Unbalanced X;Autosome Translocations May Lead to Mild Phenotypes and Are Associated with Autoimmune Diseases

2020 ◽  
Vol 160 (2) ◽  
pp. 80-84
Author(s):  
Claudia Ciaccio ◽  
Serena Redaelli ◽  
Angela Bentivegna ◽  
Susan Marelli ◽  
Francesca Crosti ◽  
...  
Keyword(s):  
X Chromosome ◽  
Clinical Presentation ◽  
Autoimmune Disorders ◽  
X Inactivation ◽  
Compensation Mechanism ◽  
Inactivation Pattern ◽  
Family Testing ◽  
Wide Variability ◽  
Mild Clinical Presentation ◽  
Skewed X Chromosome Inactivation

Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.

scholarly journals Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation [see comments]

Blood ◽  
1990 ◽  
Vol 75 (12) ◽  
pp. 2369-2374 ◽  
Author(s):  
JM Puck ◽  
KA Siminovitch ◽  
M Poncz ◽  
CR Greenberg ◽  
M Rottem ◽  
...  
Keyword(s):  
T Cell ◽  
X Chromosome ◽  
Hereditary Disease ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Negative Family History ◽  
Wiskott Aldrich Syndrome ◽  
Inactivation Pattern ◽  
Skewed X Chromosome Inactivation ◽  
Cell Defect

Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott- Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.

scholarly journals Skewness of X-chromosome inactivation increases with age and varies across birth cohorts in elderly Danish women

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Jonas Mengel-From ◽  
Rune Lindahl-Jacobsen ◽  
Marianne Nygaard ◽  
Mette Soerensen ◽  
Karen Helene Ørstavik ◽  
...  
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Chromosomal Mosaicism ◽  
Birth Cohorts ◽  
Cross Sectional ◽  
Time Points ◽  
Age Related ◽  
Skewed X Chromosome Inactivation

AbstractMosaicism in blood varies with age, and cross-sectional studies indicate that for women, skewness of X-chromosomal mosaicism increases with age. This pattern could, however, also be due to less X-inactivation in more recent birth cohorts. Skewed X-chromosome inactivation was here measured longitudinally by the HUMARA assay in 67 septuagenarian and octogenarian women assessed at 2 time points, 10 years apart, and in 10 centenarian women assessed at 2 time points, 2–7 years apart. Skewed X-chromosome inactivation was also compared in 293 age-matched septuagenarian twins born in 1917–1923 and 1931–1937, and 212 centenarians born in 1895, 1905 and 1915. The longitudinal study of septuagenarians and octogenarians revealed that 16% (95% CI 7–29%) of the women developed skewed X-inactivation over a 10-year period. In the cross-sectional across-birth cohort study, the earlier-born septuagenarian (1917–1923) and centenarian women (1895) had a higher degree of skewness than the respective recent age-matched birth cohorts, which indicates that the women in the more recent cohorts, after the age of 70, had not only changed degree of skewness with age, they had also undergone less age-related hematopoietic sub-clone expansion. This may be a result of improved living conditions and better medical treatment in the more recent birth cohorts.

scholarly journals Intelligence Quotient Variability in Klinefelter Syndrome Is Associated With GTPBP6 Expression Under Regulation of X-Chromosome Inactivation Pattern

2021 ◽  
Vol 12 ◽  
Author(s):  
Luciane Simonetti ◽  
Lucas G. A. Ferreira ◽  
Angela Cristina Vidi ◽  
Janaina Sena de Souza ◽  
Ilda S. Kunii ◽  
...  
Keyword(s):  
Gene Expression ◽  
X Chromosome ◽  
Intelligence Quotient ◽  
Klinefelter Syndrome ◽  
X Chromosome Inactivation ◽  
X Inactivation ◽  
Chromosome Inactivation ◽  
Neurocognitive Dysfunction ◽  
Inactivation Pattern ◽  
Iq Scores

Klinefelter syndrome (KS) displays a broad dysmorphological, endocrinological, and neuropsychological clinical spectrum. We hypothesized that the neurocognitive dysfunction present in KS relies on an imbalance in X-chromosome gene expression. Thus, the X-chromosome inactivation (XCI) pattern and neurocognitive X-linked gene expression were tested and correlated with intelligence quotient (IQ) scores. We evaluated 11 KS patients by (a) IQ assessment, (b) analyzing the XCI patterns using both HUMARA and ZDHHC15 gene assays, and (c) blood RT-qPCR to investigate seven X-linked genes related to neurocognitive development (GTPBP6, EIF2S3, ITM2A, HUWE1, KDM5C, GDI1, and VAMP7) and XIST in comparison with 14 (male and female) controls. Considering IQ 80 as the standard minimum reference, we verified that the variability in IQ scores in KS patients seemed to be associated with the XCI pattern. Seven individuals in the KS group presented a random X-inactivation (RXI) and lower average IQ than the four individuals who presented a skewed X-inactivation (SXI) pattern. The evaluation of gene expression showed higher GTPBP6 expression in KS patients with RXI than in controls (p = 0.0059). Interestingly, the expression of GTPBP6 in KS patients with SXI did not differ from that observed in controls. Therefore, our data suggest for the first time that GTPBP6 expression is negatively associated with full-scale IQ under the regulation of the type of XCI pattern. The SXI pattern may regulate GTPBP6 expression, thereby dampening the impairment in cognitive performance and playing a role in intelligence variability in individuals with KS, which warrants further mechanistic investigations.

X-inactivation pattern in the epididymis of sex-reversed mice heterozygous for testicular feminization

Development ◽  
1974 ◽  
Vol 32 (1) ◽  
pp. 217-225
Author(s):  
Ulrich Drews ◽  
Valentin Alonso-Lozano
Keyword(s):  
X Chromosome ◽  
Sex Reversal ◽  
Cellular Level ◽  
X Inactivation ◽  
Testicular Feminization ◽  
Wild Type ◽  
Female Mice ◽  
Inactivation Pattern ◽  
Ultrastructural Appearance ◽  
Male Sex

Female mice heterozygous for testicular feminization were sex-reversed by means of the autosomal sex reversal mutation (Sxr). Due to X-inactivation, the blastemata for male sex organs in these animals are composed of a mixture of cells, carrying either the wildtype X chromosome or the X chromosome affected with Tfm in an active state. Thus, the two types of cells are sensitive to androgens or insensitive to androgens, respectively. This mosaic could be demonstrated in the epididymis on a cellular level. Segments of undifferentiated Tfm cells were found alternating with normally differentiated wild-type cells. The ultrastructural appearance of the mosaic is described.

scholarly journals Atypical presentation of Wiskott-Aldrich syndrome: diagnosis in two unrelated males based on studies of maternal T cell X chromosome inactivation [see comments]

Blood ◽  
1990 ◽  
Vol 75 (12) ◽  
pp. 2369-2374 ◽  
Author(s):  
JM Puck ◽  
KA Siminovitch ◽  
M Poncz ◽  
CR Greenberg ◽  
M Rottem ◽  
...  
Keyword(s):  
T Cell ◽  
X Chromosome ◽  
Hereditary Disease ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Negative Family History ◽  
Wiskott Aldrich Syndrome ◽  
Inactivation Pattern ◽  
Skewed X Chromosome Inactivation ◽  
Cell Defect

Abstract Congenital thrombocytopenia may occur in isolation or accompanied by eczema and immunodeficiency, as part of the X-linked hereditary Wiskott- Aldrich syndrome (WAS). Because the clinical and immunologic picture of WAS is variable, particularly early in life, definite diagnosis cannot always be made in cases with a negative family history. Two unrelated males with sporadic congenital thrombocytopenia had only questionable immunologic abnormalities as infants, making them clinically indistinguishable from cases of isolated thrombocytopenia, although one developed episodic neutropenia and the other began to manifest a multisystem autoimmune disease at 2 years of age. Evaluation of X chromosome inactivation in the T cells of both patients' mothers showed each of these women to have the same highly skewed X chromosome inactivation pattern seen in carriers of typical familial WAS. A T-cell defect was subsequently directly demonstrated in the second patient, whose lymphocytes failed to proliferate to periodate and anti-CD43. Taken together, these data suggest the presence of T cell immunodeficiency consistent with WAS in these patients. Furthermore, their mothers were found to have a very high likelihood of being carriers, lending support to the diagnosis of a hereditary disease in these boys and making possible genetic prediction in other family members and subsequent pregnancies.

scholarly journals The pattern of X-chromosome inactivation in the embryonic and extra-embryonic tissues of post-implantation digynic triploid LT/Sv strain mouse embryos

1990 ◽  
Vol 56 (2-3) ◽  
pp. 107-114 ◽  
Author(s):  
S. Speirs ◽  
J. M. Cross ◽  
M. H. Kaufman
Keyword(s):  
X Chromosome ◽  
Sex Chromosome ◽  
Yolk Sac ◽  
X Inactivation ◽  
Tissue Samples ◽  
X Chromosomes ◽  
Embryonic Tissues ◽  
Inactive X Chromosome ◽  
Distinct Cell ◽  
Inactivation Pattern

SummarySpontaneously cycling LT/Sv strain female mice were mated to hemizygous Rb(X.2)2Ad males in order to facilitate the distinction of the paternal X chromosome, and the pregnant females were autopsied at about midday on the tenth day of gestation. Out of a total of 222 analysable embryos recovered, 165 (74·3%) were diploid and 57 (25·7%) were triploid. Of the triploids, 26 had an XXY and 31 an XXX sex chromosome constitution. Both embryonic and extra-embryonic tissue samples from the triploids were analysed cytogenetically by G-banding and by the Kanda technique to investigate their X-inactivation pattern. The yolk sac samples were separated enzymatically into their endodermally-derived and mesodermally-derived components, and these were similarly analysed, as were similar samples from a selection of control XmXp diploid embryos. In the case of the XmXmY digynic triploid embryos, a single darkly-staining Xm chromosome was observed in 485 (82·9%) out of 585, 304 (73·3%) out of 415, and 165 (44·7%) out of 369 metaphases from the embryonic, yolk sac mesodermally-derived and yolk sac endodermally-derived tissues, respectively. The absence of a darkly staining X-chromosome in the other metaphase spreads could either indicate that both X-chromosomes present were active, or that the Kanda technique had failed to differentially stain the inactive X-chromosome(s) present. In the case of the XmXmXp digynic triploid embryos, virtually all of the tissues analysed comprised two distinct cell lineages, namely those with two darkly-staining X-chromosomes, and those with a single darkly staining X-chromosome. Four X-inactivation patterns were consequently observed in this group, namely, (XmXp)Xm, (XmXm)Xp, (Xm)XmXp and XmXm(Xp) in which the inactive X is enclosed in parentheses. The incidence of these various classes varied among the tissues analysed. There was, however, a clear pattern of non-random selective paternal X-inactivation in yolk sac endodermally-derived samples which possessed two inactive X-chromosomes. This finding contrasts with the situation observed in the yolk sac mesodermally-derived and embryonic samples which possessed two inactive X-chromosomes, where the ratio of (XmXm)Xp:Xm(XmXp) was 1:1·20 and 1:1·03, respectively, being clear evidence that random X-inactivation had occurred in these tissues.

Skewed X-chromosome inactivation in monochorionic diamniotic twin sisters results in severe and mild hemophilia A

Blood ◽  
2002 ◽  
Vol 100 (8) ◽  
pp. 3034-3036 ◽  
Author(s):  
Sophie Valleix ◽  
Christine Vinciguerra ◽  
Jean-Maurice Lavergne ◽  
Marco Leuer ◽  
Marc Delpech ◽  
...  
Keyword(s):  
X Chromosome ◽  
Hemophilia A ◽  
De Novo ◽  
Germ Line ◽  
Clinical Phenotype ◽  
Monozygotic Twin ◽  
X Inactivation ◽  
Heterozygous State ◽  
Genetic Mechanisms ◽  
Skewed X Chromosome Inactivation

This study describes the genetic mechanisms responsible for the de novo occurrence of severe and mild hemophilia A in monozygotic twin females. Both twins were found to carry a previously known factor VIII mutation (Tyr16Cys) in the heterozygous state which most probably arose in the paternal germ line. Both twins showed concordant skewing of X inactivation toward the maternally derived normal X chromosome, the most severely affected twin exhibiting a higher percentage of inactivation of the normal X chromosome. The degree of skewing of X inactivation closely correlated with both the coagulation parameters and the clinical phenotype of the twins. Since these twins were monochorionic, such results suggest that the twinning event in this case has occurred after the onset of the X-inactivation period.

scholarly journals The differential staining pattern of the X chromosome in the embryonic and extraembryonic tissues of postimplantation homozygous tetraploid mouse embryos

1992 ◽  
Vol 59 (3) ◽  
pp. 205-214 ◽  
Author(s):  
S. Webb ◽  
T. J. de Vries ◽  
M. H. Kaufman
Keyword(s):  
X Chromosome ◽  
High Efficiency ◽  
Indirect Evidence ◽  
X Inactivation ◽  
Differential Staining ◽  
Hybrid Female ◽  
Cell Stage ◽  
X Chromosomes ◽  
F1 Hybrid ◽  
Inactivation Pattern

Summary(C57BL × CBA)F1 hybrid female mice were mated with hemizygous Rb(X.2)2Ad males to distinguish the paternal X chromosome. Homozygous tetraploids were produced by blastomere fusion at the 2-cell stage, and 161 of these were transferred to recipients and analysed on the 10th day of gestation. 59 implants contained resorptions and 76 contained either an embryo and/or extraembryonic membranes. 38 (20, XXXX and 18, XXYY) were analysed to investigate their X-inactivation pattern. Embryonic and yolk sac endodermally- and mesodermally-derived samples were analysed by G-banding and by Kanda analysis. In the XX and XY controls, the predicted pattern of X-inactivation was observed, though 12·2% of metaphases in the XX series displayed no X-inactivation. In the XY series the Y chromosome was seen in a high proportion of metaphases.In the XXXX tetraploids, 8 cell lineages were recognized with regard to their X-inactivation pattern, though most belonged to the following 3 categories: (XmXm)XpXp, Xm(XmXp)Xp and XmXm(XpXp). The other categories were only rarely encountered. In the embryonic and mesodermally-derived tissue the ratio of these groups was close to 1:2:1, whereas in the endodermally-derived tissue it was 1:4·11:4·88, due to preferential paternal X-inactivation. A significant but small proportion of all 3 tissues analysed displayed no evidence of X-inactivation. Indirect evidence suggests that this represents a genuine group because of the high efficiency of the Kanda staining. The presence of the Xm(XmXp)Xp category is consistent with the expectation that X-inactivation occurs randomly in 2 of the 4 X chromosomes present. The presence of small numbers of preparations with no evidence of X-inactivation and other unexpected categories suggests that these are probably selected against during development.

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