Unbalanced Translocations (unbalanced + translocation)

Distribution by Scientific Domains

Selected Abstracts

Update on the clinical features and natural history of Wolf,Hirschhorn (4p-) syndrome: Experience with 87 patients and recommendations for routine health supervision,

Agatino Battaglia
Abstract Wolf,Hirschhorn syndrome (WHS) is a well-known multiple congenital anomalies/mental retardation syndrome, firstly described in 1961 by Cooper and Hirschhorn. Its frequency is estimated as 1/50,000,1/20,000 births, with a female predilection of 2:1. The disorder is caused by partial loss of material from the distal portion of the short arm of chromosome 4 (4p16.3), and is considered a contiguous gene syndrome. No single gene deletions or intragenic mutations have been shown to confer the full WHS phenotype. Since the disorder was brought to the attention of geneticists, many additional cases have been published. Only in 1999, however, were the first data on the natural history brought to the attention of the medical community. The purpose of the present study is to help delineate in more detail and over a longer period of time, the natural history of WHS, in order to establish appropriate health supervision and anticipatory guidance for individuals with this disorder. We have collected information on 87 patients diagnosed with WHS (54 females and 33 males) both in USA and Italy. Age at first observation ranged between newborn and 17 years. Twenty patients have been followed from 4 months to 23 years. The deletion proximal breakpoint varied from 4p15.32 to 4p16.3, and, by FISH, was terminal and included both WHSCR. Deletion was detected by standard cytogenetics in 44/87 (50.5%) patients, whereas FISH was necessary in the other 43 (49.5%). Array-CGH analysis at 1 Mb resolution was performed in 34/87 patients, and, in 15/34 (44%), showed an unbalanced translocation leading to both a 4p monosomy and a partial trisomy for another chromosome arm. Six more patients had been previously shown to have an unbalanced translocation by karyotype analysis or FISH with a WHS-specific probe. Sixty-five of 87 patients had an apparent pure, de novo, terminal deletion; and 1/87 a tandem duplication of 4p16.1p16.3 associated with 4p16.3pter deletion. Age at diagnosis varied between 7 months gestation and 16 years. Ninety-three percent had a seizure disorder with a good outcome; 80% had prenatal onset growth deficiency followed by short stature and slow weight gain; 60% had skeletal anomalies; 50% had heart lesions; 50% had abnormal tooth development; and 40% had hearing loss. Distinctive EEG findings were seen in 90%. Structural CNS anomalies were detected in 80%. Global developmental delay of varying degrees was present in all patients. Almost 50% was able to walk either alone or with support. Hypotonia was present in virtually all patients. A global improvement was observed in all individuals, over time. Our survey has also shown how the characteristic facial phenotype tends to be less pronounced in those patients with a smaller deletion, and microcephaly is not observed in the patients with certain cryptic unbalanced translocations. © 2008 Wiley-Liss, Inc. [source]

Hypoplastic left heart in a female infant with partial trisomy 4q due to de novo 4;21 translocation

Milen Velinov
Abstract We present a female infant with mild dysmorphic features and congenital heart defect: hypoplastic left heart with aortic atresia and hypoplastic aortic arch, ventricular septal defect, and a nonrestrictive atrial communication. Chromosome analysis showed an unbalanced translocation that contained additional material from 4q translocated onto 21q. This resulted in partial trisomy 4 and monosomy for the 21q telomeric region. The derivative chromosome was characterized using G-banding, M-FISH, and whole chromosome painting. The karyotype was described as 46,XX,der(21)t(4;21)(q25;q22.3).ish(wcp4+;wcp21+). Additional analyses with FISH probes specific for 21q 22.3, 21q22.2, 21q21.1, and 21q11.2 did not indicate any chromosome 21 duplication within the derivative chromosome 21. Monosomy for the telomeric portion of 21q was demonstrated using a tel 21q probe (Oncor). The patient underwent stage 1 Norwood procedure to manage her heart defect. Poor feeding and failure to thrive complicated the postsurgical period. The child subsequently underwent funduplication and feeding tube placement, and at 4.5 months of age presented with microcephaly and developmental delay. Hypoplastic left heart was previously reported with increased frequency in relatively common numeric chromosomal aberrations, such as monosomy X, trisomies 21, 18, and 13, and in various structural chromosomal defects. Our report presents new evidence for the co-occurrence of hypoplastic left heart with a duplicated portion of chromosome 4 distal to 4q25. In addition, monosomy for the telomeric region of chromosome 21 may have implications in the phenotype. © 2001 Wiley-Liss, Inc. [source]

Lupus-like disease and high interferon levels corresponding to trisomy of the type I interferon cluster on chromosome 9p

Haoyang Zhuang
Objective Systemic lupus erythematosus (SLE) is associated with type I interferons (IFNs) and can be induced by IFN, treatment. This study looked for evidence of autoimmunity in a pedigree consisting of 4 family members with a balanced translocation 9;21 and 2 members with an unbalanced translocation resulting in trisomy of the short (p) arm and part of the long (q) arm of chromosome 9. These latter 2 subjects had 3 copies of the IFN gene cluster. Methods Subjects were evaluated clinically and serologically for autoimmune disease. Expression levels of IFN,4, IFN,, the type I IFN,inducible gene Mx1, the type I IFN receptor, interleukin-6, and tumor necrosis factor , were determined by real-time polymerase chain reaction. Circulating plasmacytoid dendritic cells, the main IFN-producing cells, were quantified by flow cytometry. Results Both subjects with trisomy of chromosome 9p had a lupus-like syndrome with joint manifestations and antinuclear antibodies: one had anti-RNP and antiphospholipid autoantibodies, and the other had anti,Ro 60. The 3 family members with a balanced translocation 9;21 had no clinical or serologic evidence of autoimmunity, similar to that in relatives who were unaffected by the chromosomal translocation. In the 2 subjects with trisomy of 9p, high levels of IFN,/, (comparable with those found in patients with SLE), increased signaling through the IFN receptor (as indicated by high Mx1 expression), and low levels of circulating plasmacytoid dendritic cells (as observed in patients with SLE) were evident. These abnormalities were not seen in individuals with a balanced translocation. Conclusion Trisomy of the type I IFN cluster of chromosome 9p was associated with lupus-like autoimmunity and increased IFN,/, and IFN receptor signaling. The data support the idea that abnormal regulation of type I IFN production is involved in the pathogenesis of SLE. [source]

Duplication 8q22.1-q24.1 associated with bipolar disorder and speech delay

JF Macayran
Objective:, To report a case of a child with bipolar disorder found to have an unbalanced translocation involving the long arm of chromosome 8, a region that has been previously implicated in genome-wide linkage scans. Case report:, A 7-year-old boy with a complex psychiatric symptom presentation including attention deficits, distractibility, impulsivity, pressured speech, sleep disturbance, aggressive behavior, and hypersexuality diagnosed with bipolar disorder. He also showed evidence of borderline intellectual and adaptive functioning and had mild dysmorphic features with a duplication of distal 8q that arose as an unbalanced chromosomal translocation due to a maternal 15p;8q insertion. Conclusion:, This finding of an unbalanced translocation provides further evidence to support previous linkage studies of a potential causative gene on 8q for bipolar disorder. [source]

Chromosome 1 abnormalities in myeloid malignancies: a literature survey and karyotype,phenotype associations

Domenica Caramazza
Abstract Chromosome 1 is the largest human chromosome and contains over 1600 known genes and 1000 novel coding sequences or transcripts. It is, therefore, not surprising that recurrent chromosome 1 abnormalities are regularly encountered in both neoplastic and non-neoplastic medical conditions. The current review is focused on myeloid malignancies where we summarize the relevant published literature and discuss specific karyotype,phenotype associations. We show that chromosome 1 abnormalities are most frequent in BCR-ABL -negative classic myeloproliferative neoplasms (MPN): polycythemia vera (PV), essential thrombocythemia (ET), and primary myelofibrosis (PMF). Specific abnormalities include duplications (e.g. 1q12,1q32 in PV, 1q21,32,1q32,44 in post-PV MF or PMF), deletions (e.g. 1p13,36,pter in PV or PMF, 1q21 in PMF) and unbalanced translocations involving chromosome 6, such as der(6)t(1;6)(q21,25;p21.3,23), and other partner chromosomes involving 1q10/1p11 and 1q21,25 breakpoints. Although occasionally seen in chronic phase MPN, unbalanced 1;7 translocations, e.g. der(1;7)(q10;p10), are usually seen in acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), and post-MPN AML/MDS. These observations suggest that certain chromosome 1 regions, especially 1q21,1q32 and 1p11,13, might harbor oncogenes or tumor suppressor genes that are pathogenetically relevant to both chronic and advanced phases of MPN. [source]

Spectral karyotyping in patients with acute myeloid leukemia and a complex karyotype shows hidden aberrations, including recurrent overrepresentation of 21q, 11q, and 22q

Krzysztof Mrůzek
We used spectral karyotyping (SKY) to study 29 adults with acute myeloid leukemia and a complex karyotype containing one to nine abnormalities that were not fully identifiable by G-banding. SKY showed the origin of rings and unidentified material in unbalanced translocations in all cases and the origin of markers in most, allowing reinterpretation of 136 aberrations and discovery of three aberrations hidden in normal chromosomes. SKY confirmed 10 and refined the interpretation of three balanced aberrations recognized by G-banding and identified another nine balanced aberrations, including a novel translocation involving the RUNX1 gene. Eleven of 32 deletions found by G-banding were shown to be cryptic translocations or insertions, including three of four chromosome 3 deletions, two of three del(7q), and two of 12 del(5q). Of the 92 chromosomes deemed lost entirely by G-banding, 63 (68%) were shown to be involved in structural aberrations. This was especially true for ,21 (eight of eight patients), ,5 (five of six patients), ,20 (seven of nine patients), and ,18 (six of 12 patients). Unexpectedly, SKY uncovered a hidden overrepresentation of segments from at least one chromosome in 21 patients. The most frequently overrepresented was 21q, found in eight patients, including four with high-level 21q amplification. Fluorescence in situ hybridization showed that the RUNX1 gene was not the target of amplification in seven of these patients. Also frequently gained were 11q (in seven patients, including three with high-level MLL gene amplification) and 22q (in seven patients). We conclude that SKY considerably enhances the accuracy of karyotype interpretation, and that amplification of chromosomal material may play a greater role in leukemogenesis than has been recognized. © 2002 Wiley-Liss, Inc. [source]

Molecular cytogenetic characterization of early and late renal cell carcinomas in Von Hippel-Lindau disease ,

John L. Phillips
Deletions of 3p25, gains of chromosomes 7 and 10, and isochromosome 17q are known cytogenetic aberrations in sporadic renal cell carcinoma (RCC). In addition, a majority of RCCs have loss of heterozygosity (LOH) of the Von Hippel-Lindau (VHL) gene located at chromosome band 3p25. Patients who inherit a germline mutation of the VHL gene can develop multifocal RCCs and other solid tumors, including malignancies of the pancreas, adrenal medulla, and brain. VHL tumors follow the two-hit model of tumorigenesis, as LOH of VHL, a classic tumor suppressor gene, is the critical event in the development of the neoplastic phenotype. In an attempt to define the cytogenetic aberrations from early tumors to late RCC further, we applied spectral karyotyping (SKY) to 23 renal tumors harvested from 6 unrelated VHL patients undergoing surgery. Cysts and low-grade solid lesions were near-diploid and contained 1,2 reciprocal translocations, dicentric chromosomes, and/or isochromosomes. A variety of sole numerical aberrations included gains of chromosomes 1, 2, 4, 7, 10, 13, 21, and the X chromosome, although no tumors had sole numerical losses. Three patients shared a breakpoint at 2p21,22, and three others shared a dicentric chromosome 9 or an isochromosome 9q. In contrast to the near-diploidy of the low-grade lesions, a high-grade lesion and its nodal metastasis were markedly aneuploid, revealed loss of VHL by fluorescence in situ hybridization (FISH), and contained recurrent unbalanced translocations and losses of chromosome arms 2q, 3p, 4q, 9p, 14q, and 19p as demonstrated by comparative genomic hybridization (CGH). By combining SKY, CGH, and FISH of multiple tumors from the same VHL kidney, we have begun to identify chromosomal aberrations in the earliest stages of VHL-related renal cell tumors. Our current findings illustrate the cytogenetic heterogeneity of different VHL lesions from the same kidney, which supports the multiclonal origins of hereditary RCCs. Published 2001 Wiley-Liss, Inc. [source]

Multiplex fluorescence in situ hybridization in identifying chromosome involvement of complex karyotypes in de novo myelodysplastic syndromes and acute myeloid leukemia

Summary Complex chromosomal aberrations (CCA) can be detected in a substantial proportion of myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML), which are associated with very poor prognosis. Conventional cytogenetics (CC) cannot accurately define the specific alterations in CCA. Multiplex fluorescence in situ hybridization (M-FISH) allows the comprehensive identification of CCA. In this study, M-FISH was used in 16 patients with de novo MDS and 22 with AML with CCA detected by R-banding CC, and revealed 206 aberrations involved all 24 chromosomes, including 73 numerical chromosomal abnormalities and 133 structural abnormalities. The chromosomes most often involved were, by decreasing incidence, 5, 17, 8, 11, 7 and 21 in 57.9%, 55.3%, 44.7%, 36.8%, 34.2% and 34.2% of the cases, respectively. There were 98 unbalanced translocations, which were the most frequently observed aberrations in our study. Derivative chromosome 5 and 8 were implicated most often. The other derivatives were der(11), der(12), der(7), der(14), der(15) and der(17). Fourteen balanced translocations were detected in our series, and the most frequent reciprocal translocations was t(8;21). Fifty-five monosomies, 15 partial deletions, and 18 trisomies were found in all patients. The most frequently observed were ,5/5q,, ,17/17q,, ,7, ,18, ,21, ,19, and trisomy of chromosome 8 and 6. There were some abnormalities that have not been previously described, including two complex t(8;21) and seven unbalanced translocations. M-FISH could refine CCA, find or correct the missed or misidentified aberrations by CC analysis. Our findings confirmed that M-FISH was a powerful molecular cytogenetic tool to characterize complex karyotypes in MDS and AML. [source]

Multicolour fluorescence in situ hybridization analysis of t(14;18)-positive follicular lymphoma and correlation with gene expression data and clinical outcome

Valia S. Lestou
Summary. In order fully to identify secondary chromosomal alterations, such as duplications, additions and marker chromosomes that remained unresolved by G banding, 60 cases of t(14;18)-positive follicular lymphoma (FL) were analysed by multicolour karyotyping techniques [multicolour fluorescence in situ hybridization (MFISH)/multicolour banding for chromosome 1 (MBAND1)]. A total of 165 additional structural chromosomal aberrations were delineated. An increased frequency of chromosomal gains involving X, 1q, 2, 3q27-q29, 5, 6p11-p21, 7, 8, 11, 12, 14q32, 17q, 18 and 21 and deletions of 1p36, 3q28-q29, 6q, 10q22-q24 and 17p11-p13 was revealed by the MFISH/MBAND1 analysis. Balanced translocations other than t(14;18) were uncommon, whereas unbalanced translocations were numerous. Deletion of 1p36 and duplication of 1p33-p35, 1p12-p21 and 1q21-q41 were regularly involved in chromosome 1 alterations, seen in 53% of the cases. A strong correlation was demonstrated between gains of individual chromosomal bands and increased gene expression, including 1q22/MNDA, 6p21/CDKN1A, 12q13-q14/SAS, 17q23/ZNF161, 18q21/BCL2 and Xq13/IL2RG. Unfavourable overall survival was associated with del(1)(p36) and dup(18q). These data support the notion that translocation events are primarily responsible for FL disease initiation, whereas the unbalanced chromosomal gains and losses that mirror the gene expression patterns characterize clonal evolution and disease progression, and thus provide further insights into the biology of FL. [source]