Paternal origin of the de novo constitutional t(11;22)(q23;q11)

The constitutional t(11;22)(q23;q11) is a well-known recurrent non-Robertsonian translocation in humans. Although translocations generally occur in a random fashion, the break points of t(11;22)s are concentrated within several hundred base pairs on 11q23 and 22q11. These regions are characterized by palindromic AT-rich repeats (PATRRs), which appear to be responsible for the genomic instability. Translocation-specific PCR detects de novo t(11;22)s in sperm from healthy males at a frequency of 1/10⁴–10⁵, but never in lymphoblasts, fibroblasts or other human somatic cell lines. This suggests that the generation of t(11;22) rearrangement is linked to gametogenesis, although female germ cells have not been tested. Here, we have studied eight cases of de novo t(11;22) to determine the parental origin of the translocation using the polymorphisms on the relevant PATRRs. All of the eight translocations were found to be of paternal origin. This result implicates a possible novel mechanism of sperm-specific generation of palindrome-mediated chromosomal translocations.     

High incidence of familial breast cancer segregates with constitutional t(11;22)(q23;q11)

In a family with a high incidence of postmenopausal breast cancer and a case of glioblastoma, the constitutional translocation t(11;22)(q23;q11.2) was shown to segregate with the malignancies. The breakpoints in this family coincided with the common breakpoints in t(11;22) as shown by a translocation-specific PCR assay. Loss of heterozygosity analysis of breast tumor tissue revealed deletion of the normal chromosome 22, but retention of der(22) in the tumor cells, suggesting a predisposing effect of the der(22) for breast and brain tumor development in this family.     

Spontaneous expression of fra(11)(q23) in a patient with Ewing's sarcoma and t(11;22)(q23;q11)

Cytogenetic analysis of a Ewing's sarcoma revealed a 46,XX,t(8;18)(q11;q21.3), t(11;22)(q23–24;q11–12) chromosome pattern. Observation of t(11;22) is consistent with other reported cases of Ewing's sarcoma. One breakpoint in this translocation, 11q23, coincides with the location of a folate-sensitive fragile site. Examination of peripheral blood leukocyte chromosomes from the patient revealed a 46,XX chromosome pattern with spontaneous, fluorodeoxyuridine-, and Bactrim-induced expression of fra(11)(q23). This may be the first demonstration of constitutional fra(11)(q23) expression in a patient with a neoplasm that exhibits a chromosome rearrangement involving this breakpoint and the first observation of spontaneous expression of this fragile site. These results provide a basis for discussion of the relationship between fragile sites and chromosome rearrangements.     

The most frequent constitutional translocation in humans, the t(11;22)(q23;q11) is due to a highly specific alu-mediated recombination

The t(11;22) is the most common recurrent non-Robertsonian constitutional translocation in humans, having been reported in more than 160 unrelated families. Balanced carriers are at risk of having offspring with the derivative 22 syndrome owing to 3:1 meiotic non-disjunction event. Clinical features of the der(22) syndrome include mental retardation, craniofacial abnormalities and congenital heart defects. The breakpoints for the t(11;22) translocation have been mapped to specific Alu repeats on chromosomes 11 and 22, indicating that this event is due to an Alu-Alu recombination. Remarkably, in five samples derived from individuals with no apparent common ancestry the der(11) and der(22) breakpoints appear to be almost identical at the genomic sequence level. The small number of base differences between the samples indicates some variation in the position of the breakpoints, although this appears to be quite limited. Indeed, the der(11) breakpoints are all located within a region of just 32 bp and the der(22) breakpoints within 21 bp. If, as suggested by current data, the widespread occurrence of this translocation is due to multiple independent events, our results suggest that this particular Alu-Alu recombination is subject to an unprecedented degree of selection.     

t（11;18）（q11;q23）一家系

先证者　男 ,30岁 ,表型正常。婚后 3年 ,其妻怀孕 5次 ,均在孕 2～ 3个月自然流产 ,妇科检查正常。夫妇非近亲结婚。患者外生殖器正常。精液检查精子数量正常。细胞遗传学检查 :外周血细胞染色体观察 ,常规外周血淋巴细胞培养 ,G显带分析30个细胞 ,先证者核型为 46 ,XY,t(11;18) (11pter→ 11q11∷18q2 3→ 18qter;18pter→ 18q2 3∷ 11q11→ 11qter) ,其妻染色体核型正常。先证者性细胞联会复合体 (synaptonemal complex,SC)观察 ,方法参照文献 [1]。睾丸活检微铺展的 SC电镜观察 ,分析 30个精母细胞 (从早粗线期到晚粗线期 )中 SC图…     

Alu-mediated PCR artifacts and the constitutional t(11;22) breakpoint

The breakpoints of the recurrent t(11;22)(q23;q11) have recently been cloned. We identified palindromic AT-rich repeats (PATRRs) on 11q23 and 22q11 as the mechanism responsible for the rearrangement. Contradictory to our results, A.S. Hill et al. (Hum. Mol. Genet., 9, 1525-1532) suggested that Alu-mediated recombination is responsible. To clarify this discrepancy, the cloned 4.5 kb der(11) junction fragment has been completely sequenced. This sequence has been compared with that of an inverse PCR-generated der(11) junction fragment obtained by Hill et al. This reveals that the inverse PCR product has sustained a deletion between two Alu elements, such that the true breakpoint region is deleted from the PCR product. Utilizing PCR primers designed by Hill et al. to amplify across the der(11) breakpoint, we obtained a deleted PCR product even when our cloned der(11) junction fragment was used as template. Further, we find that the PCR primers that they utilized for amplification of the der(22) junction fragment are not located on the der(22). They are oriented in opposite directions within the region deleted from the der(11) PCR product, generating an artifact derived from the der(11) chromosome. Analysis of the truncated PCR products indicates a mixture of sequences from two distinct Alu elements, suggesting that the putative junction fragment described by Hill et al. is an Alu-mediated PCR artifact. These data suggest that caution should be exercised when analyzing PCR-based data, particularly when amplification is carried out in a region containing repeat structures with specific, difficult-to-amplify sequences.     

Involvement of a palindromic chromosome 22-specific low-copy repeat in a constitutional t(X; 22)(q27;q11)

Segmental duplications or low-copy repeats (LCRs) on chromosome 22q11 have been implicated in several chromosomal rearrangements. The presence of AT-rich regions in these duplications may lead to the formation of hairpin structures, which facilitate chromosomal rearrangement. Here we report the involvement of such a low-copy repeat in a t(X;22) associated with a neural tube defect. Molecular analysis of the chromosomal breakpoints revealed that the chromosome 22 breakpoint maps in the palindromic non-AT-rich NF1-like region of low-copy repeat B (LCR-B). No palindromic region was encountered near the breakpoint on chromosome X. Our findings confirm that there is no single mechanism leading to translocations with chromosome 22q11 involvement. Because LCR-B does not contain genes involved in neural tube development, we believe that the gene responsible for the observed phenotype is most likely localized on chromosome X.     

Primary effusion lymphoma of the pericardial cavity carrying t(1;22)(q21;q11) and t(14;17)(q32;q23)

We report a case of primary effusion lymphoma (PEL) in a 75-year-old woman without human immunodeficiency virus or hepatitis C virus, which presented as fever, chest pain, and pericardial effusion. The lymphoma cells were positive for CD20 and CD79a, and were negative for CD3 and CD10. Genomic human herpes virus 8 (HHV-8) and Epstein-Barr virus were not detected in the lymphoma cells. Cytogenetic analysis showed complex abnormalities by the G-banding technique, and spectral karyotyping (SKY) analysis provided more detailed characterization of the chromosomal aberrations, including t(1;22)(q21;q11) and t(14;17)(q32;q23). We did not detect C-MYC gene rearrangement or BCL-2 expression. She was treated successfully with six courses of the CHOP regimen. The present case demonstrated a rare category of PEL that is not associated with HHV-8 or C-MYC gene rearrangement. In addition, SKY analysis disclosed cryptic chromosomal abnormalities involving 1q21 and 17q23.     

Long AT-rich palindromes and the constitutional t(11;22) breakpoint.

The constitutional t(11;22) is the most frequently occurring non-Robertsonian translocation in humans. The breakpoint (BP) of the t(11;22) has been identified within palindromic AT-rich repeats (PATRRs) on chromosomes 11 and 22, suggesting that hairpin/cruciform structures mediate double-strand breaks leading to the translocation. To further characterize the mechanism of the translocation, identification of the precise location of the translocation BP is essential. Thus, the PATRRs from normal chromosomes 11 have been analyzed in detail. The majority of individuals have a PATRR that is 445 bp in length with a nearly symmetrical structure. The shorter, previously reported 204 bp PATRR has been shown to be a rare polymorphism. There are several nucleotide differences between the proximal and distal arms of the 445 bp palindrome (cis-morphisms) that correspond to five polymorphic sites within the PATRR. Using these data, the junction fragments of 40 unrelated t(11;22) families have been examined to determine the position of their 11q23 BPs. Sequence analysis demonstrates that BPs are located at the center of the longer PATRR in 39 of 40 cases. The data suggest that the center of the palindrome is susceptible to double-strand breaks leading to translocations that sustain small symmetrical deletions at the BP junction. The sequence of the larger, chromosome 22 PATRR deduced from junction fragments has three cis-morphisms, and the derivative chromosomes sustain symmetric deletions at the center of 22q11 PATRR. In one unusual case, the BPs on both chromosomes appear to correspond to these cis-morphic sites, suggesting that double-strand breaks at mismatched regions caused this variant translocation. De novo t(11;22) BPs have been analyzed using translocations detected in sperm samples from normal males. cis-Morphisms reveal no exclusive utilization of a particular allele in meiosis to produce the translocation. Our data lend support to the hypothesis that palindrome-mediated double-strand breaks in meiosis cause illegitimate recombination between 11q23 and 22q11 resulting in this recurrent translocation.     

The 11q23 breakpoint in acute leukemia with t(11;19)(q23;p13) is distal to those of t(4;11), t(6;11) and t(9;11).

Thirteen cosmid probes were mapped on the long arm of chromosome 11 between 11q22 and 11q24 by nonradioactive in situ hybridization. Starting with these localizations and those of other probes mapped to 11q23, four acute leukemias with translocations involving 11q23 were studied with the same method. The translocation breakpoints of the t(4;11)(q21;q23), t(6;11)(q27;q23), t(9;11)(p21-p22;q23), and t(11;19)(q23;p13) were confirmed to be distal to CD3D. The probe cC111-304 was proximal to the t(11;19) breakpoint while distal to the breakpoints of the other rearrangements. In view of the diversity of chromosomal abnormalities involving band 11q23, our finding extends the molecular heterogeneity of the breakpoint localization in leukemias with rearrangements involving 11q23.     

t(6;12)(q23;q13) and t(10;16)(q22;p11) in a phyllodes tumor of breast.

Cytogenetic analysis of short-term cultures from a phyllodes tumor showed clonal chromosome changes including t(6;12)(q23;q13) and t(10;16)(q22;p11). This is the first reported karyotype in this tumor type. We discuss the breakpoints of these translocations in relation to the involvement of possible candidate genes.     

Analysis of human sperm chromosome complements from a male heterozygous for a reciprocal translocation t(11;22)(q23;q11)

A reciprocal translocation between chromosomes 11 and 22 (t(11;22)(q23;q11)) is a site-specific translocation that is of particular interest because of the propensity for 3:1 segregation of the chromosomes during meiosis. There have been no published reports of chromosomally unbalanced offspring born as a result of adjacent 1 or 2 meiotic segregations in a heterozygote for this translocation. This could be explained by a meiotic mechanism which produces only 3:1 chromosomal segregations or by differential embryonic survival in which 2:2 adjacent segregations do not produce a viable pregnancy. To distinguish between these two possibilities, sperm chromosome complements from a man heterozygous for this 11;22 translocation were studied. The human sperm chromosomes were analysed after fertilization of zona pellucida-free golden hamster eggs. All possible 2:2 (alternate, adjacent 1, adjacent 2) and 3:1 segregations were observed and these segregations occurred in approximately equal frequencies. The frequency of other chromosome abnormalities, unrelated to the translocation, did not appear to be increased. These results indicate that the 11;22 translocation does not specifically cause 3:1 disjunction of chromosomes but that this segregation of chromosomes is more likely to result in a viable pregnancy.     

46，XX，t（11q；22q）一例

先证者男,33岁,结婚2年,因“其弟曾被诊断为18-三体”前来遗传咨询。本人表型、智力均正常;身高1.71m,体重75kg,第二性征发育正常。家系调查:先证者母亲身高1.56m,表型、智力正常,有3次早期自然流产史,否认有家族史,父亲已去世。先证者的弟弟,表型异常,智力明显低下,身高约1.65     

Acute myeloid leukemia (AML) with t(8;21)(q22;q22) relapsing as AML with t(3;21)(q26;q22)

We here report on an 48-year-old male patient with a primary diagnosis of acute myeloid leukemia (AML)-M2 with t(8;21)(q22;q22), who developed complete hematologic and molecular remission after induction chemotherapy. Thirteen months later, he relapsed and showed an AML-M2 with t(3;21)(q26;q22). Retrospectively, polymerase chain reaction (PCR) for AML1-EVI1 and EVI1 overexpression was performed on bone marrow and peripheral blood samples taken at diagnosis and during the first year after the first manifestation of AML to quantify the AML1-EVI1-positive clone. In a bone marrow sample taken 25 days from diagnosis, PCR for AML1-EVI1 was negative, and EVI1 expression, as assessed by quantitative real-time PCR, was within the same range as that of healthy controls. These data suggest that this patient developed a secondary therapy-related AML rather than a relapse.     

Site-specific reciprocal translocation,t(11;22) (q23;q11), in several unrelated families with 3:1 meiotic disjunction

We have studied 32 unrelated families with a site-specific reciprocal translocation between chromosomes 11 and 22 [t(11;22) (q23;q11)]. In translocation heterozygotes 3:1 meiotic segregation occurs and results in abnormal progeny who carry the der(22) as a supernumerary chromosome. Phenotypic findings consistent with 47,XX (or XY), +der(22), t(11;22) include mental retardation, preauricular skin tag and/or sinus, ear anomaly, palate anomaly, micrognathia, congenital heart disease, and genital anomalies in males. The frequency of abortions among offspring of male and female heterozygotes is increased. Segregation analysis shows that the risk for unbalanced offspring to be born to female heterozygotes may be as high as 10%, and that there may be a significant risk to male heterozygotes as well. The overall carrier frequency among progeny of 11;22 translocation carriers is 70.6%. The occurrence of multiple 11;22 translocation events is supported by de novo occurrence of the translocation, familial heteromorphic variants of the der(22), and varied racial and ethnic backgrounds of the families. To our knowledge, with the exclusion of centric fusion translocations, this represents the only example of nonrandom exchange in a constitutional chromosomal rearrangement.     

Distinct breakpoints in band 11q23 of the t(4;11) and t(11;14) associated with leukocyte malignancy.

Several non-random translocation breakpoints associated with leukemia or lymphoma have been shown to occur in chromosome band 11q23 between the genes CD3G and PBGD, a distance of approximately 750 kb. A combination of yeast artificial chromosome (YAC) cloning, in situ hybridization, and pulsed field gel electrophoresis (PFGE) experiments has further refined the interval containing one of these breakpoints, t(4;11)(q21;q23), to within 200 kb of CD3G. We have extended the PFGE analysis to show that the t(4;11) breakpoint lies in a region of approximately 100 kb, situated 100 kb distal to CD3G. Furthermore, we show that a second 11q23 breakpoint, t(11;14)(q23;q32), which was also previously mapped between CD3G and PBGD, is distinct from that of the t(4;11) chromosome. The 11q23 sequences that are involved at the t(11;14) breakpoint are not present in a YAC containing the t(4;11) breakpoint. The t(11;14) breakpoint has been localized on the PFGE map of the CD3G-PBGD interval and is at least 110 kb distal to the t(4;11) breakpoint, thus demonstrating heterogeneity among 11q23 breakpoints.