Alternative titles; symbols
SNOMEDCT: 37193007; ICD10CM: D68.2; ORPHA: 327; DO: 2215;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 13q34 | Factor VII deficiency | 227500 | Autosomal recessive | 3 | F7 | 613878 |
A number sign (#) is used with this entry because factor VII deficiency is caused by homozygous or compound heterozygous mutation in the gene encoding coagulation factor-7 (F7; 613878) on chromosome 13q34.
Factor VII deficiency is an autosomal recessive bleeding disorder showing variable severity (summary by Millar et al., 2000).
Perry (2002) provided a comprehensive review of factor VII deficiency with a description of F7 polymorphisms, gene structure, and a summary of 120 mutations.
Arbini et al. (1996) reported a 36-year-old Italian woman with severe factor VII deficiency. She had recurrent epistaxis, easy bruisability, menorrhagia, hemarthrosis of the right knee, and major bleeding after dental extraction. Laboratory studies showed less than 1% of factor VII antigen levels and activity. A brother of the patient died at age 7 with uncontrolled epistaxis.
McVey et al. (1998) reported infant brother and sister, born of consanguineous parents, who died at 10 days and 1 month of age, respectively, of intracranial hemorrhage related to severe factor VII deficiency. In this family, complete factor VII deficiency was associated with a severe bleeding diathesis but no developmental abnormalities, suggesting that fetal factor VII is not required for the putative angiogenic functions of tissue factor (F3; 134390) in humans.
Au et al. (2000) reported a 55-year-old Chinese woman with factor VII deficiency who presented with hemoptysis and right shoulder pain and was found to have right shoulder arthritis consistent with chronic hemophilic arthropathy. She had had 3 uncomplicated vaginal deliveries and reported no history of abnormal bleeding. However, her 2 younger brothers allegedly died of bleeding, one at birth and the other at 9 months of age. Genetic analysis revealed compound heterozygous mutations in the F7 gene (613878.0018 and 613878.0019).
McVey et al. (2001) noted that complete absence of factor VII in plasma is usually incompatible with life, and individuals die shortly after birth due to severe hemorrhage. Most individuals with mutations in the F7 gene, however, are either asymptomatic or the clinical phenotype is unknown. In general, a severe bleeding phenotype is observed only in individuals homozygous for a mutation in their F7 genes, with activities of the protein below 2% of normal, although a considerable proportion of individuals with a mild-moderate bleeding phenotype have similarly low values by in vitro assay.
Takamiya and Hino (2004) reported a Japanese woman with occasional epistaxis as the only manifestation of factor VII deficiency. Laboratory studies showed that factor VII antigen and coagulant activity were reduced to 7.3% and 5%, respectively, of controls. Genetic analysis identified a homozygous missense mutation in the F7 gene (G354C; 613878.0023)
Recessive inheritance of factor VII deficiency was established by the demonstration of lower than normal levels of factor VII in both parents of an affected child (Kupfer et al., 1960).
Prenatal Diagnosis
Giansily-Blaizot et al. (2001) achieved prenatal diagnosis of severe factor VII deficiency using mutation detection and linkage analysis. The authors stated that the propositus, a 2-year-old girl, presented with soft tissue hematoma during the early days of life and intracranial hemorrhage before 2 months of age. Both parents were asymptomatic but showed reduced factor VII levels. The child was a compound heterozygote for 2 mutations in the F7 gene: a splicing mutation derived from the mother and a missense mutation derived from the father. Both parents were heterozygous for a polymorphism in intron 7 of the F7 gene, a variable number of a 37-bp monomer repeat (VNTR), with the corresponding H6 and H7 alleles depending on a 6- or a 7-repeat content (Marchetti et al., 1992). In both parents the H6 allele was associated with the mutation. At 14 weeks of a subsequent pregnancy, prenatal diagnosis was performed using amniocentesis. The fetus was homozygous for both the wildtype F7 allele and the H7 allele of intron 7. The newborn was clinically normal and the FVIIC level, determined at 6 months of age, was 71%.
Pfeiffer et al. (1982) presented evidence suggesting that factors VII and X (F10; 613872) may be located on chromosome 13q34. They found deficiency of the 2 factors in 2 cases with 46,XY,t(13;Y)(q11;q34), including probable deletion of a terminal segment of 13q. A prolonged prothrombin time was found before surgery in the first case, leading to studies of coagulation; neither patient had clinical abnormality of coagulation. In 1 case, factor VII was measured as 42%, 40%, and 45% and factor X as 59%, 44%, and 60% of normal, in 2 different laboratories; in the second case, factor VII was 55% and 54% of normal and factor X was 25% and 62%. These values were normal in all 4 parents.
Fukushima et al. (1987) investigated factors VII and X in 3 patients with terminal deletions of 13q, a patient with complete trisomy 13, and a patient with a balanced X;13 translocation. Two of the 3 patients with deletion showed about 50% deficiency of the 2 factors. Levels were normal in the trisomy and the translocation patients.
Girolami et al. (1977) observed a qualitatively abnormal factor VII, termed Verona, associated with factor VII deficiency.
In an Italian woman with severe factor VII deficiency, Arbini et al. (1996) identified compound heterozygosity for 2 mutations in the F7 gene (613878.0005 and 613878.0008).
Cooper et al. (1997) reviewed structure-function studies of factor VII based on the analysis of naturally occurring variants, including polymorphisms and the mutations underlying factor VII deficiency. They tabulated 30 different single basepair substitutions and 4 short deletions. Most of the reported lesions responsible for factor VII deficiency had been noted only once. Notable exceptions included the ala244-to-val mutation (A244V; 613878.0006) found in 23 homozygous and 10 heterozygous individuals of Moroccan/Iranian Jewish origin by Tamary et al. (1996).
In 2 infant sibs, born of consanguineous parents, with severe factor VII deficiency resulting in early death due to intracranial bleeding, McVey et al. (1998) identified a homozygous splice site mutation in the F7 gene (613878.0008).
Wulff and Herrmann (2000) performed a mutation screen in 87 unrelated probands with reduced or low factor VII activities. Among 101 F7 alleles of 77 probands, 34 different lesions were found; 22 of these were novel. The 34 different lesions comprised 31 point mutations and 3 small deletions. A transition in the CpG doublet accounted for 12 of the 34 different mutants. Sixteen mutations were noted only once. By far the most common mutations found in this study in Germany were the missense mutation A294V (613878.0010) and the double mutation A294V/11128delC (613878.0012). These mutations are located in exon 8 at the carboxy-terminal end of the gene, where the largest number of mutations causing factor VII deficiency are concentrated. Both mutations are also prevalent in Polish and Italian patients (Arbini et al., 1994; Bernardi et al., 1994), indicating that they represent the most frequent F7 mutations in European populations. Family studies showed the same haplotype for both mutations.
Millar et al. (2000) sequenced the F7 gene in 48 unrelated individuals with factor VII deficiency, yielding a total of 23 novel lesions including 15 missense mutations, 2 microdeletions, 5 splice junction mutations, and a single basepair substitution in the 5-prime untranslated region.
McVey et al. (2001) described a mutation database in which mutations in the F7 gene of 238 individuals described in the world literature are recorded. Several polymorphisms have been identified in the F7 gene and some have been shown to influence plasma factor VII antigen levels.
Shen et al. (2001) identified 4 novel mutations in the F7 gene in Taiwanese.
Using a combination of DGGE and direct sequencing of the 9 exons of the F7 gene, Giansily-Blaizot et al. (2001) investigated 37 unrelated patients, mainly of French and North African origin, with a factor VII coagulant activity less than 5% of normal. This strategy allowed detection of 68 of the 74 predicted mutated alleles (92%). A total of 40 different mutations were detected throughout the gene, 18 of which had not previously been reported. Genotypes of the patients with severe bleeding diathesis comprised mutations on both alleles, which prevented the production of a functional FVII molecule. The authors suggested that in the mild and asymptomatic groups, a nondeleterious mutation on one allele may allow the release of a minute amount of FVII protein that may be sufficient to trigger the hemostatic cascade.
Factor VII deficiency has an estimated prevalence of 1 in 500,000 individuals (summary by Millar et al., 2000).
Arbini, A. A., Bodkin, D., Lopaciuk, S., Bauer, K. A. Molecular analysis of Polish patients with factor VII deficiency. Blood 84: 2214-2220, 1994. [PubMed: 7919338]
Arbini, A. A., Mannucci, P. M., Bauer, K. A. A thr359-to-met mutation in factor VII of a patient with a hereditary deficiency causes defective secretion of the molecule. Blood 87: 5085-5094, 1996. [PubMed: 8652821]
Au, W. Y., Lam, C. C. K., Chan, E. C., Kwong, Y. L. Two novel factor VII gene mutations in a Chinese family with factor VII deficiency. Brit. J. Haemat. 111: 143-145, 2000. [PubMed: 11091194] [Full Text: https://doi.org/10.1046/j.1365-2141.2000.02332.x]
Bernardi, F., Castaman, G., Redaelli, R., Pinotti, M., Lunghi, B., Rodeghiero, F., Marchetti, G. Topologically equivalent mutations causing dysfunctional coagulation factors VII (294ala-val) and X (334ser-pro). Hum. Molec. Genet. 3: 1175-1177, 1994. [PubMed: 7981691] [Full Text: https://doi.org/10.1093/hmg/3.7.1175]
Cooper, D. N., Millar, D. S., Wacey, A., Banner, D. W., Tuddenham, E. G. D. Inherited factor VII deficiency: molecular genetics and pathophysiology. Thromb. Haemost. 78: 151-160, 1997. [PubMed: 9198146]
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Fukushima, Y., Kuroki, Y., Iizuka, A. Activity and antigen of coagulation factors VII and X in five patients with abnormal chromosome 13. Jpn. J. Hum. Genet. 32: 91-96, 1987.
Giansily-Blaizot, M., Aguilar-Martinez, P., Biron-Andreani, C., Jeanjean, P., Igual, H., Schved, J.-F., the Study Group of Factor Seven Deficiency. Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency. Europ. J. Hum. Genet. 9: 105-112, 2001. [PubMed: 11313743] [Full Text: https://doi.org/10.1038/sj.ejhg.5200593]
Giansily-Blaizot, M., Aguilar-Martinez, P., Mazurier, C., Cneude, F., Goudemand, J., Schved, J.-F., de Martinville, B. Prenatal diagnosis of severe factor VII deficiency using mutation detection and linkage analysis. (Letter) Brit. J. Haemat. 112: 251-252, 2001. [PubMed: 11225604] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02497-4.x]
Girolami, A., Cattarozzi, G., Dal Bo Zanon, R., Cella, G., Toffanin, F. Factor VII Padua-2: another factor VII abnormality with defective ox brain thromboplastin activation and a complex hereditary pattern. Blood 54: 46-53, 1979. [PubMed: 444674]
Girolami, A., Falezza, G., Patrassi, G., Stenico, M., Vettore, L. Factor VII Verona coagulation disorder: double heterozygosis with an abnormal factor VII and heterozygous factor VII deficiency. Blood 50: 603-610, 1977. [PubMed: 901936]
Girolami, A., Patrassi, G., Cappellato, G., Casonato, A. Another family with the factor VII Padua clotting defect. Acta Haemat. 62: 4-11, 1979.
Glueck, H. I., Sutherland, J. M. Inherited factor-VII defect in Negro family. Pediatrics 27: 204-213, 1961. [PubMed: 13706109]
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Kroll, A. J., Alexander, B., Cochios, F., Pechet, L. Hereditary deficiencies of clotting factors VII and X associated with carotid-body tumors. New Eng. J. Med. 270: 6-13, 1964. [PubMed: 14062129] [Full Text: https://doi.org/10.1056/NEJM196401022700102]
Kupfer, H. G., Hanna, B. L., Kinne, D. R. Congenital factor VII deficiency with normal Stuart activity: clinical, genetic and experimental observations. Blood 15: 146-163, 1960. [PubMed: 14412828]
Marchetti, G., Patracchini, P., Gemmati, D., DeRosa, V., Pinotti, M., Rodorigo, G., Casonato, A., Girolami, A., Bernardi, F. Detection of two missense mutations and characterization of a repeat polymorphism in the factor VII gene (F7). Hum. Genet. 89: 497-502, 1992. [PubMed: 1634227] [Full Text: https://doi.org/10.1007/BF00219173]
Marder, V. J., Shulman, N. R. Clinical aspects of congenital factor VII deficiency. Am. J. Med. 37: 182-194, 1964. [PubMed: 14206752] [Full Text: https://doi.org/10.1016/0002-9343(64)90004-x]
Mariani, G., Mazzucconi, M. G., Hermans, J., Ciavarella, N., Faiella, A., Hassan, H. J., Mannucci, P. M., Nenci, G. G., Orlando, M., Romoli, D., Mandelli, F. Factor VII deficiency: immunological characterization of genetic variants and detection of carriers. Brit. J. Haemat. 48: 7-14, 1981. [PubMed: 7248191] [Full Text: https://doi.org/10.1111/j.1365-2141.1981.00007.x]
McVey, J. H., Boswell, E., Mumford, A. D., Kemball-Cook, G., Tuddenham, E. G. D. Factor VII deficiency and the FVII mutation database. Hum. Mutat. 17: 3-17, 2001. [PubMed: 11139238] [Full Text: https://doi.org/10.1002/1098-1004(2001)17:1<3::AID-HUMU2>3.0.CO;2-V]
McVey, J. H., Boswell, E. J., Takamiya, O., Tamagnini, G., Valente, V., Fidalgo, T., Layton, M., Tuddenham, E. G. D. Exclusion of the first EGF domain of factor VII by a splice site mutation causes lethal factor VII deficiency. Blood 92: 920-926, 1998. [PubMed: 9680360]
Millar, D. S., Kemball-Cook, G., McVey, J. H., Tuddenham, E. G. D., Mumford, A. D., Attock, G. B., Reverter, J. C., Lanir, N., Parapia, L. A., Reynaud, J., Meili, E., von Felton, A., Martinowitz, U., Prangnell, D. R., Krawczak, M., Cooper, D. N. Molecular analysis of the genotype-phenotype relationship in factor VII deficiency. Hum. Genet. 107: 327-342, 2000. [PubMed: 11129332] [Full Text: https://doi.org/10.1007/s004390000373]
Perry, D. J. Factor VII deficiency. Brit. J. Haemat. 118: 689-700, 2002. [PubMed: 12181036] [Full Text: https://doi.org/10.1046/j.1365-2141.2002.03545.x]
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Shen, M.-C., Lin, J.-S., Lin, S.-W., Yang, W.-S., Lin, B. Novel mutations in the factor VII gene of Taiwanese factor VII-deficient patients. Brit. J. Haemat. 112: 566-571, 2001. [PubMed: 11260055] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02547.x]
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Takamiya, O., Hino, K. A patient homozygous for a gly354-to-cys mutation in factor VII that results in severely impaired secretion of the molecule, but not complete deficiency. Brit. J. Haemat. 124: 336-342, 2004. [PubMed: 14717781] [Full Text: https://doi.org/10.1046/j.1365-2141.2003.04778.x]
Takamiya, O., Okimoto, Y. Severe factor VII deficiency with recurrent intracranial haemorrhages owing to double heterozygosity for a splice site mutation of an IVS4 and a novel nonsense mutation in exon 8 (Gln211-Term). Brit. J. Haemat. 114: 369-374, 2001. [PubMed: 11529858] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.02932.x]
Tamary, H., Fromovich, Y., Shalmon, L., Reich, Z., Dym, O., Lanir, N., Brenner, B., Paz, M., Luder, A. S., Blau, O., Korostishevsky, M., Zaizov, R., Seligsohn, U. Ala244Val is a common, probably ancient mutation causing factor VII deficiency in Moroccan and Iranian Jews. Thromb. Haemost. 76: 283-291, 1996. [PubMed: 8883260]
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