Skewed Inactivation of X Chromosome: A Cause of Hemophilia Manifestation in Carrier Females

Shoukat, Hafiz Muhammad Hassan; Ghous, Ghulam; Tarar, Zahid Ijaz; Shoukat, Muhammad Mohsin; Ajmal, Namra

doi:10.7759/cureus.11216

Cited by 15 publications

(16 citation statements)

References 20 publications

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“…This might be due to female hormones such as estrogen, which can protect females from some diseases, for example, bone loss increases dramatically in women after menopause (Streicher et al, 2017). The presence of a single X chromosome in males (rather than two in females) might also explain why males are more susceptible to genetic diseases linked to the X chromosome such as hemophilia (Shoukat et al, 2020). It is worth asking what underlying mechanisms might give rise to the increased levels of circRNAs with aging.…”

Section: Discussionmentioning

confidence: 99%

Circular RNA as a Potential Biomarker for Forensic Age Prediction

Wang

Wei

et al. 2022

Front. Genet.

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In forensic science, accurate estimation of the age of a victim or suspect can facilitate the investigators to narrow a search and aid in solving a crime. Aging is a complex process associated with various molecular regulations on DNA or RNA levels. Recent studies have shown that circular RNAs (circRNAs) upregulate globally during aging in multiple organisms such as mice and C.elegans because of their ability to resist degradation by exoribonucleases. In the current study, we attempted to investigate circRNAs’ potential capability of age prediction. Here, we identified more than 40,000 circRNAs in the blood of thirteen Chinese unrelated healthy individuals with ages of 20–62 years according to their circRNA-seq profiles. Three methods were applied to select age-related circRNA candidates including the false discovery rate, lasso regression, and support vector machine. The analysis uncovered a strong bias for circRNA upregulation during aging in human blood. A total of 28 circRNAs were chosen for further validation in 30 healthy unrelated subjects by RT-qPCR, and finally, 5 age-related circRNAs were chosen for final age prediction models using 100 samples of 19–73 years old. Several different algorithms including multivariate linear regression (MLR), regression tree, bagging regression, random forest regression (RFR), and support vector regression (SVR) were compared based on root mean square error (RMSE) and mean average error (MAE) values. Among five modeling methods, regression tree and RFR performed better than the others with MAE values of 8.767 years (S.rho = 0.6983) and 9.126 years (S.rho = 0.660), respectively. Sex effect analysis showed age prediction models significantly yielded smaller prediction MAE values for males than females (MAE = 6.133 years for males, while 10.923 years for females in the regression tree model). In the current study, we first used circRNAs as additional novel age-related biomarkers for developing forensic age estimation models. We propose that the use of circRNAs to obtain additional clues for forensic investigations and serve as aging indicators for age prediction would become a promising field of interest.

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Section: Discussionmentioning

confidence: 99%

Circular RNA as a Potential Biomarker for Forensic Age Prediction

Wang

Wei

et al. 2022

Front. Genet.

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“…In females carrying two X chromosomes, during early fetal life, one of the chromosomes will be randomly inactivated. On average, 50% of the paternal chromosome and 50% of the maternal chromosome will be inactivated in all the somatic cells [ 18 ]. Similarly, this process occurs in individuals with KS, where one of the chromosomes X will be transcriptionally inactive [ 18 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…On average, 50% of the paternal chromosome and 50% of the maternal chromosome will be inactivated in all the somatic cells [ 18 ]. Similarly, this process occurs in individuals with KS, where one of the chromosomes X will be transcriptionally inactive [ 18 , 19 ]. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested; where the cells are inactivated in mosaicism.…”

Section: Discussionmentioning

confidence: 99%

Clinical, cytogenetic, and genomic analyses of an Ecuadorian subject with Klinefelter syndrome, recessive hemophilia A, and 1;19 chromosomal translocation: a case report

et al. 2022

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Background Hemophilia A is considered one of the most common severe hereditary disorders. It is an X-linked recessive disease caused by a deficiency or lack of function of the blood clotting factor VIII. Klinefelter syndrome is a genetic disorder that affects male individuals due to one or more extra X chromosomes, present in all cells or with mosaicism. The aneuploidy is due to either mitotic or meiotic chromosome non-disjunction. Chromosomal translocations are a group of genome abnormalities in which a region or regions of a chromosome break and are transferred to a nonhomologous chromosome or a new location in the same chromosome. Case presentation Our subject was born in Ecuador at 36 weeks of gestation by vaginal delivery. At 3 months old, the Factor VIII activity measure showed a 23.7% activity indicating a diagnosis of mild hemophilia A. At 1 year old, the karyotype showed an extra X chromosome, consistent with a diagnosis of Klinefelter syndrome, and a translocation between the long arms of chromosomes 1 and 19, at positions q25 and q13, respectively. Conclusions Klinefelter syndrome and hemophilia are a rare combination. In the present case report, the subject presents both, meaning that he has inherited one X chromosome from the father and one X chromosome from the mother. Since the father has severe hemophilia A; and the subject presents a below 40% Factor VIII activity, a skewed X inactivation is suggested. Additionally, the proband presents a translocation with the karyotype 47,XXY,t(1;19)(q25;q13). No similar report with phenotypic consequences of the translocation was found. The present report highlights the importance of a correct diagnosis, based not only on the clinical manifestations of a disease but also on its genetic aspects, identifying the value of integrated diagnostics. The subject presents three different genetic alterations, Klinefelter syndrome, hemophilia A, and a 1;19 chromosomal translocation.

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“…However, this is far from the truth. Some women who carry the genetic mutation may, because of compound heterozygosity, incomplete X chromosomal inactivation or skewed lyonization, have factor levels commensurate with men with a diagnosis of haemophilia [12] . Miller and Bean [10] report that there are thought to be 250 women worldwide with factor levels in the severe to moderate range, though the true figure may be even higher, with many cases going unreported.…”

Section: Case Study Simon Fletchermentioning

confidence: 99%

“I didn’t know women could have haemophilia”: A qualitative case study

Fletcher

2022

The Journal of Haemophilia Practice

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Introduction There is a historic but persistent belief in haemophilia care that women do not suffer with the condition, they merely carry and transmit it. However, around 250 women worldwide are known to have factor levels within the severe to moderate haemophilia range (<1 IU/dL to 5 IU/dL), and the true figure may be greater than this. The experience of these women may be the same as or similar to those of men with similar factor levels, but there may be significant differences. What these differences are and what they mean to the women affected are not well understood as their voices are not heard. This case study highlights the issues and experiences of one woman living severe haemophilia. Methods A single semi-structured qualitative interview was undertaken to explore the experiences of a young woman who has factor VIII levels of <1 IU/dL. The interview was recorded, transcribed and thematically analysed. Results Four interlinked themes were identified: recognition, self-advocacy, identity and access to treatment. Conclusion This case study indicates that, despite recent attempts to improve the diagnostic nomenclature, women and girls with haemophilia continue to find it difficult to access similar levels of care to men and boys. As such, they may fail to achieve parity in terms of safety, integrity and wellbeing, and have a reduced quality of life. If women and girls affected by haemophilia are to receive levels of treatment comparable to men, diagnostic criteria need to change further. Focusing on genotype, levels of factor expressed and phenotypical presentation rather than biological sex will acknowledge and validate their experiences, and improve treatment for all people with haemophilia in the future.

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Skewed Inactivation of X Chromosome: A Cause of Hemophilia Manifestation in Carrier Females

Cited by 15 publications

References 20 publications

Circular RNA as a Potential Biomarker for Forensic Age Prediction

Circular RNA as a Potential Biomarker for Forensic Age Prediction

Clinical, cytogenetic, and genomic analyses of an Ecuadorian subject with Klinefelter syndrome, recessive hemophilia A, and 1;19 chromosomal translocation: a case report

“I didn’t know women could have haemophilia”: A qualitative case study

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