scholarly journals No evidence for preferential X-chromosome inactivation as the main cause of divergent phenotypes in sisters with X-linked hypohidrotic ectodermal dysplasia

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Laura Körber ◽  
Holm Schneider ◽  
Nicole Fleischer ◽  
Sigrun Maier-Wohlfart
Keyword(s):  
X Chromosome ◽  
Peripheral Blood ◽  
Ectodermal Dysplasia ◽  
Phenotypic Variability ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Peripheral Blood Leukocytes ◽  
Hypohidrotic Ectodermal Dysplasia ◽  
Blood Leukocytes ◽  
Pathogenic Variants

Abstract Background X-linked hypohidrotic ectodermal dysplasia (XLHED), a rare genetic disorder, affects the normal development of ectodermal derivatives, such as hair, skin, teeth, and sweat glands. It is caused by pathogenic variants of the gene EDA and defined by a triad of hypotrichosis, hypo- or anodontia, and hypo- or anhidrosis which may lead to life-threatening hyperthermia. Although female carriers are less severely affected than male patients, they display symptoms, too, with high phenotypic variability. This study aimed to elucidate whether phenotypic differences in female XLHED patients with identical EDA genotypes might be explained by deviating X-chromosome inactivation (XI) patterns. Methods Six families, each consisting of two sisters with the same EDA variant and their parents (with either mother or father being carrier of the variant), participated in this study. XLHED-related data like sweating ability, dental status, facial dysmorphism, and skin issues were assessed. We determined the women`s individual XI patterns in peripheral blood leukocytes by the human androgen receptor assay and collated the results with phenotypic features. Results The surprisingly large inter- and intrafamilial variability of symptoms in affected females was not explicable by the pathogenic variants. Our cohort showed no higher rate of nonrandom XI in peripheral blood leukocytes than the general female population. Furthermore, skewed XI patterns in favour of the mutated alleles were not associated with more severe phenotypes. Conclusions We found no evidence for preferential XI in female XLHED patients and no distinct correlation between XLHED-related phenotypic features and XI patterns. Phenotypic variability seems to be evoked by other genetic or epigenetic factors.

Relative increase in leukemia-specific DNA in peripheral blood plasma from patients with acute myeloid leukemia and myelodysplasia

Blood ◽  
2004 ◽  
Vol 103 (7) ◽  
pp. 2799-2801 ◽  
Author(s):  
Anna Rogers ◽  
Youngson Joe ◽  
Taghi Manshouri ◽  
Amanda Dey ◽  
Iman Jilani ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
X Chromosome ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
X Chromosome Inactivation ◽  
Relative Increase ◽  
Chromosome Inactivation ◽  
Acute Myeloid

Abstract Using loss of heterozygosity (LOH) and X-chromosome inactivation, we compared peripheral blood (PB) plasma with bone marrow (BM) cells in detecting genomic abnormalities in patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). We detected LOH in the PB plasma of all 45 patients who had cytogenetically documented chromosomal abnormalities (5q-, 7-, +8, 17-, or 20-). BM cells from the same patients showed LOH in 89% of patients with MDS and 70% of patients with AML. Posttherapy samples from 16 of these patients demonstrated complete concordance between LOH and cytogenetics in detecting residual disease in 15 samples. Of the 16 samples, 4 showed LOH in plasma with normal BM morphology. Using X-chromosome inactivation, clonality was detectable in 19 (73%) of 26 BM samples, whereas all PB plasma samples showed clonality. These data support the conclusion that PB plasma is enriched by tumor-specific DNA and can replace BM cells for studying genomic abnormalities. (Blood. 2004;103:2799-2801)

scholarly journals Clonal patterns of X-chromosome inactivation in peripheral blood cells of female patients with chronic idiopathic neutropenia

Haematologica ◽  
2012 ◽  
Vol 97 (12) ◽  
pp. 1931-1933 ◽  
Author(s):  
S. Mastrodemou ◽  
V. Vazgiourakis ◽  
M. Velegraki ◽  
K. Pavlaki ◽  
G. N. Goulielmos ◽  
...  
Keyword(s):  
X Chromosome ◽  
Peripheral Blood ◽  
Blood Cells ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Peripheral Blood Cells ◽  
Female Patients ◽  
Chronic Idiopathic Neutropenia

scholarly journals X-chromosome inactivation patterns in females with Fabry disease examined by both ultra-deep RNA sequencing and methylation-dependent assay

2020 ◽  
Author(s):  
Rini Rossanti ◽  
Kandai Nozu ◽  
Atsushi Fukunaga ◽  
China Nagano ◽  
Tomoko Horinouchi ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Rna Sequencing ◽  
X Chromosome ◽  
Clinical Symptoms ◽  
Wide Spectrum ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Severe Phenotype ◽  
Female Patients ◽  
Pathogenic Variants

Abstract Background: Fabry disease is an X-linked inherited lysosomal storage disorder related to GLA mutations, gene encoding α-galactosidase A. In general, males has severe phenotype, while females has a wide spectrum of sign and symptoms, from asymptomatic to a more classical profile including cardiac, renal, and cerebrovascular manifestations. This variability has been assumed to be derived from organ-dependent skewed X-chromosome inactivation (XCI) patterns in each female patient. Some previous studies examined this correlation using the classical methylation-dependent method; however, conflicting results were obtained. This study was established to determine the existence of skewed XCI in nine females with heterozygous pathogenic variants in the GLA gene and its relationship to the phenotypes. Methods: We present five female patients from one family and four individual female patients with Fabry disease. In all cases, heterozygous pathogenic variants in the GLA gene were detected. The X-chromosome inactivation patterns in peripheral blood leukocytes and cells of urine sediment were determined by both classical methylation-dependent HUMARA assay and ultra-deep RNA sequencing, the latter being a method that we recently developed. Results: Among all cases, skewed XCI resulting in predominant inactivation of the normal allele was observed only in one individual case with a severe phenotype. In the other eight cases, no skewing was observed, even among cases with severe phenotypes. Conclusions: We conclude that skewed XCI could explain the severity of Fabry disease in only a limited number of female cases and is not the main factor in the onset of various clinical symptoms in females with Fabry disease.

scholarly journals Tissue specificity of X-chromosome inactivation patterns

Blood ◽  
1994 ◽  
Vol 83 (10) ◽  
pp. 2899-2905 ◽  
Author(s):  
RE Gale ◽  
H Wheadon ◽  
P Boulos ◽  
DC Linch
Keyword(s):  
X Chromosome ◽  
Peripheral Blood ◽  
Genetic Disorders ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Carrier Status ◽  
Cultured Fibroblasts ◽  
Hematopoietic Malignancies ◽  
Control Tissue ◽  
The Individual

Abstract The analysis of X-chromosome inactivation patterns has been used in a number of clinical situations such as the identification of carrier status in X-linked genetic disorders and the establishment of the monoclonal origin of tumors. Interpretation of the result obtained requires comparison with the constitutive pattern for the individual, and for hematopoietic malignancies, skin biopsies or cultured fibroblasts have often been used as the control tissue because normal cells of the same lineage as the malignancy are not generally available. However, this assumes that patterns in the different tissues are constitutionally the same. We have therefore compared X-chromosome inactivation patterns from peripheral blood (granulocytes, E- cells, and T cells), skin, and muscle from 20 hematologically normal females, and colonic mucosa from 9 individuals. In 11 patients (55%), the results obtained were similar for all tissues of an individual, but in 9 patients, significant differences were observed between tissues. The most consistent feature was a skewing in peripheral blood (> 75% expression of one allele) but not skin and/or muscle. These studies suggest that skin cannot be used as a control tissue for the interpretation of X-chromosome inactivation patterns in hematopoietic cells.

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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