Factor VIII gene mutations and RFLP analysis in hemophilia A

Abstract Intrachromosomal recombinations involving F8A, in intron 22 of the factor VIII gene, and one of two homologous regions 500 kb 5′ of the factor VIII gene result in large inversions of DNA at the tip of the X chromosome. The gene is disrupted, causing severe hemophilia A. Two inversions are possible, distal and proximal, depending on which homologous region is involved in the recombination event. A simple Southern blotting technique was used to identify patients and carriers of these inversions. In a group of 85 severe hemophilia A patients, 47% had an inversion, of which 80% were of the distal type. There was no association with restriction fragment length polymorphism (RFLP) haplotypes. The technique has identified a definitive genetic marker in families previously uninformative on RFLP analysis and provided valuable information for genetic counselling information may now be provided for carriers without the need to study intervening family members and the diagnosis of severe hemophilia A made in families with only a nonspecific history of bleeding. Analysis of intron 22 inversion should now be the first-line test for carrier diagnosis and genetic counselling for severe hemophilia A and may be particularly useful when there is no affected male family member or when intervening family members are unavailable for testing.

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Factor VIII gene mutations profile in 148 Chinese hemophilia A subjects

European Journal Of Haematology ◽

10.1111/j.1600-0609.2010.01481.x ◽

2010 ◽

Vol 85 (3) ◽

pp. 264-272 ◽

Cited By ~ 13

Author(s):

Feng Xue ◽

Lei Zhang ◽

Tao Sui ◽

Jing Ge ◽

Dongsheng Gu ◽

...

Keyword(s):

Factor Viii ◽

Hemophilia A ◽

Gene Mutations ◽

Factor Viii Gene

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Analysis of intron 22 inversions of the factor VIII gene in severe hemophilia A: implications for genetic counseling

Blood ◽

10.1182/blood.v84.7.2197.bloodjournal8472197 ◽

1994 ◽

Vol 84 (7) ◽

pp. 2197-2201

Author(s):

PV Jenkins ◽

PW Collins ◽

E Goldman ◽

A McCraw ◽

A Riddell ◽

...

Keyword(s):

Factor Viii ◽

Genetic Counselling ◽

Hemophilia A ◽

Family Members ◽

Rflp Analysis ◽

Homologous Region ◽

Severe Hemophilia ◽

Factor Viii Gene ◽

Intron 22 Inversion ◽

Blotting Technique

Intrachromosomal recombinations involving F8A, in intron 22 of the factor VIII gene, and one of two homologous regions 500 kb 5′ of the factor VIII gene result in large inversions of DNA at the tip of the X chromosome. The gene is disrupted, causing severe hemophilia A. Two inversions are possible, distal and proximal, depending on which homologous region is involved in the recombination event. A simple Southern blotting technique was used to identify patients and carriers of these inversions. In a group of 85 severe hemophilia A patients, 47% had an inversion, of which 80% were of the distal type. There was no association with restriction fragment length polymorphism (RFLP) haplotypes. The technique has identified a definitive genetic marker in families previously uninformative on RFLP analysis and provided valuable information for genetic counselling information may now be provided for carriers without the need to study intervening family members and the diagnosis of severe hemophilia A made in families with only a nonspecific history of bleeding. Analysis of intron 22 inversion should now be the first-line test for carrier diagnosis and genetic counselling for severe hemophilia A and may be particularly useful when there is no affected male family member or when intervening family members are unavailable for testing.

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Polymorphisms in the IL10 but not in the IL1beta and IL4 genes are associated with inhibitor development in patients with hemophilia A

Blood ◽

10.1182/blood-2005-09-3918 ◽

2006 ◽

Vol 107 (8) ◽

pp. 3167-3172 ◽

Cited By ~ 189

Author(s):

Jan Astermark ◽

Johannes Oldenburg ◽

Anna Pavlova ◽

Erik Berntorp ◽

Ann-Kari Lefvert ◽

...

Keyword(s):

Factor Viii ◽

Promoter Region ◽

Hemophilia A ◽

Strong Association ◽

Gene Mutations ◽

Causative Factor ◽

Factor Viii Gene ◽

Ca Repeat ◽

Inhibitor Development ◽

Mild Disease

Abstract The aim of the Malmö International Brother Study (MIBS) is to evaluate host genetic factors associated with the development of inhibitory antibodies in patients with hemophilia. Factor VIII gene mutations and genetic polymorphisms of the IL1beta, IL4, and IL10 genes, known to influence antibody production in autoimmune diseases, were analyzed in 164 patients (124 with severe, 26 with moderate, and 14 with mild disease) in 78 unrelated families with hemophilia A. Seventy-seven (47%) patients in 54 families had a history of inhibitors (57 high responding, 20 low responding). Inversions were found in 36 families (75 patients). There was no association between the development of inhibitor and the IL1beta Taq I RFLP alleles in exon 5 or the –590 C/T single nucleotide polymorphism (SNP) in the promoter region of IL4. There was, however, a strong association between an allele with 134 bp in one of the CA repeat microsatellites, IL10G, located in the promoter region of the IL10 gene, and the development of inhibitor (odds ratio [OR], 4.4; 95% confidence interval [95% CI], 2.1-9.5; P < .001). The association was consistent in the subgroup of families with severe hemophilia and inversions. IL10 is the first gene located outside the causative factor VIII gene mutation to be associated with inhibitor development.

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Faculty Opinions recommendation of AAV5-Factor VIII Gene Transfer in Severe Hemophilia A.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.732279394.793544825 ◽

2018 ◽

Author(s):

Valder Arruda ◽

Ben Samelson-Jones

Keyword(s):

Gene Transfer ◽

Factor Viii ◽

Hemophilia A ◽

Severe Hemophilia ◽

Factor Viii Gene

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Molecular characterization of severe hemophilia A suggests that about half the mutations are not within the coding regions and splice junctions of the factor VIII gene.

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.88.16.7405 ◽

1991 ◽

Vol 88 (16) ◽

pp. 7405-7409 ◽

Cited By ~ 87

Author(s):

M. Higuchi ◽

H. H. Kazazian ◽

L. Kasch ◽

T. C. Warren ◽

M. J. McGinniss ◽

...

Keyword(s):

Factor Viii ◽

Molecular Characterization ◽

Hemophilia A ◽

Severe Hemophilia ◽

Factor Viii Gene ◽

Coding Regions ◽

Splice Junctions

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THE RELATIVE EFFICACY OF GENETIC ANALYSIS AND COAGULATION TESTING IN THE DIAGNOSIS OF CARRIERS OF HEMOPHILIA A

10.1055/s-0038-1644010 ◽

1987 ◽

Author(s):

D Lillicrap ◽

A R Giles ◽

J J A Holden ◽

B N White

Keyword(s):

Factor Viii ◽

Gene Deletion ◽

Hemophilia A ◽

Fragment Length Polymorphism ◽

Genetic Diagnosis ◽

Prior History ◽

Carrier Status ◽

Factor Viii Gene ◽

Coagulation Testing ◽

History Of

This study has assessed the relative benefits of restriction fragment length polymorphism (RFLP) linkage and coagulation testing in the diagnosis of carriers of hemophilia A. 221 samples from 55 families have been studied for intragenic and flanking RFLPs. All samples were tested for the Factor VIII intragenic Bell RFLP and for the flanking marker St 14. 83% of obligate carrier females were heterozygous at oneor both of these two polymorphicsites. However, only38% of these women were heterozygous at the intragenic site and might safely be offered prenatal diagnosis using this marker for the hemophilia mutation. Carrier diagnosis was obtained in 52% of 81 potential carriers tested. Diagnosis wasbased on intragenic RFLP information in only 48% of these cases. Genetic diagnosis was possible in 27 atrisk women from families with no prior history of hemophilia. Four of these women were diagnosed as carriers on the basis of a gross Factor VIII gene deletion and the remaining 23 women were identified as non-carriers by the Bell (11) and Stl4 (12) RFLP data. 39 women remained undiagnosed after gene analysis studies. 23 of these women were female relatives of sporadic hemophiliacs and thus RFLP segregation analysis was inappropriate. A further 9 potential carriers were undiagnosed because of homozygosity in key individuals in their families. In 31 potential carriers we have quantitated Factor VIII:C (one stage assay) and vWf:Ag (Laurell and ELISA) and derived probabilities for carrier status. In 3 women there was conflicting genetic and coagulation data. Meanwhile, in 12 undiagnosed women from sporadic families, carrier diagnostic probabilities of > 0.9 were obtained. These studies indicate that optimal carrier detection for hemophilia A requires more intragenic and closely linked RFLPs and the continuance of coagulation testing to assist women from sporadic families.

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