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

2021 ◽  
Author(s):  
Rini Rossanti ◽  
Kandai Nozu ◽  
Atsushi Fukunaga ◽  
China Nagano ◽  
Tomoko Horinouchi ◽  
...  
Keyword(s):  
Fabry Disease ◽  
Rna Sequencing ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

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 X Chromosome Inactivation in Carriers of Fabry Disease: Review and Meta-Analysis

2021 ◽  
Vol 22 (14) ◽  
pp. 7663
Author(s):  
Emanuela Viggiano ◽  
Luisa Politano
Keyword(s):  
Fabry Disease ◽  
X Chromosome ◽  
Cardiac Involvement ◽  
Clinical Symptoms ◽  
Meta Analysis ◽  
Corneal Dystrophy ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
The North ◽  
Kidney Involvement

Anderson-Fabry disease is an X-linked inborn error of glycosphingolipid catabolism caused by a deficiency of α-galactosidase A. The incidence ranges between 1: 40,000 and 1:117,000 of live male births. In Italy, an estimate of incidence is available only for the north-western Italy, where it is of approximately 1:4000. Clinical symptoms include angiokeratomas, corneal dystrophy, and neurological, cardiac and kidney involvement. The prevalence of symptomatic female carriers is about 70%, and in some cases, they can exhibit a severe phenotype. Previous studies suggest a correlation between skewed X chromosome inactivation and symptoms in carriers of X-linked disease, including Fabry disease. In this review, we briefly summarize the disease, focusing on the clinical symptoms of carriers and analysis of the studies so far published in regards to X chromosome inactivation pattern, and manifesting Fabry carriers. Out of 151 records identified, only five reported the correlation between the analysis of XCI in leukocytes and the related phenotype in Fabry carriers, in particular evaluating the Mainz Severity Score Index or cardiac involvement. The meta-analysis did not show any correlation between MSSI or cardiac involvement and skewed XCI, likely because the analysis of XCI in leukocytes is not useful for predicting the phenotype in Fabry carriers.

scholarly journals Female Fabry disease patients and X-chromosome inactivation

Gene ◽  
2018 ◽  
Vol 641 ◽  
pp. 259-264 ◽  
Author(s):  
Patrycja Juchniewicz ◽  
Anna Kloska ◽  
Anna Tylki-Szymańska ◽  
Joanna Jakóbkiewicz-Banecka ◽  
Grzegorz Węgrzyn ◽  
...  
Keyword(s):  
Fabry Disease ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation

X-chromosome inactivation in female patients with Fabry disease

2015 ◽  
Vol 89 (1) ◽  
pp. 44-54 ◽  
Author(s):  
L. Echevarria ◽  
K. Benistan ◽  
A. Toussaint ◽  
O. Dubourg ◽  
A.A. Hagege ◽  
...  
Keyword(s):  
Fabry Disease ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Female Patients

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

Development of ultra-deep targeted RNA sequencing for analyzing X-chromosome inactivation in female Dent disease

2018 ◽  
Vol 63 (5) ◽  
pp. 589-595 ◽  
Author(s):  
Shogo Minamikawa ◽  
Kandai Nozu ◽  
Yoshimi Nozu ◽  
Tomohiko Yamamura ◽  
Mariko Taniguchi-Ikeda ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
X Chromosome ◽  
X Chromosome Inactivation ◽  
Chromosome Inactivation ◽  
Dent Disease

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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