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Molecular-cytogentics analysis of X and Y chromosome breakpoint. Partial metaphase plate after FISH with RP11-368D24 probe (Xq11.1). The signal (red) was detected both on der(Y) and X chromosome (arrows). CEP X probe (Cytocell, green) was used to identify X chromosome (A). Location of disomic SNP calls (small green vertical bars) is shown along the long arm of X chromosome ideogram. The blue bar below the ideogram indicates the region of monosomy. In the upper histogram the log2 intensity ratio for each SNP locus (red dots) is represented and the blue line below shows the averaged log2 values. Breakpoint is localised between SNP_A-1753661 (nt.68.182.937) and SNP_A-1659250 (nt.69.788.317) in Xq13.1(B). There is a discrepancy between the results obtained through FISH using BAC probes and Affymetrix® analysis of SNPs on X chromosome (A, B). Partial metaphase plate after FISH with RP11-65G9 (Yq11.223) probe. The signal (red) was detected on der(Y) (arrow). LSI SRY SpectrumOrange/CEPX Spectrum Green probe (Vysis, Abbott Molecular, Illinois, USA) was used as control probe (C). Dual-color FISH analysis on chromosome spreads (partial metaphase) with LSI SRY SpectrumOrange/CEPX SpectrumGreen probes. Arrows: normal and derivative chromosome showed specific hybridization signals that are localised correctly (D).
Source publication
Premature ovarian failure (POF) is a secondary hypergonadotrophic amenorrhea occurring before the age of 40 and affecting 1-3% of females. Chromosome anomalies account for 6-8% of POF cases, but only few cases are associated with translocations involving X and Y chromosomes.This study shows the cytogenetic and molecular analysis of a POF patient ca...
Citations
... This speculation is in agreement with the observation that there are no cases of male sons in the maternal lineage under analysis. Moreover, the 6.3 Mb deletion of the Xq28 region includes genes whose loss has been related to premature ovarian failure (POF) [19][20][21][22][23]. Therefore, the genetic and molecular information identified by our study, when accompanied by adequate and informative genetic counselling, could have an important impact on the perspective view of preventive medicine. ...
The translocation of the testis-determining factor, the SRY gene, from the Y to the X chromosome is a rare event that causes abnormalities in gonadal development. In all cases of males and females carrying this translocation, disorder of sex development is reported. In our study, we described a peculiar pedigree with the first evidence of four healthy females from three generations who are carriers of the newly identified t(X;Y)(q28;p11.2)(SRY+) translocation with no evidence of ambiguous genitalia or other SRY-dependent alterations. Our study was a consequence of a Non-Invasive Prenatal Test (NIPT) showing a sexual chromosomal abnormality (XXY) followed by a chorionic villus analysis suggesting a normal karyotype 46,XX and t(X;Y) translocation detected by FISH. Here, we (i) demonstrated the inheritance of the translocation in the maternal lineage via karyotyping and FISH analysis; (ii) characterised the structural rearrangement via chromosomal microarray; and (iii) demonstrated, via Click-iT® EdU Imaging assay, that there was an absolute preferential inactivation of the der(X) chromosome responsible for the lack of SRY expression. Overall, our study provides valuable genetic and molecular information that may lead personal and medical decisions.
... Patients with type "other" were more likely to have gonadal abnormalities (14/21). Almost all patients had at least one complete X-chromosome segment (details shown in Table 4) [5][6][7][8][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. ...
Background
X/Y translocations are highly heterogeneity in terms of clinical genetic effects, and most patients lack complete pedigree analysis for clinical and genetic characterization.
Results
This study comprehensively analyzed the clinical and genetic characteristics of three new patients with X/Y translocations. Furthermore, cases with X/Y translocations reported in the literature and studies exploring the clinical genetic effects in patients with X/Y translocations were reviewed. All three female patients were carriers of X/Y translocations with different phenotypes. The karyotype for patient 1 was 46,X,der(X)t(X;Y)(p22.33;q12)mat, patient 2 was 46,X,der(X)t(X;Y)(q21.2;q11.2)dn, and patient 3 was 46,X,der(X)t(X;Y)(q28;q11.223)t(Y;Y)(q12;q11.223)mat. C-banding analysis of all three patients revealed a large heterochromatin region in the terminal region of the X chromosome. All patients underwent chromosomal microarray analysis, which revealed the precise copy number loss or gain. Data on 128 patients with X/Y translocations were retrieved from 81 studies; the phenotype of these patients was related to the breakpoint of the chromosome, size of the deleted region, and their sex. We reclassified the X/Y translocations into new types based on the breakpoints of the X and Y chromosomes.
Conclusion
X/Y translocations have substantial phenotypic diversity, and the genetic classification standards are not unified. With the development of molecular cytogenetics, it is necessary to combine multiple genetic methods to obtain an accurate and reasonable classification. Thus, clarifying their genetic causes and effects promptly will help in genetic counseling, prenatal diagnosis, preimplantation genetic testing, and improvement in clinical treatment strategies.
... In such cases, degraded DNA may offer partial or no results or definite conclusion [15]. On the other hands, there exist several clinical cases, the people patients with absence of the SRY gene has a fully female phenotype despite the genetically that they have the Y chromosome [16,17], the disorder cases with 46, XX maleness and in rare cases 46, XX true hermaphrodites (both fertile men and women) caused by the found of SRY on the X chromosome [18,19]. On the contrary, the patient has a male phenotype even though carrying two X chromosomes, these types of sexual disorders caused by translocation of the SRY gene to an autosomal chromosome [20]. ...
Sex determination is indispensable in forensic anthropology, sexual disorder, and also as part of large-scale genetic population studies. The purpose of this investigation is to determine the human sex from whole blood using multiplex PCR analysis. Blood samples from 75 male and 70 female healthy volunteers were taken from Tikrit city, Iraq. Our study identified a reliable set of three primer locus, namely SRY, ALT1 (internal control) and amelogenin locus. The SRY primer on the Y chromosome showed a 254 bp of PCR product, with 100% accuracy for human male identification. Thus, the pair of SRY primers was considered a strong genetic marker for human sex identification. Amelogenin regions in the Y chromosome showed a true positive band (236 bp) with 100% accuracy on sex identification. Amelogenin regions in X chromosome also showed positive bands (330 bp) in female samples and positive band in male samples except for two samples showed a negative band (null bands). The most obvious finding from this study is that multiplex PCR of ALT1 and SRY is consider as a reliable genetic marker for human sex identification. The research has also shown that amelogenin is good genetic marker for human sex identification.
... Fluorescence in situ hybridization (FISH) was carried out according to the manufacturer's protocol for the commercial probes and as previously reported for the homemade ones [28]. ...
The presence of thousands of repetitive sequences makes the centromere a fragile region subject to breakage. In this study we collected 31 cases of rearrangements of chromosome 18, of which 16 involved an acrocentric chromosome, during genetic screening done in three centers. We noticed a significant enrichment of reciprocal translocations between the centromere of chromosome 18 and the centromeric or pericentromeric regions of the acrocentrics. We describe five cases with translocation between chromosome 18 and an acrocentric chromosome, and one case involving the common telomere regions of chromosomes 18p and 22p. In addition, we bring evidence to support the hypothesis that chromosome 18 preferentially recombines with acrocentrics: (i) the presence on 18p11.21 of segmental duplications highly homologous to acrocentrics, that can justify a NAHR mechanism; (ii) the observation by 2D-FISH of the behavior of the centromeric regions of 18 respect to the centromeric regions of acrocentrics in the nuclei of normal subjects; (iii) the contact analysis among these regions on published Hi-C data from the human lymphoblastoid cell line (GM12878).
... Fluorescence in situ hybridization (FISH) was carried out as previously reported for the homemade probes [12] and according the manufacturer's protocol for the commercial ones. To characterize the X anomalous, the following commercial probes were applied: centromeric X alpha-satellite (DXZ1, Xp11.1-q11.1), ...
Background
Neocentromeres are rare and considered chromosomal aberrations, because a non-centromeric region evolves in an active centromere by mutation. The literature reported several structural anomalies of X chromosome and they influence the female reproductive capacity or are associated to Turner syndrome in the presence of monosomy X cell line.
Case presentation
We report a case of chromosome X complex rearrangement found in a prenatal diagnosis. The fetal karyotype showed a mosaicism with a 45,X cell line and a 46 chromosomes second line with a big marker, instead of a sex chromosome. The marker morphology and fluorescence in situ hybridization (FISH) characterization allowed us to identify a tricentric X chromosome constituted by two complete X chromosome fused at the p arms telomere and an active neocentromere in the middle, at the union of the two Xp arms, where usually are the telomeric regions. FISH also showed the presence of a paracentric inversion of both Xp arms.
Furthermore, fragility figures were found in 56% of metaphases from peripheral blood lymphocytes culture at birth: a shorter marker chromosome and an apparently acentric fragment frequently lost.
Conclusions
At our knowledge, this is the first isochromosome of an entire non-acrocentric chromosome. The neocentromere is constituted by canonical sequences but localized in an unusual position and the original centromeres are inactivated.
We speculated that marker chromosome was the result of a double rearrangement: firstly, a paracentric inversion which involved the Xp arm, shifting a part of the centromere at the p end and subsequently a duplication of the entire X chromosome, which gave rise to an isochromosome. It is possible to suppose that the first event could be a result of a non-allelic homologous recombination mediated by inverted low-copy repeats.
As expected, our case shows a Turner phenotype with mild facial features and no major skeletal deformity, normal psychomotor development and a spontaneous development of puberty and menarche, although with irregular menses since the last follow-up.
... 8 Since the 2 copies of the X chromosome are necessary for ovarian development and integrity, the gonadal dysgenesis in our patient can be attributed to the partial loss of Xq, which contains various genes necessary for a normal ovarian reproductive function. 9 The tall stature in our patient is noteworthy. In line with previous case reports by other authors, one possible explanation for our patient's tall stature is estrogen deficiency caused by untreated gonadal dysgenesis because gonadal estrogen deficiency contributes to sustained growth. ...
Chromosomal translocations constitute one of the most important, yet uncommon, causes of primary amenorrhea and gonadal dysgenesis. Although X-autosome translocations are frequently associated with streak gonads and clinical features of the Turner syndrome, the majority of X-autosome carriers may present with a variable phenotype, developmental delay, and recognizable X-linked syndrome due to nonrandom X-inactivation. In this article, we describe a healthy 15.5-year-old girl with primary amenorrhea, gonadal dysgenesis, and tall stature without other manifestations of the Turner syndrome. Relevant clinical, biochemical, endocrinological, and cytogenetical evaluations were performed. Initial investigations revealed hypergonadotropic hypogonadism (FSH=134 mIU/mL [normal=10–15 mIU/mL], LH=47.5 [normal=10–15 mIU/mL], and estradiol=24.3 pmol/L). On ultrasound examination of the pelvis, streak ovaries with a hypoplastic uterus were noted. Chromosome study, performed according to routine procedures, revealed an apparently balanced reciprocal translocation involving the short arm of chromosome 1(p2) and the long arm of the X chromosome (q2) in all the cells with the following karyotype: 46,X,t(1;X)(p13;q22). She was placed on hormone replacement therapy. In our patient, X-autosome translocation was associated with gonadal dysgenesis and tall stature. We conclude that t(X;1) may be associated with gonadal dysgenesis without other congenital abnormalities. To our knowledge, normal phenotype with gonadal dysgenesis and tall stature in association with t(X;1) translocation has not been previously reported.
... There is a strong correlation between 45, XO patients and POF, in many cases of which X haploinsufficiency has been pointed out as the main mechanism because monosomy X fails to pair during meiosis and genes necessary to maintain proper function of the ovary lack one copy [7,8]. The presence of chromosome Y was also observed in few POF studies [9][10][11][12][13]. ...
... Few cases of POF reported the presence of chromosome Y in Tunisian, Chinese, and Italian population. In many cases of POF associated with the Y chromosome, Yq11.223 was translocated to the Xq region [9][10][11][12][13]. To determine structural variants such as translocation of chromosome Y, WGS was performed on P1 and P31. ...
Premature ovarian failure (POF) is characterized by heterogeneous genetic causes such as chromosomal abnormalities and variants in causal genes. Recently, development of techniques made next generation sequencing (NGS) possible to detect genome wide variants including chromosomal abnormalities. Among 37 Korean POF patients, XY karyotype with distal part deletions of Y chromosome, Yp11.32-31 and Yp12 end part, was observed in two patients through NGS. Six deleterious variants in POF genes were also detected which might explain the pathogenesis of POF with abnormalities in the sex chromosomes. Additionally, the two POF patients had no mutation in SRY but three non-synonymous variants were detected in genes regarding sex reversal. These findings suggest candidate causes of POF and sex reversal and show the propriety of NGS to approach the heterogeneous pathogenesis of POF.
... It has been observed that chromosome abnormalities are responsible for 6-8% of POI cases [14]. The abnormalities range from partial to complete absence of X chromosome to lead DNA mutations distributed in the genome abroad. ...
Premature ovarian insufficiency (POI) is an ovarian dysfunction characterized by increased FSH levels and amenorrhea before 40 years old. In recent years, the search for genetic causes of POI intensified and studies have been published relating the presence of mutations and polymorphisms in genes associated with development, recruitment and oocyte atresia. The aim of this study was to evaluate the presence of FSHR polymorphisms in our population and contribute with the elucidation of POI etiology. To achieve it, we have studied 100 patients with POI (G1), 60 patients with border line levels of FSH (G2) and 123 controls with regular menopause onset. Cytogenetic analysis of patients' samples and genotyping of Asn680Ser and Ala307Thr polymorphisms were performed in cases and controls. Cytogenetic analysis showed that 92% of G1 patients had normal karyotype, 4% presented polymorphic variants, 3% presented mosaic karyotype involving X chromosome. In G2, 91.6% had normal karyotype results, 3.2% displayed polymorphic variants, and 3.3% presented a mosaic karyotype involving X chromosome. Statistical comparison showed that the polymorphic allele of Ala307Thr polymorphism is more frequent in patients than in controls (G1: p < 0.001 and G2: p = 0.0259). This association has not been previously reported. We concluded that Ala307Thr polymorphism in FSHR can be potentially associated to POI development and can be considered as a screening marker in patients with ovarian failure signals.
... 223) (1) and der (X) t (X; 11) (q28; p13) (21). Many of these translocations occur in critical regions of X chromosome which contain various genes necessary for ovarian normal reproductive function (1,8) such as FMR1 (Xq27), FMR2(Xq28), DIAPH2 (Xq22), XPNPEP2 (Xq25), FSHPRH1 (Xq22) and some autosomal genes like, FSHR (2p21-p16), Inhibin A (2q33-q36), GALT (9p13) and NOGGIN (17q22) (18). Though, population-specific studies are still limited, occasionally a single mutation may prove significant in certain populations like FSHR in Finland and INH-A in Iran (4,22). ...
Premature ovarian failure (POF) causes hypergonadotrophic amenorrhea in 1-3% of females, occurring before the age of 40 among women with chromosomal rearrangements in the long arm of the X chromosome 'critical region'. In this article, we report a case of POF and primary amenorrheain a girl with a de novo reciprocal translocation between chromosomes X and 9. The proband was a 17 years old girl with a history of irregular menstruation and high level of follicle-stimulating hormone (FSH) (151 mlU/mL) and luteinizing hormone (LH) (56 mlU/mL). In ultrasound examination, left ovarian gonad was atrophic without any follicles. Right ovarian gonad was not seen. Cytogenetical analysis was performed on the patient and her parents. Her karyotype results was 46, X, rcp (X; 9) (q24; q13) dn. Her parents had normal karyotype. This reciprocal translocation between chromosome X and 9 and observed POF in the patient suggest either the disruption of a critical gene expression due to 'position effect' or deletion of one or more POF-related genes in the disrupted long arm of the affected X chromosome.
... This forms an unbalanced XY translocation which probably occurred during recombination as part of the process of meiosis in an intervening male relative. Recombination between the X and Y chromosome is usually limited to the pseudoautosomal region 1 and 2. 2 Occasionally, recombination outside of this region can occur because of homologous sequences between the X and Y chromosome. 3 The presence of SRY on the X chromosome can be associated with variable sexual phenotype including both fertile men and women, 46,XX maleness and in rare cases 46, XX true hermaphrodites. ...
... 3 The presence of SRY on the X chromosome can be associated with variable sexual phenotype including both fertile men and women, 46,XX maleness and in rare cases 46, XX true hermaphrodites. 2,5,6 It has also been reported to cause variable sexual phenotype within the same family. 5 In people with 46,XX testicular disorders of sexual development, the SRY gene is present in approximately 80%, usually on one of the X chromosomes. ...
What's already known about this topic? Cell‐free fetal DNA testing is commonly used as a noninvasive method of determing fetal sex.
Presence of sex‐determining region Y (SRY) on the X chromosome is associated with a variable sexual phenotype.
What does this study add? Details an unexpected cell‐free fetal DNA sexing result.
Highlights the importance of using the technique of quantitative polymerase chain reaction in free fetal DNA testing.
If a similar result is found again, we would recommend further testing of the maternal chromosomes to look for a translocation encompassing the sex‐determining region Y (SYR) gene.
