ClinVar Genomic variation as it relates to human health

Nystagmus (present) , Palpitations (present) , Reduced ejection fraction (present) , Muscular hypotonia (present) , Muscle weakness (present) , Muscle spasm (present) , Infantile muscular hypotonia (present) , Renal tubular atrophy (present) , Mesangial abnormality (present) , Tubulointerstitial fibrosis (present) , Glomerulomegaly (present) , Podocyte foot process effacement (present) , Peripheral neuropathy (present) , Proteinuria (present) , Elevated serum creatine kinase (present) , Elevated plasma acylcarnitine levels (present) , Deep venous thrombosis (present) , Cellulitis (present) (less)

This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)

This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)

This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)

This mutation is commonly referred to as 'factor V Leiden.' Thrombophilia In affected members of a family with thrombophilia due to APC resistance (188055), Bertina et al. (1994) identified a heterozygous 1691G-A transition in exon 10 of the F5 gene, resulting in an arg506-to-gln (R506Q) substitution. The R506Q substitution prevented inactivation of activated factor V by activated protein C (612283), resulting in a tendency to thrombosis. Of note, this family came to attention because of symptomatic protein C deficiency (176860). Bertina et al. (1994) identified the R506Q mutation in 56 of 64 patients with APC-resistant thrombosis from a larger cohort of 301 consecutive patients with a first episode of deep vein thrombosis. The mutation was homozygous in 6 patients. Greengard et al. (1994) identified a heterozygous R506Q mutation in 8 patients with APC resistance; 2 were Ashkenazi Jews, 5 were Europeans of varying origins, and 1 was African American. Voorberg et al. (1994) found the R506Q mutation in 10 of 27 consecutive patients with recurrent thromboembolism. Beauchamp et al. (1994) found the R506Q mutation in all affected members of 2 English families with inherited APC resistance associated with thrombosis. The molecular studies confirmed suspected homozygosity in 2 individuals. The mutation in heterozygous form was also found in approximately 3.5% of the normal population. Among 14,916 apparently healthy men in the Physicians' Health Study, including 121 with deep venous thrombosis, Ridker et al. (1995) found that the R506Q mutation of the F5 gene was present in 25.8% of men over the age of 60 in whom primary venous thrombosis developed. There was no increased risk for secondary venous thrombosis. The presence of the mutation was not associated with an increased risk of myocardial infarction or stroke. In a follow-up study, of 77 study participants who had a first idiopathic venous thromboembolism, Ridker et al. (1995) found that factor V Leiden was associated with a 4- to 5-fold increased risk of recurrent thrombosis. The data raised the possibility that patients with idiopathic venous thromboembolism and factor V Leiden may require more prolonged anticoagulation to prevent recurrent disease compared to those without the mutation. Among 7 families with 11 pseudohomozygotes and 45 relatives, Brenner et al. (1996) observed 2 patients with the HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome who were found to be heterozygous for the R506Q mutation. The HELLP syndrome is a severe presentation of preeclampsia (see 189800). The finding of the R506Q mutation suggested that the pathogenesis of HELLP syndrome may be associated with a thrombotic process. In 50 patients with meningococcal disease and thrombotic complications, Westendorp et al. (1996) found no increase in prevalence of the factor V Leiden mutation. De Bruijn et al. (1998) studied risk factors in cerebral venous sinus thrombosis in women. They found a clear and significant excess of both hereditary prothrombotic conditions, including factor V Leiden, and oral contraceptive use in 40 prospectively ascertained patients compared to 2,248 randomly sampled controls. The authors concluded that the presence of prothrombotic conditions like the factor V Leiden mutation and the use of oral contraceptives increase the risk of this rare condition in a multiplicative fashion. Gerhardt et al. (2000) studied 119 women with a history of venous thromboembolism during pregnancy and the puerperium and 233 age-matched normal women. Among the women with a history of venous thromboembolism, a prevalence of factor V Leiden was 43.7%, as compared with 7.7% among the normal women (relative risk of venous thromboembolism, 9.3). The prevalence of the 20210G-A prothrombin mutation (176930.0009) was 16.9% in the thromboembolism group as compared with 1.3% in the control group. The frequency of both factor V Leiden and the 20210G-A prothrombin mutation was 9.3% in the thromboembolism group as compared with 0 in the control group (estimated OR, 107). Assuming an overall risk of 1 in 1,500 pregnancies, the risk of thrombosis among carriers of factor V Leiden was 0.2%, among carriers of the 20210G-A prothrombin mutation, 0.5%, and among carriers of both defects, 4.6%, as calculated in a multivariate analysis. Thus, the risk among women with both mutations was disproportionately higher than that among women with only 1 mutation. In a population-based cohort study of 9,253 Danish adults, Juul et al. (2004) found that heterozygotes and homozygotes for factor V Leiden had 2.7 and 18 times higher risk for venous thromboembolism, respectively, than noncarriers. Absolute 10-year risks for thromboembolism among heterozygote and homozygote nonsmokers younger than age 40 years who were not overweight were 0.7% and 3%, respectively. The 10-year risks in heterozygotes and homozygotes older than age 60 years who smoked and were overweight were 10% and 51%, respectively. Kemkes-Matthes et al. (2005) found that presence of a heterozygous or homozygous arg225-to-his (R225H) substitution in exon 8 of the protein Z gene (PROZ; 176895) was associated with a higher frequency of thromboembolic complications in patients carrying the factor V Leiden mutation, although plasma levels of protein Z were not different between those with or without the R225H substitution. In a study of 134 carriers of factor V Leiden, the R225H mutation was found in 11 (14.4%) of 76 patients with thromboembolic events and in only 3 (5.1%) of 58 patients who did not have thromboembolic events. Stroke In a comprehensive metaanalysis of 26 case-control studies including 4,588 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the R506Q substitution (OR, 1.33). Budd-Chiari Syndrome Mahmoud et al. (1997) reported the incidence of the factor V Leiden mutation in Budd-Chiari syndrome (600880) and portal vein thrombosis. The R506Q mutation was seen in 7 (23%) of 30 patients with Budd-Chiari syndrome (6 heterozygotes and 1 homozygote), 3 of whom had coexistent myeloproliferative disease. Only 1 (3%) of 32 patients with portal vein thrombosis was found to have the R506Q mutation. The mutation was found in 3 (6%) of the 54 controls, who had liver disease but no history of thrombophilia. Mahmoud et al. (1997) concluded that the R506Q mutation seems to be an important factor in the pathogenesis of Budd-Chiari syndrome but not of portal vein thrombosis. Leebeek et al. (1998) described a 27-year-old woman, homozygous for factor V Leiden, who developed Budd-Chiari syndrome caused by hepatic vein thrombosis in association with portal and mesenteric vein thrombosis. Gurakan et al. (1999) described a child with Budd-Chiari syndrome who was homozygous for the factor V Leiden mutation. The authors noted that Budd-Chiari syndrome is rare in children. Recurrent Pregnancy Loss In a study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation; 614389) and 232 women who had had 1 or more normal pregnancies with no late fetal loss, Martinelli et al. (2000) found that both factor V Leiden and a 20210G-A mutation in prothrombin (176930.0009) were associated with an approximate tripling of the risk of late fetal loss. Evolution Zivelin et al. (2006) estimated the age of the factor V Leiden mutation to be 21,340 years. Like the prothrombin 20210G-A mutation (176930.0009), the mutation occurred in whites toward the end of the last glaciation and their wide distribution in whites suggested selective evolutionary advantages. A selective disadvantage (i.e., thrombosis) is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. On the other hand, augmented hemostasis conceivably conferred a selective advantage by reducing mortality from postpartum hemorrhage, hemorrhagia associated with severe iron deficiency anemia, and posttraumatic bleeding. For example, Lindqvist et al. (1998) found that the amount of blood lost during labor was significantly smaller in heterozygotes with factor V Leiden than in women not carrying the mutation, and Lindqvist et al. (2001) found that profuse menstrual bleeding was significantly less common in factor V heterozygotes. Among 122 pregnant women with preeclampsia or intrauterine growth retardation, Lindqvist et al. (1998) found a significantly reduced risk of intrapartum bleeding complications in the APC-resistant subgroup compared to non-APC-resistant subgroup, as indicated by reduced intrapartum blood loss and pre- and postpartum hemoglobin measurements. Lindqvist et al. (1998) speculated that the remarkably high prevalence of a potentially harmful factor V gene mutation in the general population may be the result of an evolutionary selection mechanism conferring such survival advantages as reduction in the risk of intrapartum bleeding. Pseudohomozygosity for Factor V Leiden Zehnder et al. (1999) identified a man with thrombophilia who was found to be compound heterozygous for factor V Leiden and a null allele of the F5 gene (612309.0005). The patient had 50% of normal levels of F5, all of which was of the Leiden type; hence he was 'pseudohomozygous' for factor V Leiden. Digenic Inheritance Koeleman et al. (1994) found that heterozygous carriers of both the R506Q and a mutation in the protein C gene were at higher risk of thrombosis than were patients with either defect alone. Talmon et al. (1997) described retinal arterial occlusion in a child heterozygous for the factor V R506Q mutation and homozygous for thermolabile methylene tetrahydrofolate reductase (236250.0003). Thus, the coexistence of 2 mild hereditary thrombophilic states can result in severe thrombotic manifestations in young people. Although factor V Leiden had been associated clearly with venous thrombosis, most studies had failed to demonstrate an association between isolated factor V Leiden and arterial thrombosis. De Stefano et al. (1999) examined the relative risk of recurrent deep venous thrombosis using a proportional-hazards model. The authors found that whereas patients who were heterozygous for factor V Leiden alone had a risk of recurrent deep venous thrombosis that was similar to that among patients who had neither mutation, patients who were heterozygous for both factor V Leiden and prothrombin 20210G-A (176930.0009) had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Meinardi et al. (1999) described double homozygosity for factor V Leiden and prothrombin 20210G-A in a 34-year-old man with idiopathic venous thrombosis. Meyer et al. (1999) described a method for simultaneously genotyping for factor V Leiden and the prothrombin 20210G-A variant by a multiplex PCR-SSCP assay on whole blood. Population Studies Majerus (1994) quoted estimates that 2 to 4% of the Dutch population and 7% of the Swedish population carried the factor V Leiden allele (R506Q; 612309.0001). The high frequency of a single factor V mutation in diverse groups of people raised the question of whether positive selection pressure was involved in maintaining it in the population. Majerus (1994) suggested that a slight thrombotic tendency may confer some advantage in fetal implantation. In a population study in southern Germany, Braun et al. (1996) found that 7.8% of 180 unrelated individuals were heterozygous for the factor V Leiden mutation. In a multiethnic survey of 602 Americans, Gregg et al. (1997) found that Hispanic Americans had the highest frequency of the Leiden mutant allele, 1.65%, while African Americans had a somewhat lower frequency, 0.87%. No instances of the Leiden mutation were found in 191 Asian Americans or 54 Native Americans tested. These results indicated that the Leiden mutation segregates in populations with significant Caucasian admixture and is rare in genetically distant non-European groups. Gurgey and Mesci (1997) determined that the F5 Leiden allele has a frequency of 8% in the Turkish population. Chan et al. (1998) found that the R506Q mutation was rare among Hong Kong Chinese, as it was not detected among 83 unrelated Hong Kong Chinese, 43 of whom had deep venous thromboses. (less)