 2007; Sheridan et al., 2010]. With the exception of t(17;22)(q11;q11.2), "
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    ABSTRACT: Palindromic sequences can form hairpin structures or cruciform extrusions, which render them susceptible to genomic rearrangements. A 197 bp long palindromic AT-rich repeat (PATRR17) is located within intron 40 of the neurofibromatosis type 1 (NF1) gene (17q11.2). Through comprehensive NF1 analysis, we identified six unrelated patients with a rearrangement involving intron 40 (five deletions and one reciprocal translocation t(14;17)(q32;q11.2)). We hypothesized that PATRR17 may be involved in these rearrangements thereby causing NF1. Breakpoint cloning revealed that PATRR17 was indeed involved in all of the rearrangements. As microhomology was present at all breakpoint junctions of the deletions identified, and PATRR17 partner breakpoints were located within 7.1 kb upstream of PATRR17, fork stalling and template switching (FoSTeS)/microhomology-mediated break-induced replication (MMBIR) was the most likely rearrangement mechanism. For the reciprocal translocation case, a 51 bp insertion at the translocation breakpoints mapped to a short sequence within PATRR17, proximal to the breakpoint, suggesting a multiple stalling and re-replication process, in contrast to previous studies indicating a purely replication-independent mechanism for PATRR-mediated translocations. In conclusion, we show evidence that PATRR17 is a hotspot for pathogenic intragenic deletions within the NF1 gene and suggest a novel replication-dependent mechanism for PATRR-mediated translocation.This article is protected by copyright. All rights reserved
    Human Mutation 07/2014; 35(7). DOI:10.1002/humu.22569 · 5.14 Impact Factor
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    • "'Complex’ are such sSMC which consist of chromosomal material derived from more than one chromosome [1]. Thus, besides the aforementioned large group of Emanuel or derivative chromosome 22 {der(22)t(11;22), OMIM #609029} syndrome cases, there was identified a second recurrent complex sSMC in 2010, designated as supernumerary der(22)t(8;22) syndrome {OMIM #613700} [6]. "
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    ABSTRACT: Complex small supernumerary marker chromosomes (sSMC) constitute one of the smallestsubgroups of sSMC in general. Complex sSMC consist of chromosomal material derived from more than one chromosome; the best known representative of this group is the derivative chromosome 22 {der(22)t(11;22)} or Emanuel syndrome. In 2008 we speculated that complex sSMC could be part of an underestimated entity. Here, the overall yet reported 412 complex sSMC are summarized. They constitute 8.4% of all yet in detail characterized sSMC cases. The majority of the complex sSMC is contributed by patients suffering from Emanuel syndrome (82%). Besides there are a der(22)t(8;22) (q24.1;q11.1) and a der(13)t(13;18)(q11;p11.21) or der(21)t(18;21)(p11.21;q11.1) = der(13 or 21)t(13 or 21;18) syndrome. The latter two represent another 2.6% and 2.2% of the complex sSMC-cases, respectively. The large majority of complex sSMC has a centric minute shape and derives from an acrocentric chromosome. Nonetheless, complex sSMC can involve material from each chromosomal origin. Most complex sSMC are inherited form a balanced translocation in one parent and are non-mosaic. Interestingly, there are hot spots for the chromosomal breakpoints involved. Complex sSMC need to be considered in diagnostics, especially in non-mosaic, centric minute shaped sSMC. As yet three complex-sSMC-associated syndromes are identified. As recurrent breakpoints in the complex sSMC were characterized, it is to be expected that more syndromes are identified in this subgroup of sSMC. Overall, complex sSMC emphasize once more the importance of detailed cytogenetic analyses, especially in patients with idiopathic mental retardation.
    Molecular Cytogenetics 10/2013; 6(1):46. DOI:10.1186/1755-8166-6-46 · 2.14 Impact Factor
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    • "Interestingly, DNA sequences close to the breakpoint mapped in CFS showed the potential to form secondary structures with frequent AT-rich flexible cluster [45]. These favored sites for chromosomal breakpoints are notably observed in the Robertsonian translocation [46], in the Emanuel syndrome [47] [48] or in five other characterized translocations [49] [50] [51] [52] [53]. As a consequence , these specific loci are preferential integration site for foreign DNA [54] [55] [56] [57] or chromosomal rearrangements that lead to numerous gene deletion, such as FRA3B that contains the tumor suppressor gene FHIT [58] or chromosomal amplification as those located in FRA7I loci that is implicated in breast cancer [59]. "
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    ABSTRACT: In addition to the canonical right handed double helix, DNA molecule can adopt several other non B-DNA structures. Readily formed in the genome at specific DNA repetitive sequences, these secondary conformations present a distinctive challenge for progression of DNA replication forks. Impeding normal DNA synthesis, cruciforms, hairpins, H-DNA, Z-DNA and G4 DNA considerably impact the genome stability and in some instances play a causal role in disease development. Along with previously discovered dedicated DNA helicases, the specialized DNA polymerases emerge as major actors performing DNA synthesis through these distorted impediments. In their new role, they are facilitating DNA synthesis on replication stalling sites formed by non B-DNA structures and thereby helping the completion of DNA replication, a process otherwise crucial for preserving genome integrity and concluding normal cell division. This review summarizes the evidence gathered describing the function of specialized DNA polymerases in replicating DNA through non B-DNA structures.
    Journal of Molecular Biology 10/2013; 425(23). DOI:10.1016/j.jmb.2013.09.022 · 4.33 Impact Factor
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