Deletion of the factor IX gene as a result of translocation t(X;1) in a girl affected by haemophilia B

Krepischi, Ana Cristina Victorino; Carneiro, Jorge David Aivazoglou; Svartman, Marta; Bendit, Israel; Odone-Filho, V.; Vianna‐Morgante, Angela Maria

doi:10.1046/j.1365-2141.2001.02786.x

Cited by 11 publications

(13 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Although most affected men display symptoms, female carriers are usually asymptomatic. However, women may be symptomatic and, rarely, even express a severe or moderately severe clinical phenotype . Since the first description of severe haemophilia in a small female cohort in 1978 , others have examined the obstetrical and gynaecological manifestations of bleeding disorders including haemophilia .…”

Section: Introductionmentioning

confidence: 99%

“…However, information on clinical presentation, overall haemorrhagic diathesis, disease complications and treatment practices for female patients with severe and moderate haemophilia remains scarce and anecdotal. Current understanding of haemophilia genetics in female patients also derives exclusively from published case reports . Furthermore, data from health‐related quality of life (HR‐QoL) studies in adult and paediatric haemophilic males cannot necessarily be extrapolated to female patients, given that the experience of illness may be gender‐related .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Severe and moderate haemophilia A and B in US females

et al. 2014

View full text Add to dashboard Cite

Haemophilia A and B are rare X-lined hemorrhagic disorders that typically affect men. Women are usually asymptomatic carriers, but may be symptomatic and, rarely, also express severe (factor VIII (FVIII) or factor IX (FIX) <0.01 U mL(-1)) or moderately severe (FVIII/FIX 0.01-0.05 U mL(-1)) phenotypes. However, data on clinical manifestations, genotype and the psychosocial ramifications of illness in severely affected females remain anecdotal. A national multi-centre retrospective study was conducted to collect a comprehensive data set on affected US girls and women, and to compare clinical observations to previously published information on haemophilic males of comparable severity and mildly affected haemophilic females. Twenty-two severe/moderate haemophilia A/B subjects were characterized with respect to clinical manifestations and disease complications; genetic determinants of phenotypic severity; and health-related quality of life (HR-QoL). Clinical data were compared as previously indicated. Female patients were older than male patients at diagnosis, but similarly experienced joint haemorrhage, disease- and treatment-related complications and access to treatment. Gynaecological and obstetrical bleeding was unexpectedly infrequent. F8 or F9 mutations, accompanied by extremely skewed X-chromosome inactivation pattern (XIP), were primary determinants of severity. HR-QoL was diminished by arthropathy and viral infection. Using systematic case verification of participants in a national surveillance registry, this study elucidated the genetics, clinical phenotype and quality of life issues in female patients with severe/moderate haemophilia. An ongoing international case-controlled study will further evaluate these observations. Novel mechanistic questions are raised about the relationship between XIP and both age and tissue-specific FVIII and FIX expression.

show abstract

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Severe and moderate haemophilia A and B in US females

et al. 2014

View full text Add to dashboard Cite

show abstract

“…In the second report by Krepischi-Santos [7], the gene was transected leading to the FIX deficiency. In our case, since the normal X-chromosome is inactivated, we first ruled out a mutation in the FIX gene on the derivative 14.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been related to several other chromosomal abnormalities such as testicular feminization, or X/autosome translocations. Previous reports have described two females with clinical hemophilia due to X/autosome translocations [6,7]. The first report by Schroeder describes a girl with a translocation t(X;15) that presented with clinical bleeding and a FIX level of < 1%.…”

Section: Introductionmentioning

confidence: 99%

Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene

Paola

Goldman

Qian

et al. 2004

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Summary. Hemophilia B is an X‐linked bleeding disorder caused by the deficiency of coagulation factor (F)IX, with an estimated prevalence of 1 in 30 000 male births. It is almost exclusively seen in males with rare exceptions. We report a girl who was diagnosed with severe (<1%) FIX deficiency at 4 months of age. Cytogenetic studies in the patient showed a balanced translocation between one of the X‐chromosomes and chromosome 14, with breakpoints at bands Xq27.1 and 14q32.3. Both parents were found to have normal chromosomes. Late replication studies by incorporation of 5‐bromodeoxyuridine showed non‐random inactivation of the normal X‐chromosome, a phenomenon frequently seen in balanced X/autosome translocations. To map the breakpoint, fluorescent in‐situ hybridization was performed. A PAC DNA probe, RP6‐88D7 (which contains the FIX gene) hybridized only on the normal chromosome X as well as onto the derivative 14. Using a PAC DNA probe, RP11‐963P9 that is located proximal to the FIX gene, we obtained signals on the normal and derivative X and also on the derivative 14. We conclude that the breakpoint is located within the DNA sequence of this clone mapping proximal to the FIX gene. Since the FIX gene seems to be intact in the derivative 14, the breakpoint may affect an upstream regulatory sequence that subjects the gene to position effect variegation (PEV).

show abstract

“…However, in rare cases, a skewed X chromosome inactivation could result in a symptomatic female in whom the normal X chromosome is predominantly inactivated [7,8]. In rare instances, structural X chromosome abnormalities such as translocations, iso-X chromosomes or others also cause haemophilia B in females [9][10][11][12][13].…”

mentioning

confidence: 99%

Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B

et al. 2008

View full text Add to dashboard Cite

Female carriers of haemophilia B are usually asymptomatic; however, the disease resulting from different pathophysiological mechanisms has rarely been documented in females. In this study, we investigated the mechanisms responsible for haemophilia B in fraternal female twins. We sequenced the factor IX gene (F9) of the propositus, her father, a severe haemophilia B patient and the other family members. X chromosome inactivation was assessed by the methylation-sensitive HpaII-PCR assay using X-linked polymorphisms in human phosphoglycerate kinase 1 gene (PGK1) and glutamate receptor ionotropic AMPA 3 gene (GRIA3). The twins were found to be heterozygotes with a nonsense mutation (p.Arg384X) inherited from their father. The propositus, more severely affected twin, exhibited a significantly higher percentage of inactivation in the maternally derived X chromosome carrying a normal F9. The other twin also showed a skewed maternal X inactivation, resulting in a patient with mild haemophilia B. Thus, the degree of skewing of maternal X inactivation is closely correlated with the coagulation parameters and the clinical phenotypes of the twins. Furthermore, we identified a crossing-over in the Xq25-26 region of the maternal X chromosome of the more severely affected twin. This crossing-over was absent in the other twin, consistent with their fraternal state. Differently skewed X inactivation in the fraternal female twins might cause moderately severe and mild haemophilia B phenotypes, respectively.

show abstract

Deletion of the factor IX gene as a result of translocation t(X;1) in a girl affected by haemophilia B

Cited by 11 publications

References 15 publications

Severe and moderate haemophilia A and B in US females

Severe and moderate haemophilia A and B in US females

Breakpoint of a balanced translocation (X:14) (q27.1;q32.3) in a girl with severe hemophilia B maps proximal to the factor IX gene

Skewed X chromosome inactivation in fraternal female twins results in moderately severe and mild haemophilia B

Contact Info

Product

Resources

About