X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers

Garagiola, Isabella; Mortarino, Mimosa; Siboni, Simona Maria; Boscarino, Marco; Mancuso, Maria Elisa; Biganzoli, Marina; Santagostino, Elena; Peyvandi, Flora

doi:10.1038/s41431-020-00742-4

Cited by 30 publications

(30 citation statements)

References 53 publications

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“…Variability in factor levels among HCs is poorly understood and more research is needed to find out whether there is a relationship between the type of gene mutation and plasma FVIII/IX level in HCs 13 . Rarely, a woman may inherit an affected X chromosome from both parents, leading to full expression of the hemophilia variant’s severity, or exhibit moderate/severe hemophilia due to an extremely skewed X chromosome inactivation pattern 14,15 . In addition, approximately one in four HCs with normal FVIII/IX levels >0.50 IU/ml have an increased bleeding tendency 16–18 .…”

Section: Background and Rationalementioning

confidence: 99%

“… 13 Rarely, a woman may inherit an affected X chromosome from both parents, leading to full expression of the hemophilia variant’s severity, or exhibit moderate/severe hemophilia due to an extremely skewed X chromosome inactivation pattern. 14 , 15 In addition, approximately one in four HCs with normal FVIII/IX levels >0.50 IU/ml have an increased bleeding tendency. 16 , 17 , 18 In hemophilia A carriers this may in part be due to an impaired FVIII response to hemostatic stress.…”

Section: Background and Rationalementioning

confidence: 99%

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A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH

Galen

d’Oiron

James

et al. 2021

Journal of Thrombosis and Haemostasis

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Hemophilia A and B predominantly attracts clinical attention in males due to X‐linked inheritance, introducing a bias toward female carriers to be asymptomatic. This common misconception is contradicted by an increasing body of evidence with consistent reporting on an increased bleeding tendency in hemophilia carriers (HCs), including those with normal factor VIII/IX (FVIII/IX) levels. The term HC can hamper diagnosis, clinical care, and research. Therefore, a new nomenclature has been defined based on an open iterative process involving hemophilia experts, patients, and the International Society on Thrombosis and Haemostasis (ISTH) community. The resulting nomenclature accounts for personal bleeding history and baseline plasma FVIII/IX level. It distinguishes five clinically relevant HC categories: women/girls with mild, moderate, or severe hemophilia (FVIII/IX >0.05 and <0.40 IU/ml, 0.01–0.05 IU/ml, and <0.01 IU/ml, respectively), symptomatic and asymptomatic HC (FVIII/IX ≥0.40 IU/ml with and without a bleeding phenotype, respectively). This new nomenclature is aimed at improving diagnosis and management and applying uniform terminologies for clinical research.

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Section: Background and Rationalementioning

confidence: 99%

Section: Background and Rationalementioning

confidence: 99%

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH

Galen

d’Oiron

James

et al. 2021

Journal of Thrombosis and Haemostasis

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“…Garagiola et al [29] have recently reported that low FVIII activity in HA carriers is associated with skewed XCI. Of note, analysis of XCI patterns in our cohort of HA carriers at the Israeli National Hemophilia Center revealed no evidence of significant correlation between XCI patterns and FVIII levels (data not shown), which is in agreement with the lack of correlation between XCI patterns and FVIII levels in HA carriers reported by Orstavik [30].…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

Dardik

Avishai

Lalezari

et al. 2021

IJMS

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Introduction: Hemophilia A (HA) is an X-linked bleeding disorder caused by factor VIII (FVIII) deficiency or dysfunction due to F8 gene mutations. HA carriers are usually asymptomatic because their FVIII levels correspond to approximately half of the concentration found in healthy individuals. However, in rare cases, a carrier may exhibit symptoms of moderate to severe HA primarily due to skewed inactivation of her non-hemophilic X chromosome. Aim: The aim of the study was to investigate X-chromosome inactivation (XCI) patterns in HA carriers, with special emphasis on three karyotypically normal HA carriers presenting with moderate to severe HA phenotype due to skewed XCI, in an attempt to elucidate the molecular mechanism underlying skewed XCI in these symptomatic HA carriers. The study was based on the hypothesis that the presence of a pathogenic mutation on the non-hemophilic X chromosome is the cause of extreme inactivation of that X chromosome. Methods: XCI patterns were studied by PCR analysis of the CAG repeat region in the HUMARA gene. HA carriers that demonstrated skewed XCI were further studied by whole-exome sequencing (WES) followed by X chromosome-targeted bioinformatic analysis. Results: All three HA carriers presenting with the moderate to severe HA phenotype due to skewed XCI were found to carry pathogenic mutations on their non-hemophilic X chromosomes. Patient 1 was diagnosed with a frameshift mutation in the PGK1 gene that was associated with familial XCI skewing in three generations. Patient 2 was diagnosed with a missense mutation in the SYTL4 gene that was associated with familial XCI skewing in two generations. Patient 3 was diagnosed with a nonsense mutation in the NKAP gene that was associated with familial XCI skewing in two generations. Conclusion: Our results indicate that the main reason for skewed XCI in our female HA patients was negative selection against cells with a disadvantage caused by an additional deleterious mutation on the silenced X chromosome, thus complicating the phenotype of a monogenic X-linked disease. Based on our study, we are currently offering the X inactivation test to symptomatic hemophilia carriers and plan to expand this approach to symptomatic carriers of other X-linked diseases, which can be further used in pregnancy planning.

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“…Clinical symptoms in carriers of X-linked diseases depend on the levels of the main protein in the affected tissues. Several mechanisms have been hypothesized such as gene mutation on both alleles [ 100 ], loss of one X chromosome as in Turner’s Syndrome [ 101 , 102 ], uniparental disomy [ 103 ] or skewed X chromosome inactivation (XCI), with preferential inactivation of the X chromosome carrying the normal allele [ 92 , 104 , 105 , 106 , 107 , 108 , 109 , 110 ].…”

Section: Skewed X-chromosome Inactivationmentioning

confidence: 99%

“…Previous studies have shown the correlation between skewed XCI and phenotype in carriers of X-linked diseases, such as Duchenne and Becker muscular dystrophies [ 104 , 106 , 107 , 108 ], EDMD1 or myotubular myopathy [ 124 ], haemophilia B [ 125 , 126 ], dyskeratosis congenita [ 127 ], retinitis pigmentosa [ 128 ], Lesch-Nyhan disease, haemophilia A [ 110 , 125 ], Rett-syndrome and others. In fact, skewed XCI, resulted in a higher percentage of mutant cells than normal cells and could lead to clinical symptoms in X-linked disease ( Figure 2 ).…”

Section: Skewed X-chromosome Inactivationmentioning

confidence: 99%

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

Viggiano

Politano

2021

IJMS

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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.

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X Chromosome inactivation: a modifier of factor VIII and IX plasma levels and bleeding phenotype in Haemophilia carriers

Cited by 30 publications

References 53 publications

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH

A new hemophilia carrier nomenclature to define hemophilia in women and girls: Communication from the SSC of the ISTH

Molecular Mechanisms of Skewed X-Chromosome Inactivation in Female Hemophilia Patients—Lessons from Wide Genome Analyses

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

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