Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

Castaman, Giancarlo; Giacomelli, S. H.; Ghiotto, R.; Boseggia, C.; Pojani, K.; Bulo, Anyla; Madeo, Domenico; Rodeghiero, Francesco

doi:10.1111/j.1365-2516.2007.01459.x

Cited by 16 publications

(14 citation statements)

References 14 publications

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“…2). 29 This large degree of allelic heterogeneity is similar to what has been observed in previous cross-sectional studies to identify the mutational spectrums in patients from other racial groups 42-44,46,47. Furthermore, among the 70 patients with identified F8 mutations, no difference was observed between the H1+H2 and the H3+H4 haplotype comparison groups in the proportion of patients with higher-risk or lower-risk types of mutation (P = 0.27) (Table 1).…”

Section: Resultssupporting

confidence: 84%

Inhibitors of Factor VIII in Black Patients with Hemophilia

et al. 2009

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Background Black patients with hemophilia A (factor VIII deficiency) are twice as likely as white patients to produce inhibitors against factor VIII proteins given as replacement therapy. There are six wild-type factor VIII proteins, designated H1 through H6, but only two (H1 and H2) match the recombinant factor VIII products used clinically. H1 and H2 are found in all racial groups and are the only factor VIII proteins found in the white population to date. H3, H4, and H5 have been found only in blacks. We hypothesized that mismatched factor VIII transfusions contribute to the high incidence of inhibitors among black patients. Methods We sequenced the factor VIII gene (F8) in black patients with hemophilia A to identify causative mutations and the background haplotypes on which they reside. Results from previous Bethesda assays and information on the baseline severity of hemophilia, age at enrollment, and biologic relationships among study patients were obtained from review of the patients' medical charts. We used multivariable logistic regression to control for these potential confounders while testing for associations between F8 haplotype and the development of inhibitors. Results Of the 78 black patients with hemophilia enrolled, 24% had an H3 or H4 background haplotype. The prevalence of inhibitors was higher among patients with either of these haplotypes than among patients with haplotype H1 or H2 (odds ratio, 3.6; 95% confidence interval, 1.1 to 12.3; P = 0.04), despite a similar spectrum of hemophilic mutations and degree of severity of illness in these two subgroups. Conclusions These preliminary results suggest that mismatched factor VIII replacement therapy may be a risk factor for the development of anti–factor VIII alloantibodies.

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Section: Resultssupporting

confidence: 84%

Inhibitors of Factor VIII in Black Patients with Hemophilia

et al. 2009

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“…We detected 25 different mutations as causative for sHA, with the F8 intron 22 inversion as the most common mutation (41%), which is consistent with other reports that show that this inversion affects approximately 40–50% of the cases [7,12,21–25]. The intron 1 inversion frequency varies between populations, ranging from 0% to 5% in patients with sHA [5,12,22,23,25–27]. In our study, we did not detect this mutation, which is in agreement with some of the above studies [23,26,27].…”

Section: Discussionsupporting

confidence: 93%

“…The intron 1 inversion frequency varies between populations, ranging from 0% to 5% in patients with sHA [5,12,22,23,25–27]. In our study, we did not detect this mutation, which is in agreement with some of the above studies [23,26,27].…”

Section: Discussionsupporting

confidence: 92%

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

et al. 2011

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Haemophilia A is caused by mutations in the gene encoding coagulation factor VIII (FVIII). In severe Haemophilia A (sHA), two inversions are responsible for approximately 50% of the genetic alterations (intron 22 and intron 1 inversions). The other mutations are extremely diverse and each affected family generally has its own mutation. Our aim was to detect the genetic alterations present in the FVIII gene (F8) in 54 unrelated male patients with sHA in Venezuela. We initially detected the presence of the intron 22 inversion by performing inverse PCR, and the negative patients for this inversion were analysed for the intron 1 inversion by PCR. Patients negative for both inversions were analysed using Conformation Sensitive Gel Electrophoresis for mutations in all exons, promoter region and 3¢-UTR. sHA causative mutations were identified in 49 patients. Intron-22 and -1 inversions were detected in 41% and 0% of patients respectively. Besides these two mutations, 25 different mutations were identified, including nine nonsense, four small deletions, two small insertions, four missense, three splicing mutations and three large deletions. Seven novel mutations were identified, including two nonsense mutations, two small deletions, one small insertion, one missense mutation and one splicing mutation. Thirty one percent of the patients with identified mutations developed inhibitors against exogenous FVIII. This is the first report of F8 mutations in patients with sHA in Venezuela; the data from this study suggests that the spectrum of gene defects found in these patients is as heterogeneous as reported previously for other populations.

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“…In the present study, we did not evaluate the inhibitor prevalence and FVIII antigen level. For the same reason in other developing countries, like Indian [17] and Albanian [18], the prevalence of inhibitor could be lower than that in developed countries due to the minimal administration of FVIII concentrates of haemophilia patients in China.…”

Section: Discussionmentioning

confidence: 99%

The status of carrier and prenatal diagnosis of haemophilia in China

Dai

Ding

et al. 2011

Haemophilia

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Haemophilia A (HA) and haemophilia B (HB) are the most common X-linked inherited bleeding disorders. It is important to detect the carrier women in families with HA/HB and subsequent antenatal diagnosis of confirmed carriers. This study consists of 102 HA families which include 68 mothers for prenatal diagnosis and 107 female relatives for carrier diagnosis, and 29 HB families which include 16 mothers and 31 female relatives respectively. The rapid fluorescent PCR with two groups of different combined polymorphism markers was applied for linkage analysis in HA and HB families respectively. The Amelogenin gene was added to help the detection of gender diagnosis. Gene sequencing was also used to detect the mutations directly. There were 37 causative F8C mutations (23 novel) and 24 causative F9C mutations (eight novel) found in this cohort of patients. Few of the women could not be diagnosed due to homologous recombination and/or inability to locate the mutation. Complicated cases have been found in some families. With regard to carrier and prenatal diagnosis, it was considered that genetic diagnosis by linkage analysis and direct sequencing was successful. Some special families might require combination of the linkage analysis and gene sequence for a successful diagnosis. New intragenic SNP and STR sites special to Chinese population need to be discovered.

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Spectrum of mutations in Albanian patients with haemophilia A: identification of ten novel mutations in the factor VIII gene

Cited by 16 publications

References 14 publications

Inhibitors of Factor VIII in Black Patients with Hemophilia

Inhibitors of Factor VIII in Black Patients with Hemophilia

Identification of factor VIII gene mutations in patients with severe haemophilia A in Venezuela: identification of seven novel mutations

The status of carrier and prenatal diagnosis of haemophilia in China

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