A familial X/Y translocation: cytogenetic and molecular study

In this study we describe a 3-generation family carrying a (X;Y)(p22.3;q11.2) translocation in seven individuals of both sexes. Molecular analysis of the aberrant (X;Y)(p22.3;q11.2) chromosome was performed by FISH using X and Y-specific painting probes and also PCR amplification of the Y-specific sequences. Using these approaches it was demonstrated that the translocation resulted in a deletion of both X and Y pseudoautosomal regions. Moreover, using RBG banding it was shown that in all females the X-derivative chromosome was inactive in over 90% of mitoses. From the preliminary results obtained in this study we assumed that in this particular family the observed phenotype of the patients was caused by a deletion of the cluster of pseudoaotosomal genes responsible for the stature. More proximal loci, like STS or MRX49, were probably not deleted, since neither ichtyosis nor mental retardation was observed in this family.     

Del Xq23 in a mosaic Turner female: molecular and cytogenetic studies.

We report a Turner patient aged 22 years with a 45,X/46,X,del(X)(q23) karyotype. Late replication studies showed preferential inactivation of the deleted X chromosome; FISH studies with a probe for total human telomeres showed hybridisation signal in the telomeres on both the normal and the deleted X chromosomes. Microsatellite analysis in the proposita and her family permitted us to conclude to the maternal origin of the deleted X chromosome, and to detect using the marker DXS1106 (Xq22) a probable meiotic recombination event above the breakage point suggesting that the deletion occurred underneath this point.The mild Turner stigmata may be explained by the 45,X cell line, and the gonadal dysgenesis probably by a partial deletion of the gonadal dysgenesis region Xq13-q23 (excluding Xq22).     

A 45,X male with a Yp/18 translocation

Summary A patient described as a 45,X male (Forabosco et al. 1977) was examined for the presence of Y-specific DNA by using various probes detecting restriction fragments from different regions of the Y chromosome. Positive hybridization signals were obtained for Yp fragments only. In situ hybridization with two different probes, pDP31 and the pseudoautosomal probe 113F, led to a clear assignment of the Yp sequences to the short arm of one chromosome 18. Cytogenetically, the presence of all of Yp including the Y centromere on 18p could be demonstrated replacing a segment of similar size of 18p. Thus, the Y/18 translocation chromosome is dicentric structurally, but it was shown to be monocentric functionally with the no. 18 centromere active. Gene dosage studies with the probe B74 defining a sequence at 18p11.3 demonstrated a single dose of this sequence in the patient. In agreement with these observations, the patient shows clinical signs of the 18p-syndrome. It is concluded that in XO males in general, the X is of maternal origin while the maleness is due to a de novo Y/autosome translocation derived from the father. Depending on the nature of the autosomal deficiency caused by the Y/autosome translocation, the patient may have congenital malformations.     

Chondrodysplasia punctata with X;Y translocation

Summary We have studied a family in which the mother and her son were carriers of an X;Y translocation, der(X)t(X;Y) (p22.3;q11). The mother was of slightly short stature and had mildly short upper extremities. The son had epiphyseal punctate calcifications, mildly short extremities, a flattened nasal bridge, and mental retardation (chondrodysplasia punctata). The extra bands on the short arm of the X chromosome were identified as deriving from the long arm of the Y chromosome, using in situ hybridization with a Y-chromosome-specific DNA probe (pHY10). The chondrodysplasia punctata seen in our case may be associated with the abnormality of the distal short arm of the X chromosome caused by X;Y translocation.     

A jumping Robertsonian translocation: a molecular and cytogenetic study

We report a patient with mosaicism for two different Robertsonian translocations, both involving chromosome 21. She carries an unbalanced cell line with an i(21q) and a balanced cell line with a rob(21q22q). She is phenotypically normal but has two children who inherited the i(21q) and have Down syndrome. We demonstrate that both abnormal chromosomes are dicentric and that the proband’s 21/21 rearrangement is an isochromosome formed from a maternally derived chromosome 21. We propose a model in which the i(21q) is the progenitor rearrangement in the proband, which subsequently participated in a nonreciprocal rearrangement characteristic of a jumping translocation. In addition, we review other cases of constitutional mosaicism involving jumping translocations. Received: 4 October 1995 / Revised: 14 February 1996     

Y-autosome translocation and infertility: usefulness of molecular, cytogenetic and meiotic studies

An apparently balanced reciprocal translocation 46,X,t(Y;6) (q11.23 ∼ q12;p11.1) was observed in an infertile man with severe oligozooteratozoospermia. Different mitotic chromosome banding patterns were performed and fluorescence in situ hybridization indicated a breakpoint in the fluorescent Yq heterochromatin. Molecular genetic deletion experiments for the azoospermia factor region in distal Yq11 showed the retention of the DAZ gene and meiotic pairing configurations suggested that the man’s infertility could be due to the pairing behaviour of the Y;6 translocation chromosome with the X chromosome visualised by synaptonemal complex analysis at the electron microscopy level. The morphological appearance of the normal chromosome 6 and the Y;6 translocated chromosome included in the compartment of the sex vesicle may allow an explanation of the degeneration of most spermatocytes after the pachytene stage. Received: 1 August 1997 / Accepted: 25 September 1997     

A sterile male with 45,X0 and a Y;22 translocation

Summary Cytogenetic analysis of a 20-year-old sterile male revealed a 45,X0 karyotype with no evidence for Y-chromosomal material on any of the chromosomes analysed by Q-, G- and C-banding. DNA analysis with 17 different Y chromosome-derived probes revealed the presence of Yp DNA sequences in the patient's genome. In situ hybridization with the Yp-derived probe pJA36B disclosed a translocation of Y-chromosomal material onto the short arm of a chromosome 22.     

A 45,X male with molecular evidence of a translocation of Y euchromatin onto chromosome 1

Summary A 45,X complement was found in lymphocyte and fibroblast cultures of a male infant with severe growth and mental retardation and mild dysmorphism. Lymphocyte DNA from this patient was found to contain Yp chromosome sequences. In situ hybridization (ISH) with the 50f2 probe led to a clear assignment of euchromatic material on the short arm of chromosome 1. This observation and others from the literature argue in favour of the conclusion that all 45.X males are probably either the result of undetected mosaicism or are carriers of Y translocated material.     

Isodicentric Y chromosome: cytogenetic,molecular and clinical studies and review of the literature

Dicentrics are among the most common structural abnormalities of the human Y chromosome. Predicting the phenotypic consequences of different duplications and deletions of dicentric Y chromosomes is usually complicated by varying degrees of mosaicism (45,X cell lines), which may, in some cases, remain undetected. Molecular studies in patients with dicentric Y chromosomes have been few, and only two studies have attempted to determine the presence of SRY (the putative testis-determining factor gene). We report an 18-year-old female with short stature, amenorrhea, hirsutism, hypoplastic labia minora, and clitoromegaly who has a 45,X/46,X,idic(Y)(p11.32)/47,X,idic(Y)(p11.32),idic(Y) (p11.32) karyotype. Southern analysis using Y-specific probes (Y97, 2D6, 1F5, pY3.4) and polymerase chain reaction (PCR) analysis using primers for ZFY and SRY were positive for all loci tested, indicating that almost all of the Y chromosome was present. Our findings and an extensive review of the literature emphasize the importance of molecular analyses of abnormal Y chromosomes before any general conclusions can be reached concerning the relative effects of the Y-chromosome abnormality and mosaicism on sexual differentiation.     

A 45,X male with translocation of euchromatic Y chromosome material

Summary A phenotypically normal 32-year-old male with azoospermia was found to have a 45,X karyotype with presence of excess euchromatic material on 14p. The parents' karyotypes are normal. This observation is interpreted as a Y/14 translocation with loss of the heterochromatic Y chromosome material.     

Combined cytogenetic techniques and non-fluorescent Y. Cytologic evidences of dic(Yp)(q11) in a previously interpreted 46,X,Yq-

mos 45,X/46,X,Y with no bright fluorescence was studied in 4 patients presenting variable phenotypes, from Turner's syndrome, with or without virilization, to ambiguous external genitalia, with combined cytogenetic techniques. G-11 staining demonstrated, in all cases, that the abnormal Y was a dic(Yp). Considerations about the possibility that some of the 46,X,Yq-males attending infertility clinics may be examples of dic(Yp) are made.     

A sporadic case of the sex-reversed mare (64,XY; SRY-negative): molecular and cytogenetic studies of the Y chromosome

A sex-reversal syndrome appears frequently in the horse. The mare carriers of this syndrome lack of SRY gene. It is suggested that sex-reversal syndrome is probably caused by transfer of the SRY gene from Y to the X chromosome, due to abnormal meiotic exchange. The aim of the study was molecular analysis of the Y-linked genes in a case of the sex-reversed infertile mare with 64,XY karyotype. The karyotype was established on the basis of analysis of 350 metaphase spreads stained by CBG banding. Molecular analysis of the loci assigned to the Y chromosome revealed absence of the SRY gene and presence of the other studied loci (ZFY, AMEL-Y and STS-Y). In this animal all fragments representing X chromosome (ZFX, AMEL-X and STS-X) were detected. External genitalia in the mare were normal, uterus was small and ovaries (examined by ultrasonography) extremely small. The mechanism of sex-reversal syndrome formation was discussed. It is postulated that during spermatogenesis in the sire two crossing-over events between the X and Y chromosomes occurred. One of them took place between the ZFY and SRY loci and another one between the SRY locus and the centromere.     

18q部分单体患儿的细胞和分子遗传学研究

临床发现1例智力低下伴轻度发育迟缓的女性患儿,对患儿进行G显带高分辨染色体核型分析, 发现18q21→qter缺失, 经多色荧光原位杂交和双色荧光原位杂交证实, 确定其核型为46,XX,del(18)(pter→q21:),ish del(18)(D18Z1+, qter-)。用DNA多态性方法分析, 该患儿从18q22.1至18qter区域内至少有8.7 Mbp丢失, 有MBP基因和GALNR基因缺失。缺失的18号染色体源自父亲。患者的智力低下和生长发育迟缓是18q21→qter缺失的结果, 或许与MBP基因和GALNR基因的缺失有关。     

Molecular definition of breakpoints associated with human Xq isochromosomes: implications for mechanisms of formation.

To test the centromere misdivision model of isochromosome formation, we have defined the breakpoints of cytogenetically monocentric and dicentric Xq isochromosomes (i(Xq)) from Turner syndrome probands, using FISH with cosmids and YACs derived from a contig spanning proximal Xp. Seven different pericentromeric breakpoints were identified, with 10 of 11 of the i(Xq)s containing varying amounts of material from Xp. Only one of the eight cytogenetically monocentric i(Xq)s demonstrated a single alpha-satellite (DXZ1) signal, consistent with classical models involving centromere misdivision. The remaining seven were inconsistent with such a model and had breakpoints that spanned proximal Xp11.21: one was between DXZ1 and the most proximal marker, ZXDA; one occurred between the duplicated genes, ZXDA and ZXDB; two were approximately 2 Mb from DXZ1; two were adjacent to ALAS2 located 3.5 Mb from DXZ1; and the largest had a breakpoint just distal to DXS1013E, indicating the inclusion of 8 Mb of Xp DNA between centromeres. The three cytologically dicentric i(Xq)s had breakpoints distal to DXS423E in Xp11.22 and therefore contained > or = 12 Mb of DNA between centromeres. These data demonstrate that the majority of breakpoints resulting in i(Xq) formation are in band Xp11.2 and not in the centromere itself. Therefore, we hypothesize that the predominant mechanism of i(Xq) formation involves sequences in the proximal short arm that are prone to breakage and reunion events between sister chromatids or homologous X chromosomes.     

Familial skewed X inactivation: a molecular trait associated with high spontaneous-abortion rate maps to Xq28.

We report a family ascertained for molecular diagnosis of muscular dystrophy in a young girl, in which preferential activation (> or = 95% of cells) of the paternal X chromosome was seen in both the proband and her mother. To determine the molecular basis for skewed X inactivation, we studied X-inactivation patterns in peripheral blood and/or oral mucosal cells from 50 members of this family and from a cohort of normal females. We found excellent concordance between X-inactivation patterns in blood and oral mucosal cell nuclei in all females. Of the 50 female pedigree members studied, 16 showed preferential use (> or = 95% cells) of the paternal X chromosome; none of 62 randomly selected females showed similarly skewed X inactivation was maternally inherited in this family. A linkage study using the molecular trait of skewed X inactivation as the scored phenotype localized this trait to Xq28 (DXS1108; maximum LOD score [Zmax] = 4.34, recombination fraction [theta] = 0). Both genotyping of additional markers and FISH of a YAC probe in Xq28 showed a deletion spanning from intron 22 of the factor VIII gene to DXS115-3. This deletion completely cosegregated with the trait (Zmax = 6.92, theta = 0). Comparison of clinical findings between affected and unaffected females in the 50-member pedigree showed a statistically significant increase in spontaneous-abortion rate in the females carrying the trait (P < .02). To our knowledge, this is the first gene-mapping study of abnormalities of X-inactivation patterns and is the first association of a specific locus for recurrent spontaneous abortion in a cytogenetically normal family. The involvement of this locus in cell lethality, cell-growth disadvantage, developmental abnormalities, or the X-inactivation process is discussed.     

Sinus histiocytosis with massive lymphadenopathy: immunological, cytogenetic and molecular studies

We describe a case of "sinus histiocytosis with massive lymphadenopathy" (SHML) studied by immunohistochemical, cytogenetic and molecular analysis. The immunophenotyping showed that the lymph node histiocytes were strongly positive for the S-100 protein and MoAb LeuM3, OKM5, KP1 and DRC-1; a portion of these cells was also positive for OKT6 and Leu3A, suggesting a possible relationship with the veiled cells, which represent an intermediate step in the pathway from the Langerhans cell to the interdigitating reticulum cell. Cytogenetic analysis showed a normal prevalent clone and a small hypodiploid clone and the molecular study showed no detectable involvement of the c-fms proto-oncogene, which is related to monocyte/macrophages. Unfortunately all these data do not seem sufficient to define the benign or neoplastic nature of the disease. Further investigations, immunophenotypical, cytogenetic and molecular, are needed to elucidate the pathogenesis of the disease, especially for more aggressive cases or for cases with unfavorable evolution.     

Mapping around the Xq13.1 breakpoints of two X/A translocations in hypohidrotic ectodermal dysplasia (EDA) female patients.

Cellular hybrids were obtained from a t(X;12) identified in a female patient with hypohidrotic ectodermal dysplasia (EDA). This rearrangement had the same Xq13.1 cytogenetic breakpoint as a t(X;9) found in a previously observed EDA patient. A comparative analysis of these two rearrangements with nine probes was performed at the molecular level. These probes could define three subregions: three are proximal, two are distal, and four are between the two breakpoints. These last probes should prove useful for cloning the gene.     

Prenatal diagnosis of a translocation (X;Y) and genetic counseling

A cytogenetic prenatal diagnosis due to maternal age led us to find a male fetus with a (X;Y) translocation. This translocation is found in the mother, who presents no phenotypic abnormalities or mental retardation. The 22 cases described in the literature indicate that among male carriers of an (X;Y) translocation, half the cases present mental retardation and 2/3 phenotypic anomalies. These findings led us to give a genetic counselling of therapeutic abortion. Post mortem histological examination revealed no morphodysplasia.