Translocation Mosaicism Research Articles

Ten new cases of Balanced Reciprocal Translocation Mosaicism (BRTM): Reproductive implications, frequency and mechanism

Chromosomal anomalies are well known to be an important cause of infertility, sterility and pregnancy loss. Balanced Reciprocal Translocation Mosaicism (BRTM) is an extremely rare phenomenon, mainly observed in subjects with a normal phenotype accompanied by reproductive failure. To date the mechanism of origin and the incidence of BRTM are poorly defined.Here we describe 10 new cases of BRTM. In 9 cases chromosome analysis revealed the presence of two different cell lines, one with a normal karyotype and the second with an apparently balanced reciprocal translocation. In the remaining case, both cell lines showed two different, but apparently balanced, reciprocal translocations.We document the clinical implications of BRTM, discuss its frequency in our referred population and suggest that carrier individuals might be more frequent than expected.

Familial Turner syndrome with an X;Y translocation mosaicism: Implications for genetic counseling

Spontaneous fertility is rare among patients with Turner syndrome and is most likely in women with mosaicism for a normal 46,XX cell line. We report an unusual case of familial Turner syndrome with mosaicism for a novel X;Y translocation involving Xp and Yp. The chromosomal analysis was carried out through cytogenetics and molecular karyotyping using a SNP array platform. The mother, a Turner syndrome woman, diagnosed in midchildhood because of short stature, was found to have a 45,X/46,X,der(X)t(X;Y)(p11.4;p11.2) karyotype, with a predominant 45,X cell line. Her parents decided against prophylactic gonadectomy, generally recommended at an early age when Y chromosome has been identified, because at age 13, she had spontaneous puberty and menarche. She reached a final height of 154 cm after treatment with growth hormone. At age 24, she became spontaneously pregnant. She had a mild aortic coarctation and close follow-up cardiac evaluation, including cardiac magnetic resonance imaging, had been performed during her pregnancy, which progressed uneventfully, except for intra-uterine growth retardation. Prenatal diagnosis revealed a female karyotype, with transmission of the maternal translocation with an unexpected different mosaic:47,X,der(X)t(X;Y)x2/46,X,der(X)t(X;Y) karyotype. This complex and unusual karyotype, including a mosaic partial trisomy X and a non-mosaic Xpter-Xp11.4 monosomy, results in transmission of Turner syndrome from mother to daughter. At birth, the girl had normal physical examination except for growth retardation. This family illustrates the complexity and difficulties, in term of patient counseling and management in Turner syndrome, in determining ovarian status, fertility planning, risks associated with pregnancies, particularly when mosaicism for Y material chromosome is identified.

First cryptic balanced reciprocal translocation mosaicism and familial transmission

American Journal of Medical Genetics Part AVolume 146A, Issue 22 p. 2971-2974 Research Letter First cryptic balanced reciprocal translocation mosaicism and familial transmission† Celine Dupont, Corresponding Author Celine Dupont celine.dupont@jvr.aphp.fr Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, France Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceService d'Histologie-Embryologie et Cytogénétique, Biologie de la Reproduction, Hôpital Jean Verdier, AP-HP, Bondy, France; UFR-SMBH, Paris XIII, France; Unité fonctionnelle de Cytogénétique, Hôpital Robert Debré, AP-HP, France.Search for more papers by this authorAndree Delahaye, Andree Delahaye Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this authorLydie Burglen, Lydie Burglen Service de Genetique et Embryologie Medicales, Hopital Trousseau, AP-HP, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorAzzedine Aboura, Azzedine Aboura Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorSamia Kanafani, Samia Kanafani Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this authorFrançoise Baverel, Françoise Baverel AP-HP, Hopital Cochin, Service Histologie Embryologie Cytogenetique, Universite Paris-Descartes, Faculte de Medecine, Unite INSERM U709, Paris, FranceSearch for more papers by this authorThierry Billette de Villemeur, Thierry Billette de Villemeur Service de Neuropediatrie, Hopital Trousseau, AP-HP, FranceSearch for more papers by this authorBrigitte Benzacken, Brigitte Benzacken Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, France Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorEva Pipiras, Eva Pipiras Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this author Celine Dupont, Corresponding Author Celine Dupont celine.dupont@jvr.aphp.fr Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, France Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceService d'Histologie-Embryologie et Cytogénétique, Biologie de la Reproduction, Hôpital Jean Verdier, AP-HP, Bondy, France; UFR-SMBH, Paris XIII, France; Unité fonctionnelle de Cytogénétique, Hôpital Robert Debré, AP-HP, France.Search for more papers by this authorAndree Delahaye, Andree Delahaye Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this authorLydie Burglen, Lydie Burglen Service de Genetique et Embryologie Medicales, Hopital Trousseau, AP-HP, FranceSearch for more papers by this authorAnne-Claude Tabet, Anne-Claude Tabet Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorAzzedine Aboura, Azzedine Aboura Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorSamia Kanafani, Samia Kanafani Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this authorFrançoise Baverel, Françoise Baverel AP-HP, Hopital Cochin, Service Histologie Embryologie Cytogenetique, Universite Paris-Descartes, Faculte de Medecine, Unite INSERM U709, Paris, FranceSearch for more papers by this authorThierry Billette de Villemeur, Thierry Billette de Villemeur Service de Neuropediatrie, Hopital Trousseau, AP-HP, FranceSearch for more papers by this authorBrigitte Benzacken, Brigitte Benzacken Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, France Unite fonctionnelle de Cytogenetique, Hopital Robert Debre, AP-HP, FranceSearch for more papers by this authorEva Pipiras, Eva Pipiras Service d'Histologie-Embryologie et Cytogenetique, Biologie de la Reproduction, Hopital Jean Verdier, AP-HP, Bondy, France UFR-SMBH, Paris XIII, FranceSearch for more papers by this author First published: 27 October 2008 https://doi.org/10.1002/ajmg.a.32547Citations: 3 † How to cite this article: Dupont C, Delahaye A, Burglen L, Tabet A-C, Aboura A, Kanafani S, Baverel F, de Villemeur TB, Benzacken B, Pipiras E. 2008. First cryptic balanced reciprocal translocation mosaicism and familial transmission. Am J Med Genet Part A. Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume146A, Issue2215 November 2008Pages 2971-2974 RelatedInformation

Squamous Cell Carcinoma Associated with Epidermal Nevus

We present the case of a 27 year‐old female with a linear array of brown keratotic papules with a raised nodule within, located in the right mid upper inner thigh. A biopsy of the nodule showed a superficially invasive squamous cell carcinoma. Subsequent excision of the entire lesion showed an epidermal nevus without residual carcinoma. Squamous cell carcinomas developing within an epidermal nevus constitute an unusual association, mostly occurring in long standing lesions of elderly patients. Other epithelial neoplasms described arising within epidermal nevi include basal cell carcinomas, malignant eccrine tumors and keratoacanthomas. Although our patient did not have an identifiable epidermal nevus syndrome, the presence of a squamous cell carcinoma within an epidermal nevus in a young person suggests increased susceptibility to tumor development. Moreover, chromosomal aberrations have been described in epidermal nevi, including chromosomal breakage and variegated translocation mosaicism. We suggest that the presence of an epidermal nevus should alert the clinician for the potential development of a malignant neoplasm within it, including squamous cell carcinoma, even in the absence of an identifiable hamartoma‐neoplasm syndrome.

Chromosomal rearrangements in cattle and pigs revealed by chromosome microdissection and chromosome painting.

A pericentric inversion of chromosome 4 in a boar, as well as a case of (2q-;5p+) translocation mosaicism in a bull were analysed by chromosome painting using probes generated by conventional microdissection. For the porcine inversion, probes specific for p arms and q arms were produced and hybridised simultaneously on metaphases of a heterozygote carrier. In the case of the bovine translocation, two whole chromosome probes (chromosome 5, and derived chromosome 5) were elaborated and hybridised independently on chromosomal preparations of the bull who was a carrier of the mosaic translocation. The impossibility of differentiating chromosomes 2 and der(2) from other chromosomes of the metaphases did not allow the production of painting probes for these chromosomes. For all experiments, the quality of painting was comparable to that usually observed with probes obtained from flow-sorted chromosomes. The results obtained allowed confirmation of the interpretations proposed with G-banding karyotype analyses. In the bovine case, however, the reciprocity of the translocation could not be proven. The results presented in this paper show the usefulness of the microdissection technique for characterising chromosomal rearrangements in species for which commercial probes are not available. They also confirmed that the main limiting factor of the technique is the quality of the chromosomal preparations, which does not allow the identification of target chromosomes or chromosome fragments in all cases.

Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle.

Werner's syndrome (WS) is an autosomal recessive disorder, characterized at the cellular level by genomic instability in the form of variegated translocation mosaicism and extensive deletions. Individuals with WS prematurely develop multiple age-related pathologies and exhibit increased incidence of cancer. WRN, the gene defective in WS, encodes a 160-kDa protein (WRN), which has 3'-5'exonuclease, DNA helicase and DNA-dependent ATPase activities. WRN-defective cells are hypersensitive to certain genotoxic agents that cause replication arrest and/or double-strand breaks at the replication fork, suggesting a pivotal role for WRN in the protection of the integrity of the genoma during the DNA replication process. Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage. However, we provide evidence that WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Finally, we show that WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase.

Chromosomal instability in B-lymphoblasotoid cell lines from Werner and Bloom syndrome patients

Werner’s syndrome (WS) and Bloom’s syndrome (BS) are rare autosomal genetic diseases that predispose to cancer and are associated with genomic instability. To characterize the genomic instability of WS and BS, we analyzed and compared the cytogenetics of B-lymphoblastoid cell lines (LCLs) from WS and BS patients and healthy donors. Although, similar spontaneous frequencies of micronuclei (MN) and sister chromatid exchanges (SCE) were observed in LCLs from WS patients and healthy donors, they were much higher in BS-LCLs. We also examined the cells’ cytotoxic and cytogenetic formation (MN) response to camptothecin (CAM), etoposide (ETO), 4-nitroquinoline 1-oxide (4NQO), and mitomycin C (MMC). Compared to healthy donor LCLs, BS-LCLs but not WS-LCLs tended to be resistant to cytotoxicity and sensitive to MN induction by 4NQO and MMC. Spectrum karyotyping analysis revealed that most WS- and BS-LCLs generated “variegated translocation mosaicism” at high frequencies during cell culture. These findings support the idea that the basis of genomic instability in WS is different from that in BS.

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.

Centromeric dna break in a 10;16 reciprocal translocation associated with trisomy 16 confined placental mosaicism and maternal uniparental disomy for chromosome 16

Stable centromeric breakage in non-acrocentric chromosomes and balanced reciprocal translocation mosaicism are both rare events. We studied a family in which the mother had mosaicism for a balanced reciprocal translocation between chromosomes 10 and 16 which was associated with a break in chromosome 16 centromere alpha-satellite DNA ¿146,XX,t(10;16)(q11.2;q11.1) [29]/46,XX[25]¿. The derivative chromosome 16 contained only a very small amount of 16 alpha-satellite DNA while the derivative 10 contained all of the 10 alpha-satellite DNA as well as a large amount of the 16 alpha-satellite DNA. The same translocation was present in all cells in her son who was found prenatally to have trisomy 16 mosaicism ¿46,XY,t(10;16) (q11.2;q11.1)mat[22]/47,idem,+16[4]¿. Trisomy 16 cells were subsequently determined to be confined to the placenta. DNA polymorphism analyses in the family demonstrated maternal uniparental disomy for chromosome 16 in the diploid child. The child, at age 7 months, had minor facial anomalies similar to a previously reported case of maternal uniparental disomy for chromosome 16. In addition to illustrating several rare events, this family further demonstrated that substantial deletion of the centromeric alpha-satellite DNA does not impair centromere function and both mitotic and meiotic stability are retained in such cases.

Cytogenetic aspects of Werner's syndrome lymphocyte cultures

Lymphocyte cultures from five patients with Werner's syndrome (WS) and five healthy controls revealed significantly slower proliferation kinetics in four out of five patients. Higher frequencies of chromosome aberration and aneuploidy were also present with evidence of variegated translocation mosaicism in one of the patients. The study revealed no differences in sister chromatid exchange frequencies.

Chromosomal mosaicism in two patients with epidermal verrucous nevus: Demonstration of chromosomal breakpoint

Linear epidermal nevi are hamartomas that originate in embryonic ectoderm. For epidermal nevi associated with involvement of other systems, such as the skeleton or central nervous system, the term epidermal nevus syndrome has been introduced. Chromosomal aberrations have been suggested but not proven as an underlying cause. We performed cytogenetic studies of skin cells from two unrelated men who had a verruciform epidermal nevus. Variegated translocation mosaicism with an identical breakpoint localized at the long arm of chromosome 1 was present in both patients. Normal skin and blood lymphocytes showed normal karyotypes.

Balanced reciprocal translocation mosaicism: New cases and a literature review

Mosaicism for a balanced reciprocal translocation is uncommon. These two new cases were detected during investigation of infertility and miscarriages. Otherwise, the probands were normal. Of five previously described cases, only one was possibly syndromal. More reports of this class of chromosomal aberration are needed to assess accurately the risk of phenotypic abnormalities.

Chromosome instability in lymphocytes from a patient with Werner's syndrome is not associated with DNA repair defects.

Different cellular parameters used to detect genetic instability were analyzed in lymphocytes from a patient affected by Werner's syndrome (WS). Cytogenetic studies indicated the presence of structural and numerical chromosomal abnormalities and the occurrence of variegated translocation mosaicism. The baseline mutation frequency was similar to that observed in normal donor samples. DNA repair investigations showing a normal capability to perform UV-induced DNA repair synthesis and a normal sensitivity to various mutagens (UVC light, mono- and bi-functional alkylating agents) indicate that different DNA repair mechanisms act normally in WS. In this feature, WS appears to differ from the other genetically determined syndromes in which chromosomal instability is associated with a marked hypersensitivity to specific DNA-damaging agents.

Reciprocal translocation mosaicism in man

Reciprocal translocation mosaicism in man

Cytogenetic aspects of Werner syndrome.

Cultured skin fibroblast-like (FL) cells from patients with Werner syndrome display frequent pseudodiploidy involving multiple, variable structural chromosome rearrangements that are clonal (Salk et al., 1981a). This cytogenetic abnormality, which has been called variegated translocation mosaicism (VTM), has also recently been observed in peripheral blood lymphocytes (Scappaticci et al., 1982). Werner syndrome may properly be classified as a chromosome instability syndrome because, like Bloom syndrome, ataxia telangiectasia, Fanconi anemia, and xeroderma pigmentosum, it is autosomal recessive, displays chromosome instability, and is associated with an increased incidence of neoplasia.

Werner's syndrome and aging: a reappraisal.

Although a clear distinction between the Werner syndrome and premature aging was made in our review published in 1966, repeated allusions in the literature indicate either an ambivalence about this relationship or a belief that the two conditions are fundamentally related to one another. Therefore, the criteria for premature aging originally used have been reexamined and found to be still acceptable. Evaluation of the features of the Werner syndrome in the light of these criteria once again indicates that there is no substantial evidence to support and considerable evidence to oppose equating the Werner syndrome with aging. This conclusion applies not only to the Werner syndrome in toto, but also to those aspects of the syndrome considered to qualify it as a segmental progeroid syndrome and to its characteristic cellular abnormalities (severely limited in vitro proliferation and variegated translocation mosaicism). The Werner syndrome should not, therefore, be forced into the mold of premature aging but should be studied on its own merits as a condition which may provide us with clues to the pathogenesis of many important problems.

Clonal structural chromosomal rearrangements in primary fibroblast cultures and in lymphocytes of patients with Werner's Syndrome.

The cytogenetics of six cases of adult progeria (Werner's syndrome) from three Sardinian families were investigated. The overall increased incidence of chromosome breakage found in cultured lymphocytes and fibroblasts seems to be age-dependent. The occurrence of clonal variegated translocation mosaicism, previously found by other authors in fibroblast cell lines derived from Werner patients was demonstrated also in fibroblasts analyzed in situ on the outgrowth halos from primary skin explants; a strong indication that these aberrations are present in the in vivo precursors. The same type of clonal structural aberration was found for the first time also in 72h-cultured lymphocytes. These findings demonstrate that Werner's syndrome is indeed a further example of a chromosome rearrangement syndrome.

Cytogenetics of Werner's syndrome cultured skin fibroblasts: variegated translocation mosaicism.

Skin fibroblast-like (FL) cells from patients with Werner's syndrome (adult progeria) regularly demonstrate frequent pseudodiploidy involving variable structural rearrangements that are clonal: variegated translocation mosaicism (VTM). Ninety-two percent of 1,538 metaphases from 29 independent strains derived from five patients with Werner's syndrome demonstrated this cytogenetic abnormality. In contrast, only eight (8.4%) of 95 non-Werner's syndrome FL cell cultures demonstrated VTM: seven with low-grade VTM (approximately 5% of 300 metaphases), and one with VTM affecting 90-100% of metaphases. Unlike the cytogenetic abnormalities observed in the terminal stages of normal FL cell cultures, VTM occurs throughout the entire lifespan of Werner's syndrome cultures. Ten of the identifiable break points in 1,005 banded metaphases accounted for 27% of all definable rearrangements. Baseline sister chromatid exchanges were not increased. Cocultivation of Werner's syndrome and normal strains did not induce VTM in the normal strain. The relationship between VTM and the reduced growth potential of Werner's syndrome FL cells is not yet understood, nor is the relationship between these in vitro abnormalities and the presumptive single gene defect that causes the progeroid clinical manifestations of Werner's syndrome.

Evidence of clonal attenuation, clonal succession, and clonal expansion in mass cultures of aging Werner's syndrome skin fibroblasts.

Skin fibroblast-like (FL) cells from patients with Werner's syndrome (adult progeria) demonstrate multiple, stable, structural chromosome rearrangements (variegated translocation mosaicism) which can be used to identify cytogenetically marked clones of cells within a mass culture. We have cytogenetically followed eight FL cell strains (from two patients) throughout their entire in vitro replicative lifespans, and we show a correlation between the expansion and attenuation of individual clones and the growth of the mass cultures. One strain, which was aged several times, demonstrated a generally reproducible pattern of clonal succession but, surprisingly, also demonstrated, in two parallel derivative cultures, the late emergence of two relatively rapidly growing clones that had not been observed in the parental culture. These observations suggest that clonal succession and clonal attenuation occur in mass cultures, as had been predicted on the basis of dilute-plating cloning experiments. Our results may have implications for models of in vitro cellular senescence. In addition, there are interesting parallels with the tissue hyperplasia associated with in vivo aging, and this observation is compatible with the suggestion that skin FL cells in vitro provide a model for hyperplasia in vivo.

Variegated translocation mosaicism in human skin fibroblast cultures.

The term "variegated translocation mosaicism" is used to describe the repeated occurrence, within cultures of human skin fibroblasts, of a multiplicity of chromosomal rearrangements. With respect to the frequencies of such cytogenetically aberrant clones we found that they (1) were not detectable in routine diagnostic skin fibroblast cultures from 29 subjects with a wide variety of indications for biopsy; (2) were not detectable during in vitro aging of diploid strains with four normal individuals; (3) could be detected after rescue from bacterial contamination of a culture from an otherwise normal diploid male; (4) occurred with high frequencies in independent cultures from another apparently normal subject; (5) occurred with high frequencies in multiple biopsies obtained at autopsy from a patient with Werner's syndrome who died of sepsis; (6) were of pseudodiploid nature; and (7) involved a different spectrum of chromosomes in different individuals. A consistent association with mycoplasma contamination could not be made.