The molecular analysis of haemophilia A: a guideline from the UK haemophilia centre doctors’ organization haemophilia genetics laboratory network

Mitchell, Mike; Keeney, S.; Goodeve, Anne

doi:10.1111/j.1365-2516.2005.01111.x

Cited by 70 publications

(48 citation statements)

References 45 publications

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“…Haplotype analysis of three markers among 86 normal Iranian women showed strong linkage disequilibrium between the polymorphisms as reported previously in other populations [11,[14][15][16]. The strong linkage disequilibrium, which presents between particular alleles of FVIII gene markers, is deemed to be due to a high turnover of hemophilia A severe mutations because approximately one third of the causative mutations of severe hemophilia A are lost per generation [21].…”

Section: Discussionsupporting

confidence: 61%

Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection

2006

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Hemophilia A is an X-linked recessive bleeding disorder caused by a quantitative or qualitative deficiency of blood coagulation factor VIII (FVIII). ARMS (amplification refractory mutation system) primers were designed to determine allele frequencies of three FVIII gene linked markers, IVS7 nt 27 G/A SNP, BclI/intron 18, and HindIII/intron 19 among 85 normal Iranian women from unrelated families. Then same method was applied to perform carrier detection for hemophilia A families. The allele frequencies of IVS7 nt 27 ''G''/''A'' allele, BclI ''T''/''A'' allele, and HindIII ''C''/''T'' allele among normal women were 0.88/0.12, 0.52/0.48, and 0.48/0.52, respectively. The three polymorphisms were found to be in strong linkage disequilibrium, which decreased the overall heterozygosity to 51%. Twenty-one women from 15 unrelated hemophilia A families were referred to us for hemophilia A carrier detection. Taking advantage of these three biallelic polymorphisms in conjunction with multiallelic St14 VNTR (locus DXS52), IVS13 (CA)n STR, and IVS22 (CA)n STR, carrier status was determined in 16 women (16/21 or 76% of the at-risk women) from 11 families (11/15 or 73% of the families). The used ARMS methods are rapid and can easily be applied in conjunction with other

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Section: Discussionsupporting

confidence: 61%

Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection

2006

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“…In these cases, F8 intrachromosomal inversions may be sought and DNA sequence analysis or mutation scanning of F8 exons 1–26 undertaken. 73–74 In females, dosage analysis using MLPA can also be used to identify heterozygous partial or complete gene deletions or duplications. 75–76 F8 mutations may be detected in >50% of cases referred for “possible 2N VWD or hemophilia A”.…”

Section: Differential Diagnosismentioning

confidence: 99%

von Willebrand disease

James

Goodeve

2011

Genetics in Medicine

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von Willebrand disease (VWD) is a common inherited bleeding disorder characterized by excessive mucocutaneous bleeding. Characteristic bleeding symptoms include epistaxis, easy bruising, oral cavity bleeding, menorrhagia, bleeding after dental extraction, surgery and/or childbirth and in severe cases, bleeding into joints and soft tissues. There are three subtypes: types 1 and 3 represent quantitative variants and type 2 is a group of four qualitative variants: 1) type 2A - characterized by defective von Willebrand factor (VWF) -dependent platelet adhesion because of decreased high molecular weight (HMW) VWF multimers, 2) type 2B - caused by pathologically increased VWF-platelet interactions, 3) type 2M - caused by decreased VWF-platelet interactions not based on the loss of HMW multimers and 4) type 2N - characterized by abnormal binding of VWF to FVIII. The diagnosis of VWD requires specialized assays of von Willebrand factor (VWF) and/or molecular genetic testing of VWF. Severe bleeding episodes can be prevented or controlled with intravenous infusions of virally-inactivated plasma-derived clotting factor concentrates containing both VWF and FVIII. Depending on the VWD type, mild bleeding episodes usually respond to intravenous or subcutaneous treatment with desmopressin, a vasopressin analog. Other treatments that can reduce symptoms include fibrinolytic inhibitors and hormones for menorrhagia.

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“…Genomic DNA was obtained from EDTA-anticoagulated blood from the patient. Inversions in introns 1 and 22 were first screened using long-distance PCR (13). All exons and their flanking regions of F8 were amplified by PCR using specific primers, as described previously (14).…”

Section: Case Reportmentioning

confidence: 99%

Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile

Qiao

Ren

et al. 2013

Molecular Medicine Reports

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Hemophilia A (HA) in females is rare. Female HA cases are often misdiagnosed as acquired HA (AHA) or as von Willebrand disease type 2N (vWD-2N). Here, we report the case of a 37-year-old female HA patient with a moderate factor VIII (FVIII) deficiency. The patient had no personal or family history of bleeding disorders, but presented with heavy uterine bleeding following surgery to remove an intrauterine device. IgG inhibitory antibodies against FVIII were undetected. A compound heterozygote mutation of the FVIII gene (F8) was found in this patient. The p.Val502Asp mutation, which has been reported previously, affects A2 domain function. A novel missense point mutation, p.Met1093Ile, was identified in the B domain. The compound heterozygote mutations in F8, p.Val502Asp and p.Met1093Ile, caused HA in this female patient, with a moderate phenotype.

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The molecular analysis of haemophilia A: a guideline from the UK haemophilia centre doctors’ organization haemophilia genetics laboratory network

Cited by 70 publications

References 45 publications

Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection

Allele frequencies of three factor VIII gene polymorphisms in Iranian populations and their application in hemophilia A carrier detection

von Willebrand disease

Compound heterozygous hemophilia A in a female patient and the identification of a novel missense mutation, p.Met1093Ile

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