scholarly journals Case Report: Wiskott-Aldrich Syndrome Caused by Extremely Skewed X-Chromosome Inactivation in a Chinese Girl

2021 ◽  
Vol 9 ◽  
Author(s):  
Xuening Hou ◽  
Jie Sun ◽  
Chen Liu ◽  
Jihong Hao
Keyword(s):  
X Chromosome ◽  
Clinical Manifestations ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Exon 2 ◽  
Wiskott Aldrich Syndrome ◽  
Chinese Girl ◽  
Skewed X Chromosome Inactivation ◽  
Female Carriers

Wiskott-Aldrich syndrome (WAS) is a rare X-linked immunodeficiency disorder caused by abnormal expression of Wiskott-Aldrich syndrome protein due to WAS gene mutation, which is generally characterized by microthrombocytopenia, eczema, recurrent infections, and high risk of autoimmune complications and hematological malignancies. Although affected males with WAS usually manifest severe symptoms, female carriers have no significant clinical manifestations. Here, we describe a Chinese girl diagnosed with WAS carrying a heterozygous missense mutation in exon 2 of the WAS gene. The patient presented with persistent thrombocytopenia with small platelets and decreased WAS protein detected by flow cytometry and western blot analysis. The methylation analysis of the HUMARA gene displayed an extremely skewed X-chromosome inactivation (SXCI) pattern, where the X-chromosomes bearing normal WAS gene were predominantly inactivated, leaving the mutant gene active. Hence, our results suggest that completely inactivating the unaffected paternal X-chromosomes may be the reason for such phenotype in this female patient. SXCI has important implications for genetic counseling of female carriers with a family history of WAS.

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.

Wiskott–Aldrich syndrome in a female with skewed X-chromosome inactivation

2003 ◽  
Vol 31 (3) ◽  
pp. 332-337 ◽  
Author(s):  
Nuria Andreu ◽  
Núria Pujol-Moix ◽  
Luis Martinez-Lostao ◽  
Marta Oset ◽  
Eduardo Muñiz-Diaz ◽  
...  
Keyword(s):  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Wiskott Aldrich Syndrome ◽  
Skewed X Chromosome Inactivation

scholarly journals Detection of skewed X-chromosome inactivation in Fragile X syndrome and X chromosome aneuploidy using quantitative melt analysis

2015 ◽  
Vol 17 ◽  
Author(s):  
David E. Godler ◽  
Yoshimi Inaba ◽  
Charles E. Schwartz ◽  
Quang M. Bui ◽  
Elva Z. Shi ◽  
...  
Keyword(s):  
Fragile X Syndrome ◽  
X Chromosome ◽  
Sex Chromosome ◽  
Fragile X ◽  
Venous Blood ◽  
Reference Method ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
X Chromosomes ◽  
Skewed X Chromosome Inactivation

Methylation of the fragile X mental retardation 1 (FMR1) exon 1/intron 1 boundary positioned fragile X related epigenetic element 2 (FREE2), reveals skewed X-chromosome inactivation (XCI) in fragile X syndrome full mutation (FM: CGG > 200) females. XCI skewing has been also linked to abnormal X-linked gene expression with the broader clinical impact for sex chromosome aneuploidies (SCAs). In this study, 10 FREE2 CpG sites were targeted using methylation specific quantitative melt analysis (MS-QMA), including 3 sites that could not be analysed with previously used EpiTYPER system. The method was applied for detection of skewed XCI in FM females and in different types of SCA. We tested venous blood and saliva DNA collected from 107 controls (CGG < 40), and 148 FM and 90 SCA individuals. MS-QMA identified: (i) most SCAs if combined with a Y chromosome test; (ii) locus-specific XCI skewing towards the hypomethylated state in FM females; and (iii) skewed XCI towards the hypermethylated state in SCA with 3 or more X chromosomes, and in 5% of the 47,XXY individuals. MS-QMA output also showed significant correlation with the EpiTYPER reference method in FM males and females (P < 0.0001) and SCAs (P < 0.05). In conclusion, we demonstrate use of MS-QMA to quantify skewed XCI in two applications with diagnostic utility.

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 X-autosome and X-Y translocations in female carriers: X-chromosome inactivation easily detectable by 5-ethynyl-2-deoxyuridine (EdU)

2017 ◽  
Vol 20 (1) ◽  
pp. 87-90 ◽  
Author(s):  
M Donat ◽  
A Louis ◽  
K Kreskowski ◽  
M Ziegler ◽  
A Weise ◽  
...  
Keyword(s):  
X Chromosome ◽  
Chromosome Translocation ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Correct Interpretation ◽  
Cell Level ◽  
Diagnostic Use ◽  
Autosome Translocation ◽  
Skewed X Chromosome Inactivation ◽  
Female Carriers

Abstract Here we report one new case each of an X-autosome translocation (maternally derived), and an X-Y-chromosome translocation. Besides characterizing the involved breakpoints and/or imbalances in detail by molecular cyto-genetics, also skewed X-chromosome inactivation was determined on single cell level using 5-ethynyl-2-deoxyuridine (EdU). Thus, we confirmed that the recently suggested EdU approach can be simply adapted for routine diagnostic use. The latter is important, as only by knowing the real pattern of the skewed X-chromosome inactivation, correct interpretation of obtained results and subsequent reliable genetic counseling, can be done.

scholarly journals Lack of MECP2 gene transcription on the duplicated alleles of two MECP2 duplication females with opposite skewed X chromosome inactivation

2021 ◽  
Author(s):  
Yixi Sun ◽  
Yali Yang ◽  
Yuqin Luo ◽  
Min Chen ◽  
Liya Wang ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
X Chromosome ◽  
Neurodevelopmental Disorder ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Inhibition Mechanism ◽  
Transcriptional Level ◽  
X Chromosomes ◽  
Xq28 Duplication ◽  
Skewed X Chromosome Inactivation

Xq28 (involving MECP2) duplication syndrome is a severe neurodevelopmental disorder in males, most females are asymptomatic carriers, but there are phenotypic heterogeneities in the females. Skewed X-chromosome inactivation (XCI) seems to prevent duplicated region activation in asymptomatic females, but it remains controversial. Herein we reported two asymptomatic females (daughter and mother) with interstitial Xq28 duplication. HUMARA and RP2 assays showed that both had complete skewed XCI, the Xq28 duplicated chromosome was inactivated in the daughter, but surprisingly, it was activated in her mother. Interestingly, by combining RNA sequencing and whole-exome sequencing, we confirmed that XIST only expressed in the Xq28 duplication chromosomes of the two females, indicating that the Xq28 duplication chromosomes were inactive. Meanwhile, MECP2 and most XCI genes in the duplicated X-chromosomes were not transcriptionally expressed or upregulated, precluding major clinical phenotypes in the two females, especially the mother. We showed that XCI status detected by RNA sequencing was more relevant for establishing the clinical phenotype of MECP2 duplication females. It suggested there were other factors maintaining the XCI status in addition to DNA methylation, a possible additional inhibition mechanism occured at the transcriptional level in the unmethylated X-chromosome, counter balancing the MECP2 duplication’s detrimental phenotype effects

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%).

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