T-lymphocytes with 7;14 translocations: frequency of occurrence, breakpoints, and clinical and biological significance.

Among 11,915 consecutive patients and 37 normal controls who had chromosome analysis at the Mayo Clinic between 1978 and 1984, 83 had a single sporadic metaphase with a 7;14 translocation. In 81 of the translocations, the breakpoints were at 14q11 and either 7q34 (type I) or 7p13 (type II): type I translocations occurred in 42 patients, and type II, in 39. The two other translocations had different breakpoints: one was t(7;14)(q11;q32), and the other was t(7;14)(p13;q32). All type I and type II translocations occurred in phytohemagglutinin-stimulated lymphocyte cultures; their combined incidence was 4.88 X 10(-4) per metaphase (81 of 165,991 metaphases) in such cultures. No type I or II translocation was found among 6,713 fibroblast metaphases, 33,463 amniocyte metaphases, or 68,972 bone marrow and unstimulated peripheral blood metaphases. One variant 7;14 translocation occurred in a phytohemagglutinin-stimulated culture, and the other occurred in a fibroblast culture. We did not find a correlation of sporadic 7;14 translocations with any month or season of the year or with patient age or sex. Of the 83 patients, 78 had various clinical disorders, three had ataxia-telangiectasia, one was a normal control, and one was an artificial insemination donor. Follow-up studies on 64 (77%) patients indicate that, to date, none have developed any malignant process subsequent to chromosome analysis. Except for ataxia-telangiectasia, the occurrence of types I and II translocations in lymphocyte cultures may have little, if any, clinical significance. The biological significance of these translocations may be the association of genes in chromosome bands 14q11, 7p13, and 7q34 with the normal physiology of lymphocytes such as the alpha- and beta-chains for T-cell antigen receptor.     

Human chromosome variation with two Robertsonian translocations

Summary A woman was found to have 42 autosomes due to engagement of both chromosomes 14 in Robertsonian rearrangements, one with a chromosome 21 and the other with a chromosome 22: t(14q21q) and t(14q22q). The two translocations appear monocentric and by silver staining have no rRNA activity. The t(14q21q) translocation is familial and was ascertained through a nephew with Down syndrome, while the origin of the t(14q22q) translocation was not established. In addition to these two translocations, the woman had XX/XXX sex chromosome mosaicism. She has had two recognized pregnancies, each resulting in the birth of a child with one of the two translocations. Both children are phenotypically normal, as is their mother, the first normal liveborn individual identified with two Robertsonian translocations.     

Growth of large chromosomally abnormal T cell clones in ataxia telangiectasia patients is associated with translocation at 14q11

Summary Human T cell malignancies often show chromosome breaks at 14q11, within the chain locus of the human T cell antigen receptor, with translocation of the distal portion of 14 to one of several sites. In patients with ataxia telangiectasia (A-T) the majority of T cell chromosome translocations associated with this disorder appear to occur at the sites of the T cell antigen receptor genes 7p14, 7q35, and 14q11 and may result in clone formation. In three large proliferating A-T T cell clones we have observed (including one which became malignant) and in most T cell tumours reported, the clonal chromosome exchange involves one breakpoint at 14q11 with the second breakpoint occurring in a gene not involved in the immunoglobulin supergene family. Our observations on A-T patients confirm the suggestion that chromosome exchanges involving either t(7;14)(p14;q11), t(7;14)(q35;q11), inv(7) (p14q35), or t(7;7)(p14;q35) confer only a small proliferative advantage on T cells in vivo without the capacity for malignant transformation and that the potential for malignant change is not a feature of all these rearrangements, but is restricted to cells or clones with other chromosome exchanges.     

Homozygous Robertsonian translocations in a fetus with 44 chromosomes

Summary We report the unique finding of a human fetus with 44 chromosomes with homozygous 14;21 translocations. This fetus appeared phenotypically normal but the long-term neurodevelopmental outcome had this pregnancy continued could not be predicted. We speculate one 14;21 translocation was inherited from her father and one arose de novo being maternal in origin. A previous sibling with psychomotor retardation has an abnormal chromosome complement of 45,XX,dup(7)(q21pter), t(14;21)(p11;q11). The mother's underlying disease, systemic lupus erythematosis (SLE), and her prior chemotherapy may have contributed to the appearance of these chromosome aberrations. It is interesting that although 14;21 translocations are among the commonest structural chromosome rearrangements in man, there are no previous reports in newborn surveys of a child with 44 chromosomes resulting from the mating of two identical Robertsonian translocation carrier parents.     

Molecular cytogenetic characterization of 17 rob(13q14q) Robertsonian translocations by FISH, narrowing the region containing the breakpoints.

We have characterized 17 rob(13q14q) Robertsonian translocations, using six molecular probes that hybridize to the repetitive sequences of the centromeric and shortarm regions of the five acrocentric chromosomes by FISH. The rearrangements include six de novo rearrangements and the chromosomally normal parents, five maternally and three paternally inherited translocations, and three translocations of unknown origin. The D21Z1/D13Z1 and D14Z1/D22Z1 centromeric alpha-satellite DNA probes showed all rob(13q14q) chromosomes to be dicentric. The rDNA probes did not show hybridization on any of the 17 cases studied. The pTRS-47 satellite III DNA probe specific for chromosomes 14 and 22 was retained around the breakpoints in all cases. However, the pTRS-63 satellite III DNA probe specific for chromosome 14 did not show any signals on the translocation chromosomes examined. In 16 of 17 translocations studied, strong hybridization signals on the translocations were detected with the pTRI-6 satellite I DNA probe specific for chromosome 13. All parents of the six de novo rob(13q14q), including one whose pTRI-6 sequence was lost, showed strong positive hybridization signals on each pair of chromosomes 14 and 13, with pTRS-47, pTRS-63, and pTRI-6. Therefore, the translocation breakpoints in the majority of rob(13q14q) are between the pTRS-47 and pTRS-63 sequences in the p11 region of chromosome 14 and between the pTRI-6 and rDNA sequences within the p11 region of chromosome 13.     

Localization of human variable and constant region immunoglobulin heavy chain genes on subtelomeric band q32 of chromosome 14

Analysis of a group of human/rodent somatic cell hybrids with nucleic acid probes prepared from cloned human variable region (VH), junctional (JH), and constant region (C epsilon) heavy chain immunoglobulin genes indicates that all of these IgH genes are localized on the subtelomeric (q32) band of chromosome 14. Somatic cell hybrids were isolated in selective medium after fusing human fibroblasts with hprt- Chinese hamster cells. The human parental cells contained two translocation chromosomes representing a reciprocal translocation between chromosomes X and 14. Only those hybrid cell lines retaining a complete human autosome 14 or the X/14 translocation chromosome (i.e. containing band 14q32) retained the human IgH genes. Retention of these genes did not correlate with the presence of the other translocation chromosome, 14/X. These results indicate that all human IgH genes (VH, JH, and CH) map to the same chromosomal band (14q32) which is commonly involved in reciprocal translocations with human chromosome 8 (8q24) in B-cell neoplasms.     

Evidence for structural heterogeneity from molecular cytogenetic analysis of dicentric Robertsonian translocations.

Most Robertsonian translocations are dicentric, suggesting that the location of chromosomal breaks leading to their formation occur in the acrocentric short arm. Previous cytogenetic and molecular cytogenetic studies have shown that few Robertsonian translocations retain ribosomal genes or beta-satellite DNA. Breakpoints in satellite III DNA, specifically between two chromosome 14-specific subfamilies, pTRS-47 and pTRS-63, have been indicated for most of the dicentric 14q21q and 13q14q translocations that have been studied. We have analyzed the structure of 36 dicentric translocations, using several repetitive DNA probes that localize to the acrocentric short arm. The majority of the translocations retained satellite III DNA, while others proved variable in structure. Of 10 14q21q translocations analyzed, satellite III DNA was undetected in 1; 6 retained one satellite III DNA subfamily, pTRS-47; and 3 appeared to contain two 14-specific satellite III DNA sub-families, pTRS-47 and pTRS-63. In 10/11 translocations involving chromosome 15, the presence of satellite III DNA was observed. Our results show that various regions of the acrocentric short arm, and, particularly, satellite III DNA sequences, are involved in the formation of Robertsonian translocations.     

Investigations with fluorescence in situ hybridization (FISH) demonstrate loss of the telomeres on the reciprocal chromosome in three unbalanced translocations involving chromosome 15 in the Prader-Willi and Angelman syndromes

Two patients with classical features of Angelman syndrome (AS) and one with Prader-Willi syndrome (PWS) had unbalanced reciprocal translocations involving the chromosome 15 proximal long arm and the telomeric region of chromosomes 7, 8 and 10. Fluorescence isitu hybridization (FISH) was used for the detection of chromosome 15(q11-13) deletions (with probes from the PWS/AS region) and to define the involvement of the telomere in the derivative chromosomes (with library probes and telomere-specific probes). The 15(q11-13) region was not deleted in one patient but was deleted in the other two. The telomere on the derivative chromosomes 7, 8 and 10 was deleted in all three cases. Thus, these are true reciprocal translocations in which there has been loss of the small satellited reciprocal chromosome (15) fragment.     

New chromosomal translocations correlate with specific immunophenotypes of childhood acute lymphoblastic leukemia

Cytogenetic analysis of leukemic cells obtained at diagnosis from 122 patients with childhood acute lymphoblastic leukemia (ALL) disclosed chromosomal translocations in 36 cases. Two new nonrandom translocations were identified and found to be associated with specific immunophenotypes of the disease. The first, identified in 4 of 16 cases of T-cell ALL positive for sheep erythrocyte receptors (E+), involved the short arm (p) of chromosome 11 and the long arm (q) of chromosome 14 and was designated t(11;14) (p13;q13). The second, found in 7 of 23 cases with a pre-B-cell phenotype, involved the long arm of chromosome 1 and the short arm of chromosome 19; it was designated t(1;19) (q23;p13.3). A third abnormality involving a common breakpoint on chromosome 12 (band p 12) was also identified. These two new differentiation-specific translocations suggest a mechanism for aberrant expression of genes that influence lymphoid cell growth and development, as well as leukemogenesis.     

A detailed analysis of chromosomal changes in heritable and non-heritable retinoblastoma

Summary Full cytogenetic analysis of 27 different retinoblastoma tumors is presented. Gross aneuploidy of chromosome arms 6p and 1q were very common, being observed in 15/27 and 21/27 tumors, respectively. However, we found that chromosome 13 was rarely missing: only 3/27 had a detectable monosomy affecting 13q14. Monosomy of chromosome 13 by small deletion or rearrangement was also not observed in any of 12 retinoblastoma tumor lines analyzed detail at the 300–400 chromosome band level. A novel observation in retinoblastoma was the discovery of non-random translocations at three specific breakpoints, 14q32 (4/12), 17p12 (5/12), and 10q25 (3/12). Genomic rearrangements similar to those described involving C-myc in Burkitt lymphoma 14q+ cells could not be demonstrated in the four 14q+ retinoblastoma lines using molecular techniques, and a probe mapping to the site implicated to have an activating role in lymphoma. These data suggest that there is a target for rearrangement at 14q32 but it is not the same sequence used in some Burkitt lymphomas. Two other breakpoints (2p24 and 8q24) coincided with the mapped position of cellular oncogenes, but also failed to show a molecular rearrangement with the oncogene probes. The breakpoints, 10q25 and 17p12, are constitutional fragile sites which may predispose these regions to act as acceptors of translocations in malignant cells. One line had double minute chromosomes, and was the only one of 16 (6%) tested with the N-myc probe which had an amplification. Different tumors from single patients with multifocal heritable retinoblastoma showed independent karyotype evolution. Unilateral non-heritable tumors exhibited a high level of karyotype stability throughout both in vivo and in vitro growth. The various common patterns of aneuploidy and translocations probably confer an early selective advantage to malignant cells, rather than induce malignant transformation.     

Cytogenetic findings in 122 couples with recurrent abortions

Summary R-banded chromosome complements were analysed from 122 couples who had experienced three or more spontaneous abortions. Five women and one man were found to be carriers of translocations t(2;17), t(5;9), t(11;22), t(17;22), and t(13q14q). Two other karyotypes were abnormal: 46,XXq- and 47,XXX. Banded chromosome studies are recommended for couples with repeated abortions.     

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.     

Four familial translocations ascertained through spontaneous abortions

Summary In a study of 514 spontaneous abortions, 194 were found to have a chromosome anomaly. Of these, 4 (2.1%) were unbalanced translocations. Three of the translocations were Robertsonian (13q14q) and one was reciprocal. Each translocation was ascertained independently and each was associated with a balanced rearrangement in a carrier parent.     

A Somatic Origin of Homologous Robertsonian Translocations and Isochromosomes

One t(14q14q), three t(15q15q), two t(21q21q), and two t(22q22q) nonmosaic, apparently balanced, de novo Robertsonian translocation cases were investigated with polymorphic markers to establish the origin of the translocated chromosomes. Four cases had results indicative of an isochromosome: one t(14q14q) case with mild mental retardation and maternal uniparental disomy (UPD) for chromosome 14, one t(15q15q) case with the Prader-Willi syndrome and UPD(15), a phenotypically normal carrier of t(22q22q) with maternal UPD(22), and a phenotypically normal t(21q21q) case of paternal UPD(21). All UPD cases showed complete homozygosity throughout the involved chromosome, which is supportive of a postmeiotic origin. In the remaining four cases, maternal and paternal inheritance of the involved chromosome was found, which unambiguously implies a somatic origin. One t(15q15q) female had a child with a ring chromosome 15, which was also of probable postmeiotic origin as recombination between grandparental haplotypes had occurred prior to ring formation. UPD might be expected to result from de novo Robertsonian translocations of meiotic origin; however, all de novo homologous translocation cases, so far reported, with UPD of chromosomes 14, 15, 21, or 22 have been isochromosomes. These data provide the first direct evidence that nonmosaic Robertsonian translocations, as well as isochromosomes, are commonly the result of a mitotic exchange.     

Karyotype instability with multiple 7/14 and 7/7 rearrangements

Summary Chromosomes were studied in a mentally retarded boy with microcephaly, growth retardation, facial erythema, café-au-lait spots, and IgA deficiency. In the lymphocytes there was a remarkable tendency to exchange parts of the chromosomes Nos. 7 and 14, the translocations almost exclusively taking place in bands 7p13, 7q32 and 14q11. Seven different types of rearrangements between Nos. 7 and 14, and some other chromosomal aberrations were found. No abnormalities could be detected in the bone marrow. The patient somewhat resembles those affected with ataxia-telangiectasia or with Bloom's syndrome, but on clinical and cytogenetic grounds these disorders could be excluded.7/14 Translocations similar to those found in our patient's lymphocytes have been reported to occur very rarely in the lymphocyte cultures of individuals with apparently normal chromosome constitution. A relationship between these phenomena may exist.     

Phenotypic heterogeneity in three cases of lymphoid malignancy with chromosomal translocations in 14q11

Lymphoid malignancies bearing translocations involving the region 14q11 are thought to have a T-cell phenotype because their pathogenesis is postulated to involve the aberrant juxtaposition of DNA sequences active in T-cell differentiation (T-cell antigen receptor genes) and proto-oncogenes. We present here three lymphoid malignancies with translocations involving 14q11. Although one had a T-cell phenotype, the other two had B-cell lineage phenotypes. Our findings confirm that not all lymphoid malignancies with translocations involving 14q11 represent T-cell clonal expansions.     

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.