Clustered 11q23 and 22q11 Breakpoints and 3:1 Meiotic Malsegregation in Multiple Unrelated t(11;22) Families

Shaikh, Tamim H.; Budarf, Marcia L.; Celle, Livija; Zackai, Elaine H.; Emanuel, Beverly S.

doi:10.1086/302666

Cited by 77 publications

(83 citation statements)

References 41 publications

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“…Carriers of the balanced constitutional t(11;22) are phenotypically normal, but at risk of having progeny with the supernumerary der(22)t(11;22) karyotype, which includes severe mental retardation (28). This represents the resulting 3:1 meiotic segregation with tertiary trisomy, i.e., der(22) as the SMC (28).…”

Section: Discussionmentioning

confidence: 99%

Characterization of 23 small supernumerary marker chromosomes detected at pre-natal diagnosis: The value of fluorescence in situ hybridization

Manolakos¹,

Kefalas²,

Neroutsou³

et al. 2010

Mol Med Rep

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Abstract. Small supernumerary marker chromosomes (sSMCs) cannot be identified or characterized unambiguously by conventional cytogenetic banding techniques. Until recently, the large variety of marker chromosomes, as well as the limitations in their identification, have presented a diagnostic problem. In order to determine the origin of sSMCs, we used a variety of fluorescence in situ hybridization (FISH) methods, including centromere-specific multicolor FISH, acrocentric specific multicolor FISH, subcentromere-specific multicolor FISH and multicolor FISH with whole chromosome paint probes. Moreover, uniparental disomy testing was in all cases attempted. From a total of 28,000 pre-natal samples from four diagnostic genetics laboratories in Greece, 23 (0.082%) supernumerary marker chromosomes were detected. The mean maternal age was 36.2 years (range 27-43) and the mean gestational age at which amniocentesis was performed was 18.5 weeks (range 16-23). Eighteen markers were de novo and 5 markers were inherited. Molecular cytogenetic methods were applied to determine the chromosomal origin and composition of the sSMC. In total, 17 markers were derived from acrocentric chromosomes (14, 15, 21 and 22) and 6 markers were non-acrocentric, derived from chromosomes 9, 16, 18, 20 and Y. Uniparental disomy was not detected in any of the cases studied. With regard to pregnancy outcome, 13 pregnancies resulted in normal healthy neonates, while 10 pregnancies were terminated due to ultrasound abnormalities. A total of 23 marker chromosomes from 28,000 pre-natal samples (0.082%) were identified. Molecular cytogenetic techniques provided valuable information on the chromosomal origin and composition of all the sSMCs. Especially in cases with normal ultrasound, the FISH results rendered genetic counseling possible in a category of cases previously considered a diagnostic problem. Abnormal outcome was observed in 10 cases (43,5%), 7 of which showed abnormal ultrasound findings. New technologies, such as array-comparative genomic hybridization, should be used in future genotype-phenotype correlation studies, although the high mosaicism rate poses a problem. IntroductionSmall supernumerary marker chromosomes (sSMcs) are structurally abnormal chromosomes, equal in size or smaller than chromosome 20, which cannot be identified or characterized unambiguously by conventional cytogenetic banding techniques (1). These chromosomes are detected in 0.04% of newborn children, whereas in developmentally retarded patients the rate is 0.22% (1-3). sSMCs are also present in 0.08% of unselected pre-natal cases and in 0.20% of pre-natal cases with ultrasound abnormalities (2). The large variety of sSMCs, as well as the limitations in their cytogenetic identification, have presented a diagnostic problem in their interpretation. In general, the risk for an abnormal phenotype is approximately 13%, varying from 7% when de novo sSMCs derived from chromosomes 13, 14, 21 and 22 are encountered, to 28% for non-acrocentric

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Section: Discussionmentioning

confidence: 99%

Characterization of 23 small supernumerary marker chromosomes detected at pre-natal diagnosis: The value of fluorescence in situ hybridization

Manolakos¹,

Kefalas²,

Neroutsou³

et al. 2010

Mol Med Rep

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“…Most CES and DG/VCFS rearrangements were reported to occur by near-homologous recombination at two distinct LCRs22, the proximal FISH study of supernumerary marker chromosomes 22 O Bartsch et al LCR-A and the distal LCR-D, while nonhomologous recombination at another low-copy repeat, LCR-B, was reported to lead to the constitutional 11;22 translocation. 9,24,25,30 From the perspective of FISH diagnostics, the DNA probes used here defined six distinct intervals on chromosome 22q (Table 2). We observed no SMC (22) that contained euchromatin between interval 1 (centromere heterochromatin) and interval 2 (the CECR), that is, that had some detectable euchromatin, but not from the cat eye region.…”

Section: Discussionmentioning

confidence: 99%

“…The der(22) syndrome and CES share a similar region of extra dosage on chromosome 22q11.21, but the der (22) syndrome is always associated with a partial trisomy of 11q23.3-qter in addition to the partial trisomy of 22pter-q11.21. The resulting phenotypes differ significantly: the der(22) syndrome is more severe than the CES and includes numerous additional signs that can be attributed to the partial trisomy of 11q 10,11,30 such as congenital hernia of diaphragm, renal dysplasia, and multiple renal cysts (patient 9). We have only sporadic data of the other subjects, which mainly represented prenatal diagnoses precluding detailed phenotypic description.…”

Section: Discussionmentioning

confidence: 99%

FISH of supernumerary marker chromosomes (SMCs) identifies six diagnostically relevant intervals on chromosome 22q and a novel type of bisatellited SMC(22)

Bartsch

Rasi²,

Hoffmann

et al. 2005

Eur J Hum Genet

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Supernumerary marker chromosomes (SMCs) are frequently found at pre-and postnatal cytogenetic diagnosis and require identification. A disproportionally large subset of SMCs is derived from the human chromosome 22 and confers tri-or tetrasomy for the cat eye chromosomal region (CECR, the proximal 2 Mb of chromosome 22q) and/or other segments of 22q. Using fluorescence in situ hybridization (FISH) and 15 different DNA probes, we studied nine unrelated patients with an SMC(22) that contained the CECR. Five patients showed the small (type I) cat eye syndrome (CES) chromosome and each one had the larger (type II) CES chromosome, small ring chromosome 22, der(22)t(11;22) extrachromosome, and a novel type of bisatellited SMC (22) with breakpoints outside the low-copy repeats (LCRs22). By size and morphology, the novel bisatellited SMC(22) resembled the typical (types I and II) CES chromosomes, but it might have been associated with the chromosome 22q duplication syndrome, not CES. This SMC included a marker from band 22q12.3 and conferred only one extra copy each of the 22 centromere, CECR, and common 22q11 deletion area. There has been no previous report of a bisatellited SMC(22) predicting the chromosome 22q duplication syndrome. Accounting for the cytogenetic resemblance to CES chromosomes but different makeup and prognosis, we propose naming this an atypical (type III) CES chromosome. In this study, we found six distinct intervals on 22q to be relevant for FISH diagnostics. We propose to characterize SMCs(22) using DNA probes corresponding to these intervals.

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“…FISH using a probe for the ATM gene mapping to 11q22 hybridized to its normal position on both the chromosomes 11, indicating that the translocation breakpoint was distal to the ATM locus. Further FISH analysis was performed using the probes described by Shaikh et al (1999). BAC 442e11, from the RPCI11 human BAC library (Roswell Park Cancer Institute), was used as a FISH probe.…”

Section: Case Reportmentioning

confidence: 99%

“…Most carriers of this translocation are ascertained because of abnormal offspring with the karyotype 47,XX or XY,+der(22)t(11;22)(q23;q11.2), resulting from 3 : 1 meiosis I segregation (Shaikh et al, 1999). This suggests either that this is a preferential mode of segregation or that this segregation product is the most likely to be viable to the time of amniocentesis and to term.…”

Section: Introductionmentioning

confidence: 99%

A unique case of der(11)t(11;22),-22 arising from 3:1 segregation of a maternal t(11;22) in a family with co-segregation of the translocation and breast cancer

et al. 2005

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Objective-To report the first tertiary monosomy in a pregnancy loss to a female t(11;22) carrier.Methods-The patient was a 34-year-old G10P1 female known to have a balanced translocation t (11;22)(q23;q11.2). She had one female livebirth (a translocation carrier) and eight miscarriages. Five female relatives known to be translocation carriers had a history of breast cancer, three of them premenopausally. The patient herself had a malignant melanoma.Results-During the 10th pregnancy, ultrasound showed a viable embryo at 6 weeks of gestation, but loss of embryonic heartbeat by 7.5 weeks. Culture of the products of conception at 8 weeks of gestation showed the karyotype: 46,XY,+2,der(11)t(11;22)(q23;q11.2)mat, −22[4]/45,XY,der(11)t (11;22)(q23;q11.2)mat,−22[4], resulting from fertilization of the maternal 3 : 1 segregation product containing only the der(11) by a normal gamete. Subsequently, she became pregnant with a normal 46,XX fetus. FISH analysis indicated that the breakpoints on 11q and 22q in the patient were in the previously described region common to typical recurrent t(11;22). In addition, a nested-PCR-based approach showed that they were located within the same palindromic AT-rich sequence previously described.Conclusion-This case demonstrates that the tertiary monosomy resulting from the 3 : 1 segregation is compatible with embryonic survival into the first trimester. It is also another example of apparent association of the constitutional translocation t(11;22) and breast cancer.

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Clustered 11q23 and 22q11 Breakpoints and 3:1 Meiotic Malsegregation in Multiple Unrelated t(11;22) Families

Cited by 77 publications

References 41 publications

Characterization of 23 small supernumerary marker chromosomes detected at pre-natal diagnosis: The value of fluorescence in situ hybridization

Characterization of 23 small supernumerary marker chromosomes detected at pre-natal diagnosis: The value of fluorescence in situ hybridization

FISH of supernumerary marker chromosomes (SMCs) identifies six diagnostically relevant intervals on chromosome 22q and a novel type of bisatellited SMC(22)

A unique case of der(11)t(11;22),-22 arising from 3:1 segregation of a maternal t(11;22) in a family with co-segregation of the translocation and breast cancer

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