Characterization of a (Y;4) translocation by DNA hybridization

Summary A phenotypically normal male with azoospermia was found to have a translocation between the short arm of the Y chromosome and the distal long arm of a chromosome 4. By cytogenetic analysis it could not be determined whether the translocation was reciprocal, nor whether it was balanced. In situ DNA hybridization with two pseudoautosomal and one Y-specific probe demonstrated that the breakpoint was on distal Yp and that there was Y chromosome material on 4q. Thus the translocation was reciprocal and could be characterized as t(Y;4)(pll;q32). There was no evidence for loss of Y-DNA sequences as judged by Southern blotting with Y-DNA probes. Thus the translocation may be balanced. We conclude that DNA hybridization can be used to refine considerably the cytogenetic analysis of such translocations.     

Balanced translocations in mental retardation

Over the past few decades, the knowledge on genetic defects causing mental retardation has dramatically increased. In this review, we discuss the importance of balanced chromosomal translocations in the identification of genes responsible for mental retardation. We present a database-search guided overview of balanced translocations identified in patients with mental retardation. We divide those in four categories: (1) balanced translocations that helped to identify a causative gene within a contiguous gene syndrome, (2) balanced translocations that led to the identification of a mental retardation gene confirmed by independent methods, (3) balanced translocations disrupting candidate genes that have not been confirmed by independent methods and (4) balanced translocations not reported to disrupt protein coding sequences. It can safely be concluded that balanced translocations have been instrumental in the identification of multiple genes that are involved in mental retardation. In addition, many more candidate genes were identified with a suspected but (as yet?) unconfirmed role in mental retardation. Some balanced translocations do not disrupt a protein coding gene and it can be speculated that in the light of recent findings concerning ncRNA’s and ultra-conserved regions, such findings are worth further investigation as these potentially may lead us to the discovery of novel disease mechanisms.     

Recombination in a balanced complex translocation of a mother leading to a balanced reciprocal translocation in the child. Review of 60 cases of balanced complex translocations

We report an unusual case of a balanced reciprocal translocation with a recombinant chromosome which has arisen from a familial balanced complex translocation. Fluorescence in situ hybridization studies were essential for the identification of the breakpoints. A review of 60 cases of balanced complex translocations (BCT) has revealed three cases similar to ours. Carriers of BCT have a high risk of having spontaneous abortions or a child with an unbalanced karyotype. Certain types of balanced rearrangements involving an insertion can give rise to a simpler balanced translocation as a result of crossover. Our observations support the assumption that the chance that a de novo balanced complex translocation is associated with an abnormal phenotype increases with the number of breakpoints. Received: 27 March 1996 / Revised: 28 January 1997     

The role of chromosomal alterations in human cancer development

Cancer cells become unstable and compromised because several cancer-predisposing mutations affect genes that are responsible for maintaining the genomic instability. Several factors influence the formation of chromosomal rearrangements and consequently of fusion genes and their role in tumorigenesis. Studies over the past decades have revealed that recurring chromosome rearrangements leading to fusion genes have a biological and clinical impact not only on leukemias and lymphomas, but also on certain epithelial tumors. With the implementation of new and powerful cytogenetic and molecular techniques the identification of fusion genes in solid tumors is being facilitated. Overall, the study of chromosomal translocations have revealed several recurring themes, and reached important insights into the process of malignant transformation. However, the mechanisms behind these translocations remain unclear. A more thorough understanding of the mechanisms that cause translocations will be aided by continuing characterization of translocation breakpoints and by developing in vitro and in vivo model systems that can generate chromosome translocation.     

Segregation of two independent chromosomal translocations in one family

Summary A family with two independent reciprocal translocations t(3;19) and t(16;22) is described. The proband, a 4-week-old male, was phenotypically conspicious with multiple congenital anomalies. Cytogenetic examination revealed a balanced reciprocal translocation (3;19) and a supernumerary small marker chromosome. His mother carried two balanced reciprocal translocations, the one found in the proband and a reciprocal translocation (16;22). The maternal grandmother and a maternal uncle were identified as carriers of a single translocation (16;22). The findings in the family members permitted the identification of the proband's marker chromosome as a derivative chromosome 22 resulting in partial trisomy 16 and 22.     

Causes of oncogenic chromosomal translocation

Non-random chromosomal translocations are frequently associated with a variety of cancers, particularly hematologic malignancies and childhood sarcomas. In addition to their diagnostic utility, chromosomal translocations are increasingly being used in the clinic to guide therapeutic decisions. However, the mechanisms that cause these translocations remain poorly understood. Illegitimate V(D)J recombination, class switch recombination, homologous recombination, non-homologous end-joining and genome fragile sites all have potential roles in the production of non-random chromosomal translocations. In addition, mutations in DNA-repair pathways have been implicated in the production of chromosomal translocations in humans, mice and yeast. Although initially surprising, the identification of these same oncogenic chromosomal translocations in peripheral blood from healthy individuals strongly suggests that the translocation is not sufficient to induce malignant transformation, and that complementary mutations are required to produce a frank malignancy.     

A dynamic study in two new cases of X chromosome translocations

Summary The authors discuss the clinical and cytogenetic problems raised in two new cases of X-chromosome translocations.The first case involves a child who presented marked growth retardation, behavioral anomalies, and discrete facial malformations at age 3 months. Chromosome analysis revealed the presence of a translocation between a 22 and X chromosome resulting in partial X monosomy and partial trisomy 22: 46,X,der(X),t(X;22)(q112;q13)mat. The balanced translocation form was detected in the mother. Dynamic study after 5-Brdu treatment revealed inactivation of the translocated X chromosome in the proband, while in the mother the normal X chromosome was inactivated.In addition to magnesium dependent hypocalcemia resulting from a specific absorption anomaly, Case 2 presented discrete malformations and psychomotor retardation. Chromosome analysis revealed an apparently balanced translocation between a 9 and X chromosome: 46,X,r(9;X)(q12; p22). Treatment with 5-Brdu demonstrated that the translocated X chromosome was inactivated but that inactivation did not extend to the translocated part of chromosome 9. Finally, a pericentric inversion of a 9 chromosome was detected in the father, grandfather, and brother of the proband.     

"Pure" partial trisomy 3p due to the malsegregation of a balanced maternal translocation t (X;3) (p22.3;p21)

The authors present the clinical and cytogenetic studies of a white malformed baby with dup (3p) secondary to the malsegregation of a maternal balanced (X;3) (p22.3;p21) translocation. Besides the typical clinical features he also presented polydactyly of both hands. X-replication findings of the mother's lymphocytes did not strictly follow the usual inactivation pattern of balanced X;A translocations.     

Karyotypes ofMegaselia scalaris (Diptera) wild-type and translocation strains

Making use of somatic pairing of homologous chromosome arms and of balanced translocations as cytogenetic markers, the three chromosome pairs of the phorid flyMegaselia scalaris have been identified and described. From measurements of the compliments a standard karyotype was constructed. Identification of the chromosomes allows cytogenetic, phenotypic and molecular markers to be assigned to specific chromosomes. Sex linkage of t(1;2) and t(2;3) translocations define chromosome 2 as the normal sex determining chromosome pair in our translocation strains, and therefore also, probably, in the wild-type strain from which they were derived. No differences between X and Y with respect to size of arms or C-bands were detected.     

Cytogenetically balanced translocations are associated with focal copy number alterations

Current cytogenetic methods (e.g., G-banding and multicolor chromosomal painting) allow detection of translocation events but lack the resolution to (a) locate the breakpoints precisely at the chromosome band level or (b) discriminate balanced translocations from translocations with copy number alterations not previously reported, or imperfectly balanced translocations. In this study, we demonstrate that cytogenetically balanced translocations are in fact frequently associated with segmental gain or loss of DNA. The recent development of a whole genome tiling path BAC array has enabled tiling resolution analysis of genomic segmental copy number status. Combining tiling resolution BAC array comparative genomic hybridization (array CGH) with G-Banding analysis and multicolor chromosomal painting approaches such as spectral karyotyping (SKY) facilitates high-resolution mapping of genomic alterations associated with imperfectly balanced translocations. Using a refined version of our CGH array we have deduced the copy number status throughout the genomes of three cytogenetically well-characterized prostate cancer cell lines (PC3, DU145, LNCaP) to determine whether translocations are associated with focal gains and losses of DNA. At 78 kb tiling resolution we identified the boundaries of 170, 80, and 34 known and novel copy number alterations (CNA) in these cell line genomes, respectively. Thirty-three of the 36 known translocations (92%, P < 0.001) in DU145 were associated with segmental CNA. Likewise, 80% (P < 0.001) of the known translocations showed association in LNCaP. Although many translocation breakpoints exhibit segmental alteration in PC3, the pattern of chromosomal rearrangements is too complex for use in comprehensive association with CNA boundaries. Our results reveal that imperfectly balanced translocations in tumor genomes are a phenomenon that occurs at frequencies much higher than previously demonstrated. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users.     

Familial (11;21)(p13;q22)pat balanced reciprocal translocation in a female child with regression of milestones

The role of balanced translocations in the human morphogenesis is difficult to interpret. A balanced reciprocal translocation (BRT) was observed in a female child referred with a history of regression of milestones. The cytogenetic findings by GTG-banding and fluorescence in situ hybridization revealed a BRT involving chromosomes 11p and 21q, i.e. 46,XX, t(11;21)(p13;q22). The father was found to be a carrier of the same BRT. This is the first report of reciprocal translocation involving 11p and 21q. The possible reasons for the manifestation of clinical features in the proband due to inherited BRT are discussed.     

Genomic Profiling Identifies Discrete Deletions Associated with Translocations in Glioblastoma Multiforme

Glioblastoma multiforme is the most common tumor arising in the central nervous system. Patients with these tumors have limited treatment options and their disease is invariably fatal. Molecularly targeted agents offer the potential to improve patient treatment, however the use of these will require a fuller understanding of the genetic changes in these complex tumors. In this study, we identify copy number changes in a series of glioblastoma multiforme tumors and cell lines by applying high-resolution microarray comparative genomic hybridization. Molecular cytogenetic characterization of the cell lines revealed that copy number changes define translocation breakpoints. We focused on chromosome 6 and further characterized three regions of copy number change associated with translocations including a discrete deletion involving IGF2R, PARK2, PACRG and QKI and an unbalanced translocation involving POLH, GTPBP2 and PTPRZ1.     

Analysis of translocations observed in three different populations. I. Reciprocal translocations

A sample of 437 reciprocal translocations was classified into three groups according to their method of ascertainment (Group I = couples with repeated abortions; Group II = karyotypically unbalanced carriers; Group III = balanced translocation heterozygotes). Statistical analysis showed that the distributions of chromosome breaks observed in the three groups could not be accounted for by chromosome arm length alone. In couples with repeated abortions, an excess of breaks in 7p, 17p, and 22q was found, whereas in the balanced translocation heterozygotes an excess of breaks was found only in 11q. An excess of breaks was found in arms 9p, 14p, 18p, 18q, 21q, and 22q in karyotypically unbalanced probands. A significant decrease of breaks in the medial chromosome regions was accompanied by a concomitant increase in the terminal regions in all groups. The three groups demonstrated different distributions of chromosome arm involvement in the observed translocations. Balanced translocation heterozygotes had the highest frequency of large (greater than the length of 4p) translocated segments and an excess in the frequency of large-large translocations, whereas karyotypically unbalanced probands had the highest frequency of small (shorter than 21q) translocations and an excess in the frequency of small-small translocations. For each type of chromosomal imbalance observed, the balanced translocation heterozygotes demonstrated the greatest potential imbalance and the karyotypically unbalanced probands the least.     

An apparent balanced translocation [t(9;11)(p21.2;p14.2)] in a neonate with dysmorphic features.

The role of so called balanced translocations in human morphogenesis remains puzzling. An eleven month old hispanic female was referred for neurological evaluation. The major dysmorphic features include: epicanthal folds, flat nasal bridge, small mouth, micrognathia, low set ears and cleft-palate. The cytogenetic findings by multiple banding techniques revealed an apparent balanced translocation involving chromosomes 9p and 11p i.e. 46,XX,t(9;11)(p21.2;p14.2) which, according to the authors, has not been previously reported.     

De novo balanced translocation (2;10)(q24;q22) associated with mental retardation

We report a case of a reciprocal translocation between the long arms of the 2 and 10 chromosomes observed in a 14-year-old male with mild mental impairment, compulsive and obsessive behavior. The apparently balanced translocation was characterized by fluorescence in situ hybridization and the karyotype was 46, XY, t(2;10)(q24;q22). The way by balanced chromosomal translocations can lead to a disease phenotype are reviewed and discussed.     

De novo microdeletion on an inherited Robertsonian translocation chromosome: a cause for dysmorphism in the apparently balanced translocation carrier.

Robertsonian translocations are usually ascertained through abnormal children, making proposed phenotypic effects of apparently balanced translocations difficult to study in an unbiased way. From molecular genetic studies, though, some apparently balanced rearrangements are now known to be associated with phenotypic abnormalities resulting from uniparental disomy. Molecular explanations for other cases in which abnormality is seen in a balanced translocation carrier are being sought. In the present paper, an infant is described who has retarded growth, developmental delay, gross muscular hypotonia, slender habitus, frontal bossing, micrognathia, hooked nose, abundant wispy hair, and blue sclerae. Cytogenetically, she appeared to be a carrier of a balanced, paternally derived 14;21 Robertsonian translocation. Analysis of DNA polymorphisms showed that she had no paternal allele at the D14S13 locus (14q32). Study of additional DNA markers within 14q32 revealed that her previously undescribed phenotype results from an interstitial microdeletion within 14q32. Fluorescent in situ hybridization was used to show that this microdeletion had occurred de novo on the Robertsonian translocation chromosome. These observations may reactivate old suspicions of a causal association between Robertsonian translocations and de novo rearrangements in offspring; a systematic search for similar subcytogenetic rearrangements in other families, in which there are phenotypically abnormal children with apparently balanced translocations, may be fruitful. The clinical and molecular genetic data presented also define a new contiguous gene syndrome due to interstitial 14q32 deletion.     

Chromosome translocations: study of 232 cases originating from 144 families

Between 1974 and 1987, 232 translocation carriers have been detected in our Center; they belong to 144 different families. Indications for chromosome analysis were the following: familial studies in relation with a patient suggesting a chromosome anomaly (25.4%); mental retardation with or without malformations (24.6%); 2 or more spontaneous abortions (17.2%); infertility problems, mainly male (16.4%); genetic counseling for a non-chromosomal disease (9.5%); prenatal diagnosis in risk pregnancies (6.9%). The chromosome anomalies detected were the following; balanced Robertsonian fusions (114 cases = 49.1%); balanced translocations (74 cases = 31.9%); unbalanced translocations, Robertsonian fusions included (44 cases = 19%). Two groups may be distinguished: the first one confirms data already known, such as high frequency of balanced translocations in couples with multiple abortions, or in infertile males. The second group on the contrary shows more unusual observations: 4 cases of standard trisomy 21 born to young parents carriers of a balanced translocation not involving chromosome 21; 5 cases of trisomy 13 with 46 chromosomes and a Robertsonian fusion, born to parents carriers of a t(13q; Dq) (twice the mother and thrice the father); 14 cases of apparently balanced translocations, however with an abnormal phenotype; and finally 22 cases of balanced translocations incidentally detected during the course of investigations in patients with a genetic problem generally not associated with a chromosome defect.     

Reciprocal Translocations and Translocation Disomics of Aspergillus and Their Use for Genetic Mapping

Two new techniques are described for genetic mapping of reciprocal translocations in A. nidulans, which can be used to locate centromeres and meiotically unlinked markers. They both make use of unbalanced disomics from heterozygous translocation crosses. These are mainly hyperhaploids of two classes: either typical-looking n + 1 with a normal chromosome in addition to a haploid set containing the translocation, or translocation disomics. When large chromosome segments are involved, such disomics, as well as stable aneuploids and duplication types, show characteristic phenotypes and can be classified visually. The first method maps translocation breaks qualitatively, since translocated markers can be identified when translocation disomics are analyzed for heterozygous markers. The second method measures meiotic linkage of any marker to the translocation breaks when allele ratios in the balanced haploid sectors of either or both classes of disomics are determined: linked markers show reciprocal deviations from 1:1—In addition, it can be shown that frequencies of nondisjunction and recovery of specific translocation disomics both depend on the relative position of the break within a chromosome arm. Such information can provide a rough estimate of the positions of breaks for a new translocation.—Using these techniques, as well as mitotic mapping in homo- and heterozygous translocation diploids, four reciprocal translocations were mapped. From these results, information on the sequence and orientation of most of the "meiotic fragments" of the current maps (groups III, VI, VII and VIII) was obtained, and the position of the centromeres of groups VI and VII were identified. Translocation disomics are also used to map meiotically unlinked single genes, e.g. oliA of group VII, to specify chromosome segments.     

Spectral karyotyping of Werner syndrome fibroblast cultures

Fibroblast cultures from two Werner syndrome patients were analyzed by spectral karyotyping. There were multiple, pseudodiploid clones in both cultures, mostly marked by random balanced reciprocal translocations. One of the cultures contained a clone with three-way exchanges involving chromosomes 2, 3, and 16. Duplication-deficiencies were exceptional, as were completely normal metaphases. The most frequent breakpoint occurred at 16q22 which corresponds to FRA16B, possibly reflecting difficulties of WS cells in replicating AT-rich repetitive DNA structures. Both cultures ceased proliferation after eight in vitro passages, but a single clone with exceptional growth potential emerged in one of the senescing cultures. Due to its identical translocations, the derivation of this near tetraploid clone (with tetrasomy for all autosomes except chromosomes 4 and 6) could be traced to the most prevalent pseudodiploid clone of the parental mass culture. Our study confirms the existence of variegated translocation mosaicism as the cytogenetic hallmark of WS fibroblast cultures and suggests that tetraploidization in combination with certain chromosome rearrangements and selective chromosome dosage may overcome the severely limited in vitro lifespan of WS fibroblasts.     

The most frequent chromosomal abnormalities in karyotypes of patients with reproductive disorders

Cytogenetic and molecular cytogenetic characteristics have been studied in 210 couples with fertility problems. The patients’ karyotypes contained various chromosomal rearrangements in 46 cases (10.95%). The structural chromosomal rearrangements such as pericentric inversions, Robertsonian translocations, balanced reciprocal translocations, and marker chromosomes were more frequent than numerical chromosome aberrations (89.13 and 10.87% of cases, respectively). We have found 19 (4.52%) karyotypes with “hidden’ low mosaicism in X and Y chromosomes. We believe that the patients with chromosomal anomalies in the karyotype need differentiated treatment.