Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay

Tomkins, Darrell J.; McDonald, Helen; Farrell, Sandra A.; Brown, Carolyn J.

doi:10.1038/sj.ejhg.5200757

Cited by 36 publications

(32 citation statements)

References 41 publications

(24 reference statements)

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“…It has been shown that the severity in cases with small ring X chromosome is because of failure of small ring chromosome to be inactivated due to deletion of X-inactive specific transcript (XIST) at Xq13 [22,43]. In our cases, XIST was intact with the ring chromosome in both the cases negating the role of XIST inactivation in clinical phenotype of patients (Fig.…”

Section: Discussionmentioning

confidence: 60%

Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome

Chauhan

Jaiswal

Lakhotia

et al. 2016

J Assist Reprod Genet

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Purpose In the present study, we reported two cases of TS with mosaic ring X chromosome showing common clinical characteristics of TS like growth retardation and ovarian dysfunction. The purpose of the present study was to cytogenetically characterize both cases. Methods Whole blood culture and G-banding were performed for karyotyping the cases following standard protocol. Origin of the ring chromosome and degree of mosaicism were further determined by fluorescence in situ hybridization (FISH). Breakpoints and loss of genetic material in formation of different ring X chromosomes r (X) in cases were determined with the help of cytogenetic microarray. Results Cases 1 and 2 with ring chromosome were cytogenetically characterized as 45, X [114]/46Xr (X) (p22.11q21.32) [116] and 45, X [170]/46, Xr (X) (p22.2q21.33) [92], respectively. Sizes of these ring X chromosomes were found to be~7 5 and~95 Mb in cases 1 and 2, respectively, using visual estimation as part of cytogenetic observation. In both cases, we observed breakpoints on Xq chromosome were within relatively narrow region between Xq21.33 and Xq22.1 compared to regions in previously reported cases associated with ovarian dysgenesis. Conclusions Our observation agrees with the fact that despite of large heterogeneity, severity of the cases with intact Xinactive specific transcript (XIST) is dependent on degree of mosaicism and extent of Xq deletion having crucial genes involved directly or indirectly in various physiological involving ovarian cyclicity.

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Section: Discussionmentioning

confidence: 60%

Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome

Chauhan

Jaiswal

Lakhotia

et al. 2016

J Assist Reprod Genet

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“…Mutations of the XIST promoter can completely bias XCIRs. One dominant promoter mutation prevents the X chromosome carrying the mutant XIST from being inactivated, 24 whereas another causes the mutant X to always be inactivated. 21 Thus, XIST promoter mutations result in complete XCIR skewing (100:0).…”

Section: Discussionmentioning

confidence: 99%

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

et al. 2007

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Factor VIII gene, F8, mutations cause haemophilia A (HA), an X-linked recessive disorder. Expression in heterozygous females has been ascribed to skewed X-chromosome inactivation (XCI). To investigate the cause of HA in three heterozygous females within an Atlantic Canadian kindred, the proband (severely affected girl, FVIII activity: 2%) and 17 relatives across three generations were studied. F8 genotype, FVIII activity, XCI ratio (XCIR) (paternal active X: maternal active X), karyotype, submegabase resolution tiling set array competitive genome hybridization (competitive genomic hybridization (SMRT)), and microsatellite analyses were utilized. A positive linear relationship between FVIII activity and percentageactivated normal X-chromosome was found in HA heterozygous females (R 2 ¼ 0.87). All affected, but no unaffected females, had an XCIR skewed toward activation of the mutant X-chromosome (proband 92:8, SD 2). Unexpectedly, high numbers of females have dramatically skewed XCIRs (480:20 or o20:80) (Po0.05). The distribution of XCIR frequencies within this family was significantly different than predicted by normal population data or models of random XCI (Po0.025), with more females having higher degrees of skewing. Known causes of skewing, such as chromosomal abnormalities, selection against deleterious alleles, and X-inactive-specific transcript mutations, are not consistent with our results. This study shows that FVIII activity in HA heterozygous females can be directly related to XCI skewing, and that low FVIII activity in females in this family is due to unfavourable XCI skewing. Further, the findings suggest that these XCI ratios are genetically influenced, consistent with a novel heritable human X controlling element (XCE) functioning similarly to the mouse Xce.

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“…DNA methylation, X-chromosome inactivation (XCI), and genomic imprints are the most important epigenetic modifications. The appropriate initiation and maintenance of XCI is very important for embryogenesis and cell physiology [15]. Aberrant allele-specific imprinted gene expression can also cause genetic disorders, such as Prader Willi/ Angelman syndrome [16].…”

Section: Introductionmentioning

confidence: 99%

Genetic and epigenetic X-chromosome variations in a parthenogenetic human embryonic stem cell line

Liu

Yin

Jiang

et al. 2010

J Assist Reprod Genet

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Purpose To assess the genetic and epigenetic status of parthenogenetic human embryonic stem cells (phESCs). Methods Cytogenetics, X chromosome inactivation (XCI) and gene expression patterns were analyzed in one phESC line (FY-phES-018) that was derived from our laboratory. Results FY-phES-018 cells displayed the classical characteristics of normal hESCs. These cells had a 46, XX karyotype, and no inactive X chromosomes were observed before passage 20. After being cultured long term in vitro, some cells lost one X, and the proportion of cells with only one X gradually increased. At passage 35, almost all the cells displayed a 45, XO karyotype. Interestingly, at passage 45, the recovery of the X-chromosome was observed, and XCI became detectable; the mosaic ratio of 46, XX to 45, XO was 67:33. After passage 60, most cells displayed the 46, XX karyotype again with a mosaic ratio of 97:3. Some aberrant genomic imprinting was also observed in these cells. Conclusions The phESCs line FY-phES-018 is both genetically and epigenetically unstable; therefore, further research is needed before using these cells.

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Lack of expression of XIST from a small ring X chromosome containing the XIST locus in a girl with short stature, facial dysmorphism and developmental delay

Cited by 36 publications

References 41 publications

Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome

Molecular cytogenetic characterization of two Turner syndrome patients with mosaic ring X chromosome

Heritable skewed X-chromosome inactivation leads to haemophilia A expression in heterozygous females

Genetic and epigenetic X-chromosome variations in a parthenogenetic human embryonic stem cell line

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