scholarly journals Identification of an SRY-Negative 46,XX Infertility Male with a Heterozygous Deletion Downstream of SOX3 Gene

2021 ◽  
Author(s):  
Shengfang Qin ◽  
Xueyan Wang ◽  
Jin Wang
Keyword(s):  
X Chromosome ◽  
Copy Number ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosomal Microarray Analysis ◽  
Fluorescence Signal ◽  
Whole Genome ◽  
Heterozygous Deletion ◽  
Indel Mutation ◽  
Fluorescence Peak

Abstract Background: A male individual with a non-chimeric karyotype of 46,XX is very rare. We explored the genetic aetiology of an infertility male with 46,XX and SRY negative.Methods: The peripheral blood sample was collected from the patient and subjected to a range of genetic testing, including conventional chromosomal karyotyping, short tandem repeat (STR) analysis for chromosome 13, 18, 21, X, Y contained SRY gene, azoospermia factor (AZF) deletion analysis including SRY gene, fluorescence in situ hybridization (FISH) with specific probes for CSP X/CSP Y/SRY, chromosomal microarray analysis (CMA) for genomic copy number variations (CNVs), and whole-genome analysis(WGA) for SNV&InDel variants, and the X chromosome inactivation (XCI) analysis for AR gene.Results: The patient was found to have a 46,XX karyotype. Neither AZFa+b+c nor SRY band was detected in the electrophoresis result. FISH results of both interphase cells with CSPX/CSPY probe and metaphase cells with CSPX/CSPY/SRY probe showed two green fluorescence signals at the centromeres of X chromosomes, but no Y chromosome and SRY fluorescence signal. QF-PCR results showed that the patient had only the AMELX fluorescence peak of the X chromosome but no AMELY and SRY fluorescence peak. All results of the Karyotype, FISH, and STR did not suggest limited Y chimerism. CMA showed he had a heterozygous deletion of about 867 kb in Xq27.1 (hg19: chrX: 138,612,879-139,480,163 bp), located at 104 kb downstream of SOX3 gene, including F9, CXorf66, MCF2 and ATP11C; Meanwhile, whole-genome sequencing also found no SNV&InDel mutation associated with abnormal sex development. 75% X chromosome inactivation was detected.Conclusions: Although the pathogenicity of 46,XX male patients with SRY negative remains unclear, SOX3 expression of the acquired function may be associated with partial testis differentiation. Therefore, copy number variation of SOX3 gene and regulatory region should be performed routinely for these patients.

X-linked CNV and skewed X-chromosome inactivation

2020 ◽  
pp. 19-21
Author(s):  
Е.А. Фонова ◽  
Е.Н. Толмачева ◽  
А.А. Кашеварова ◽  
М.Е. Лопаткина ◽  
К.А. Павлова ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Intellectual Disability ◽  
X Chromosome ◽  
Copy Number ◽  
Copy Number Variations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromosome X ◽  
Skewed X Chromosome Inactivation

Смещение инактивации Х-хромосомы может быть следствием и маркером нарушения клеточной пролиферации при вариациях числа копий ДНК на Х-хромосоме. Х-сцепленные CNV выявляются как у женщин с невынашиванием беременности и смещением инактивации Х-хромосомы (с частотой 33,3%), так и у пациентов с умственной отсталостью и смещением инактивацией у их матерей (с частотой 40%). A skewed X-chromosome inactivation can be a consequence and a marker of impaired cell proliferation in the presence of copy number variations (CNV) on the X chromosome. X-linked CNVs are detected in women with miscarriages and a skewed X-chromosome inactivation (with a frequency of 33.3%), as well as in patients with intellectual disability and skewed X-chromosome inactivation in their mothers (with a frequency of 40%).

scholarly journals A Functional Chromatin Domain Does Not Resist X Chromosome Inactivation: Silencing of cLys Correlates with Methylation of a Dual Promoter-Replication Origin

2002 ◽  
Vol 22 (13) ◽  
pp. 4667-4676 ◽  
Author(s):  
Suyinn Chong ◽  
Joanna Kontaraki ◽  
Constanze Bonifer ◽  
Arthur D. Riggs
Keyword(s):  
X Chromosome ◽  
Copy Number ◽  
Cpg Island ◽  
Regulatory Elements ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Chromatin Domain ◽  
Specific Expression ◽  
Position Effects ◽  
Chicken Lysozyme

ABSTRACT To investigate the molecular mechanism(s) involved in the propagation and maintenance of X chromosome inactivation (XCI), the 21.4-kb chicken lysozyme (cLys) chromatin domain was inserted into the Hprt locus on the mouse X chromosome. The inserted fragment includes flanking matrix attachment regions (MARs), an origin of bidirectional replication (OBR), and all the cis-regulatory elements required for correct tissue-specific expression of cLys. It also contains a recently identified and widely expressed second gene, cGas41. The cLys domain is known to function as an autonomous unit resistant to chromosomal position effects, as evidenced by numerous transgenic mouse lines showing copy-number-dependent and development-specific expression of cLys in the myeloid lineage. We asked the questions whether this functional chromatin domain was resistant to XCI and whether the X inactivation signal could spread across an extended region of avian DNA. A generally useful method was devised to generate pure populations of macrophages with the transgene either on the active (Xa) or the inactive (Xi) chromosome. We found that (i) cLys and cGas41 are expressed normally from the Xa; (ii) the cLys chromatin domain, even when bracketed by MARs, is not resistant to XCI; (iii) transcription factors are excluded from lysozyme enhancers on the Xi; and (iv) inactivation correlates with methylation of a CpG island that is both an OBR and a promoter of the cGas41 gene.

scholarly journals Genome and transcriptome analysis of the mealybug Maconellicoccus hirsutus: A model for genomic Imprinting

2020 ◽  
Author(s):  
Surbhi Kohli ◽  
Parul Gulati ◽  
Jayant Maini ◽  
Shamsudheen KV ◽  
Rajesh Pandey ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
X Chromosome ◽  
Epigenetic Regulation ◽  
Transcriptome Analysis ◽  
Radiation Resistance ◽  
Copy Number ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Maconellicoccus Hirsutus ◽  
Epigenetic Regulators

AbstractIn mealybugs, transcriptional inactivation of the entire paternal genome in males, due to genomic imprinting, is closely correlated with sex determination. The sequencing, de-novo assembly and annotation of the mealybug, Maconellicoccus hirsutus genome and its comparison with Planococcus citri genome strengthened our gene identification. The expanded gene classes, in both genomes relate to the high pesticide and radiation resistance; the phenotypes correlating with increased gene copy number rather than the acquisition of novel genes. The complete repertoire of genes for epigenetic regulation and multiple copies of genes for the core members of polycomb and trithorax complexes and the canonical chromatin remodelling complexes are present in both the genomes. Phylogenetic analysis with Drosophila shows high conservation of most genes, while a few have diverged outside the functional domain. The proteins involved in mammalian X-chromosome inactivation are identified in mealybugs, thus demonstrating the evolutionary conservation of factors for facultative heterochromatization. The transcriptome analysis of adult male and female M.hirsutus indicates the expression of the epigenetic regulators and the differential expression of metabolic pathway genes and the genes for sexual dimorphism. The depletion of endosymbionts in males during development is reflected in the significantly lower expression of endosymbiont genes in them.Author summaryThe mealybug system offers a unique model for genomic imprinting and differential regulation of homologous chromosomes that pre-dates the discovery of dosage compensation of X chromosomes in female mammals. In the absence of robust genetics for mealybugs, we generated and analysed the genome and transcriptome profile as primary resources for effective exploration. The expanded gene classes in the mealybugs relate to their unique biology; the expansion of pesticide genes, trehalose transporter, SETMAR and retrotransposons correlate with pesticide, desiccation and radiation resistance, respectively. The similarity in the genomic profile of two species of mealybugs strengthens our gene prediction. All the known epigenetic modifiers and proteins of the primary complexes like the PRC1,2 and the trithorax are conserved in mealybugs, so also the homologues of mammalian proteins involved in X chromosome inactivation. The high copy number of genes for many partners in these complexes could facilitate the inactivation of a large part of the genome and raise the possibility of formation of additional non-canonical complexes for sex specific chromosome inactivation. In adult males and females, the status of epigenetic regulation is likely to be in a maintenance state; therefore, it is of interest to analyze the expression of epigenetic regulators during development.

scholarly journals Human induced pluripotent stem cells from two azoospermic patients with Klinefelter syndrome show similar X chromosome inactivation behavior to female pluripotent stem cells

2019 ◽  
Vol 34 (11) ◽  
pp. 2297-2310 ◽  
Author(s):  
Sarita Panula ◽  
Magdalena Kurek ◽  
Pankaj Kumar ◽  
Halima Albalushi ◽  
Sara Padrell Sánchez ◽  
...  
Keyword(s):  
Stem Cells ◽  
Induced Pluripotent Stem Cells ◽  
Clinical Features ◽  
X Chromosome ◽  
Pluripotent Stem Cells ◽  
Klinefelter Syndrome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Whole Genome ◽  
Induced Pluripotent

Abstract STUDY QUESTION Does the X chromosome inactivation (XCI) of Klinefelter syndrome (KS)-derived human induced pluripotent stem cells (hiPSCs) correspond to female human pluripotent stem cells (hPSCs) and reflect the KS genotype? SUMMARY ANSWER Our results demonstrate for the first time that KS-derived hiPSCs show similar XCI behavior to female hPSCs in culture and show biological relevance to KS genotype-related clinical features. WHAT IS KNOWN ALREADY So far, assessment of XCI of KS-derived hiPSCs was based on H3K27me3 staining and X-inactive specific transcript gene expression disregarding the at least three XCI states (XaXi with XIST coating, XaXi lacking XIST coating, and XaXe (partially eroded XCI)) that female hPSCs display in culture. STUDY DESIGN, SIZE, DURATION The study used hiPSC lines generated from two azoospermic patients with KS and included two healthy male (HM) and one healthy female donor. PARTICIPANTS/MATERIALS, SETTING, METHODS In this study, we derived hiPSCs by reprograming fibroblasts with episomal plasmids and applying laminin 521 as culture substrate. hiPSCs were characterized by karyotyping, immunocytochemistry, immunohistochemistry, quantitative PCR, teratoma formation, and embryoid body differentiation. XCI and KS hiPSC relevance were assessed by whole genome transcriptomics analysis and immunocytochemistry plus FISH of KS, HM and female fibroblast, and their hiPSC derivatives. MAIN RESULTS AND THE ROLE OF CHANCE Applying whole genome transcriptomics analysis, we could identify differentially expressed genes (DEGs) between KS and HM donors with enrichment in gene ontology terms associated with fertility, cardiovascular development, ossification, and brain development, all associated with KS genotype-related clinical features. Furthermore, XCI analysis based on transcriptomics data, RNA FISH, and H3K27me3 staining revealed variable XCI states of KS hiPSCs similar to female hiPSCs, showing either normal (XaXi) or eroded (XaXe) XCI. KS hiPSCs with normal XCI showed nevertheless upregulated X-linked genes involved in nervous system development as well as synaptic transmission, supporting the potential use of KS-derived hiPSCs as an in vitro model for KS. LIMITATIONS, REASONS FOR CAUTION Detailed clinical information for patients included in this study was not available. Although a correlation between DEGs and the KS genotype could be observed, the biological relevance of these cells has to be confirmed with further experiments. In addition, karyotype analysis for two hiPSC lines was performed at passage 12 but not repeated at a later passage. Nevertheless, since all XCI experiments for those lines were performed between passage 11 and 15 the authors expect no karyotypic changes for those experiments. WIDER IMPLICATIONS OF THE FINDINGS As KS patients have variable clinical phenotypes that are influenced by the grade of aneuploidy, mosaicism, origin of the X chromosome, and XCI ‘escapee’ genes, which vary not only among individuals but also among different tissues within the same individual, differentiated KS hiPSCs could be used for a better understanding of KS pathogenesis. STUDY FUNDING/COMPETING INTEREST(S) This study was supported by grants from the Knut and Alice Wallenberg Foundation (2016.0121 and 2015.0096), Ming Wai Lau Centre for Reparative Medicine (2-343/2016), Ragnar Söderberg Foundation (M67/13), Swedish Research Council (2013-32485-100360-69), the Centre for Innovative Medicine (2–388/2016–40), Kronprinsessan Lovisas Förening För Barnasjukvård/Stiftelsen Axel Tielmans Minnesfond, Samariten Foundation, Jonasson Center at the Royal Institute of Technology, Sweden, and Initial Training Network Marie Curie Program ‘Growsperm’ (EU-FP7-PEOPLE-2013-ITN 603568). The authors declare no conflicts of interest.

scholarly journals Copy Number Changes on the X Chromosome in Women with and without Highly Skewed X-Chromosome Inactivation

2012 ◽  
Vol 136 (4) ◽  
pp. 264-269 ◽  
Author(s):  
V. Jobanputra ◽  
B. Levy ◽  
A. Kinney ◽  
S. Brown ◽  
M. Shirazi ◽  
...  
Keyword(s):  
X Chromosome ◽  
Copy Number ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Copy Number Changes ◽  
Skewed X Chromosome Inactivation

scholarly journals X-Linked Emery–Dreifuss Muscular Dystrophy: Study Of X-Chromosome Inactivation and Its Relation with Clinical Phenotypes in Female Carriers

Genes ◽  
2019 ◽  
Vol 10 (11) ◽  
pp. 919 ◽  
Author(s):  
Viggiano ◽  
Madej-Pilarczyk ◽  
Carboni ◽  
Picillo ◽  
Ergoli ◽  
...  
Keyword(s):  
Muscular Dystrophy ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Fibrous Tissue ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Cardiac Conduction ◽  
Asymptomatic Carriers ◽  
Cardiac Symptoms ◽  
Female Carriers

X-linked Emery–Dreifuss muscular dystrophy (EDMD1) affects approximately 1:100,000 male births. Female carriers are usually asymptomatic but, in some cases, they may present clinical symptoms after age 50 at cardiac level, especially in the form of conduction tissue anomalies. The aim of this study was to evaluate the relation between heart involvement in symptomatic EDMD1 carriers and the X-chromosome inactivation (XCI) pattern. The XCI pattern was determined on the lymphocytes of 30 symptomatic and asymptomatic EDMD1 female carriers—25 familial and 5 sporadic cases—seeking genetic advice using the androgen receptor (AR) methylation-based assay. Carriers were subdivided according to whether they were above or below 50 years of age. A variance analysis was performed to compare the XCI pattern between symptomatic and asymptomatic carriers. The results show that 20% of EDMD1 carriers had cardiac symptoms, and that 50% of these were ≥50 years of age. The XCI pattern was similar in both symptomatic and asymptomatic carriers. Conclusions: Arrhythmias in EDMD1 carriers poorly correlate on lymphocytes to a skewed XCI, probably due to (a) the different embryological origin of cardiac conduction tissue compared to lymphocytes or (b) the preferential loss of atrial cells replaced by fibrous tissue.

scholarly journals Loss of p53 Causes Stochastic Aberrant X-Chromosome Inactivation and Female-Specific Neural Tube Defects

Cell Reports ◽  
2019 ◽  
Vol 27 (2) ◽  
pp. 442-454.e5 ◽  
Author(s):  
Alex R.D. Delbridge ◽  
Andrew J. Kueh ◽  
Francine Ke ◽  
Natasha M. Zamudio ◽  
Farrah El-Saafin ◽  
...  
Keyword(s):  
X Chromosome ◽  
Neural Tube ◽  
Neural Tube Defects ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Female Specific
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