Tightly Clustered 11q23 and 22q11 Breakpoints Permit PCR-Based Detection of the Recurrent Constitutional t(11;22)

Abstract

Palindromic AT-rich repeats (PATRRs) on chromosomes 11q23 and 22q11 at the constitutional t(11;22) breakpoint are predicted to induce genomic instability, which mediates the translocation. A PCR-based translocation-detection system for the t(11;22) has been developed with PCR primers flanking the PATRRs of both chromosomes, to examine the involvement of the PATRRs in the recurrent rearrangement. Forty unrelated carriers of the t(11;22) balanced translocation, plus two additional, independent cases with the supernumerary-der(22) syndrome, were analyzed to compare their translocation breakpoints. Similar translocation-specific junction fragments were obtained from both derivative chromosomes in all 40 carriers of the t(11;22) balanced translocation and from the der(22) in both of the offspring with unbalanced supernumerary-der(22) syndrome, suggesting that the breakpoints in all cases localize within these PATRRs and that the translocation is generated by a similar mechanism. This PCR strategy provides a convenient technique for rapid diagnosis of the translocation, indicating its utility for prenatal and preimplantation diagnosis in families including carriers of the balanced translocation.

Cruciform DNA Structure Underlies the Etiology for Palindrome-mediated Human Chromosomal Translocations

“…We have often observed strand separation of the PATRR fragment even at 37°C. 2 The temperature-induced drop in cruciform formation might be attributed to the competition for superhelix energy release, taking place between cruciform and open regions within the premelting range. We previously reported that only meiotic cells undergo this translocation (7).…”

“…We have analyzed only one case of a de novo t(11;22), and it indicated an origin in the paternal germ line. 2 Thus, it is not unreasonable to imagine that PATRR-mediated translocations might occur only in male meiotic cells generated at a lower body temperature.…”

Diagnosis and fine mapping of a deletion in distal 11q in two Chinese patients with developmental delay

“…Alternatively, some smaller deletions are likely to occur through different mechanisms; for example, chromosome recombinations can be mediated by palindromic AT-rich repeats, low copy repeats or olfactory receptor gene clusters. [8][9][10] Consequently, there are likely to be multiple mechanisms that result in the generation of deletions in long arm of chromosome 11.…”

Recent advance in our understanding of the molecular nature of chromosomal abnormalities

“…A more detailed characterization of the junction involved further revealed remnants of DSBs at the center of the two PATRRs, followed by repair through the non-homologous end joining pathway. [29][30][31][32] Two unrelated constitutional t(17;22)(q11;q11) translocations associated with NF1 disease have been reported. 33,34 These two translocations disrupt the NF1 gene on 17q11, which produces the NF1 phenotype in the affected patients.…”

“…We thereby successfully amplified the der(11) and der(22) junction fragments of balanced t(11;22) carriers as well as the der(22) of patients with Emanuel syndrome. 29 Translocation-specific PCR was then performed using conditions that would allow for the detection of a single molecule of the target DNA. When DNA derived from sperm samples obtained from healthy male volunteers was amplified using our assay, we obtained both positive and negative PCR results, indicating that we had successfully detected translocation products that were de novo in origin (Figure 2d).…”