Moderate X‐chromosome inactivation skewing underlies factor <scp>VIII</scp> activity in symptomatic carriers from a family with mild haemophilia A

Cygan, Peter H.; Carrel, Laura; Eyster, M. Elaine

doi:10.1111/hae.13083

Cited by 5 publications

(7 citation statements)

References 15 publications

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“…Therefore, phenotypic severity of F8 mutations is modulated by XCI in hemophilia A carriers (Fig. 2), such that individuals with extremely skewed XCI can have baseline FVIII levels and bleeding phenotype equivalent to a male with the same F8 mutation, or the opposite condition in which FVIII levels are well within the normal range and bleeding is absent because of essentially complete inactivation of the X with the F8 mutation [39][40][41][42][43][44]. Relationship between baseline factor VIII levels and bleeding symptoms (top) with X chromosome inactivation skewing (bottom) in hemophilia A carriers.…”

Section: Molecular Mechanisms Causing Factor VIII Deficiency In Femal...mentioning

confidence: 99%

Regulation and importance of factor VIII levels in hemophilia A carriers

Cygan

Kouides

2021

Current Opinion in Hematology

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Purpose of review To summarize the recent literature related to female hemophilia A carriers with respect to prevalence in the population, the impact of baseline factor VIII levels and other influences on bleeding phenotype, and clinical management needs. Recent findings Many female hemophilia A carriers are at risk for abnormal bleeding, yet they are underrecognized by healthcare providers and their bleeding symptoms are underreported. Low FVIII levels are consistently associated with clinically significant bleeding and correlate well with skewed X chromosome inactivation (XCI). Most interestingly, bleeding tendency is also observed in some hemophilia A carriers with normal factor VIII levels and requires further investigation. Well controlled studies investigating peripartum and periprocedural FVIII levels and adequate hemostatic treatment are necessary to inform management guidelines. Summary Prevalence and bleeding tendency of hemophilia A carriers remain underreported, despite a significant proportion having low FVIII levels. Skewed XCI may explain low FVIII but does not explain the bleeding risk encountered in a larger proportion of hemophilia A carriers with random XCI and borderline/normal FVIII.

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Section: Molecular Mechanisms Causing Factor VIII Deficiency In Femal...mentioning

confidence: 99%

Regulation and importance of factor VIII levels in hemophilia A carriers

Cygan

Kouides

2021

Current Opinion in Hematology

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“…8,9 Skewed XCI resulting in females with mild to severe hemophilia has been documented in several studies since then. 5,[10][11][12][13][14] Increased research and advocacy have significantly improved the recognition of females with bleeding disorders, including recently revised nomenclature for hemophilia diagnosis in this group by the International Society of Thrombosis and Haemostasis. 15 Given the phenomenon of skewed XCI, consideration of hemophilia in the diagnostic evaluation for a bleeding diathesis is essential in both females and males.…”

Section: Discussionmentioning

confidence: 99%

“…Skewed XCI, also referred to as lyonization, was first described by Mary F. Lyon 8,9 . Skewed XCI resulting in females with mild to severe hemophilia has been documented in several studies since then 5,10–14 . Increased research and advocacy have significantly improved the recognition of females with bleeding disorders, including recently revised nomenclature for hemophilia diagnosis in this group by the International Society of Thrombosis and Haemostasis 15 .…”

Section: Discussionmentioning

confidence: 99%

The impact of concurrent X chromosome anomalies on diagnosis and bleeding phenotype in children with hemophilia: A single‐institution case series

Soffer

Coleman

Batsuli

2023

Pediatric Blood & Cancer

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Hemophilia is an inherited X‐linked bleeding disorder characterized by deficiencies of factors VIII or IX. Concomitant X chromosome disorders can impact bleeding phenotype, complicating timely diagnosis and disease management. Herein, we describe three cases of female and male pediatric patients with hemophilia A or B diagnosed between 6 days and 4 years old in the setting of skewed X chromosome inactivation, Turner syndrome, or Klinefelter syndrome. All of these cases had significant bleeding symptoms, and two patients required initiation of factor replacement therapy. One female patient developed a factor VIII inhibitor similar to that described in males with hemophilia A.

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“…The methylated one corresponding to the X‐inactive region was amplified through PCR (Mundo‐Ayala & Jaloma‐Cruz, 2008). Fluorescent fragments were solved by capillary electrophoresis and analyzed by GeneScan (ThermoFisher Scientific) (Cygan, Carrel, & Eyster, 2016). XIST is needed for the X‐inactivation process, so C43G and C43A transversions (Plenge et al, 1997; Tomkins, McDonald, Farrell, & Brown, 2002), were analyzed.…”

Section: Methodsmentioning

confidence: 99%

“…We integrated a questionnaire using the guidelines of the World Federation of Hemophilia for the management of SCs (Mauser-Bunschoten, 2009). This evaluation must be updated by a bleeding assessment tool, which consider factor quantitation and other aspects in all cases (Cygan et al, 2016).…”

Section: Genetic Analysis In Symptomatic Ha and Hb Carriersmentioning

confidence: 99%

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

González-Ramos¹,

Mantilla-Capacho²,

Luna-Záizar

et al. 2020

American J of Med Genetics Pt C

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Our 25 years of experience in carrier diagnosis of hemophilia A (HA) and B (HB) in Mexican population comprises linkage analysis of intragenic F8/F9 neutral variants along with, in severe HA (SHA), detection of F8 int22h and int1h inversions. In symptomatic carriers (SCs) we explored Lyonization to explain their symtomatology. From a DNA-Bank of 3,000 samples, intragenic restriction fragment length (RFLPs) and short tandem repeats (STRs) of F8/F9 genes were assessed by PCR-PAGE and GeneScan. In SHA patients, F8 inversions were detected by inverse shifting-PCR/ diagnostic and complementary tests. In SCs, we evaluated hemorrhagic symptoms, clotting FVIII/FIX and X-chromosome inactivation (XCI) patterns were assessed by HUMARA assay and the search of XIST promoter pathogenic variants. Informativeness of linkage analysis for HA carrier diagnosis with RFLP's/STR's increased to 74% and reached 80% with five RFLPs for HB. Combined Inv22/Inv1 diagnosed 113 possible carriers, three de novo Inv22-1, and confirmed 45 mothers as obligate or sporadic carriers. Among 21 SCs, four showed extreme skewed XCI pattern (80:20) but had normal karyotype and no C43G pathogenic variant in XIST promoter. Clotting FVIII/ FIX correlated with the active X in leukocytes. Our data integrate the largest comprehensive research worldwide on the molecular diagnosis of HA and HB carriers in terms of the number of studied and diagnosed cases, in addition to the genetic analysis in SCs. Intragenic RFLPs and STRs of F8/F9 genes along with F8 int22h/int1h inversions in SHA emerge as optimal variants for molecular diagnosis in Mexican population. In counseling SCs, inheritance of skewed X-inactivation should be considered.

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Moderate X‐chromosome inactivation skewing underlies factor VIII activity in symptomatic carriers from a family with mild haemophilia A

Cited by 5 publications

References 15 publications

Regulation and importance of factor VIII levels in hemophilia A carriers

Regulation and importance of factor VIII levels in hemophilia A carriers

The impact of concurrent X chromosome anomalies on diagnosis and bleeding phenotype in children with hemophilia: A single‐institution case series

Genetic analysis for carrier diagnosis in hemophilia A and B in the Mexican population: 25 years of experience

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