ClinVar Genomic variation as it relates to human health

Rosendaal et al. (1998) presented data from 11 centers and 9 countries, representing a total of 5,527 tested individuals. Among these, 111 heterozygous carriers of the 20210A mutation were found, yielding an overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%, nearly twice as high as the prevalence in northern Europe (1.7%). The prothrombin variant appeared to be rare in individuals of Asian and African descent. To discern whether the 20210G-A polymorphism originated from a single or recurrent mutation event, Zivelin et al. (1998) determined allele frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (p = 0.0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p less than 0.0001). These data strongly supported a single origin for the factor II polymorphism. Because the polymorphism is rare or absent in non-Caucasian populations, it probably occurred after divergence of Africans from non-Africans and of Caucasoids from Mongoloid subpopulations. Rees et al. (1999) analyzed samples from 22 different non-European countries and found that the prothrombin 20210G-A variant, like factor V Leiden (612309.0001), is rare outside Europe. Of 1,811 non-Europeans tested, they found only 1 individual, in India, who had the mutation in heterozygous state. Zivelin et al. (2006) analyzed the frequencies of 5 SNPs and 9 microsatellites flanking the prothrombin gene in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G-A mutation, they analyzed linkage disequilibrium between the mutation and the multiple markers that had been assessed. The analysis yielded an age estimate of 23,720 years. A similar analysis was performed for factor V Leiden (612309.0001) yielding an age estimate of 21,340 years. The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggested selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections). The selected disadvantage from thrombosis is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. Thrombophilia Poort et al. (1996) found that a common genetic 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (Degen and Davie, 1987) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; 188050). The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (Doggen et al., 1998). Franco et al. (1999) found a frequency of the 20210A allele of 1% in a 400-member healthy control population and 2.7% in 263 patients with proven premature atherosclerotic disease. All heterozygotes in the patient group were found to have had a myocardial infarction. In addition, the data provided evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease. Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. The frequency of the factor V Leiden mutation (612309.0001) was similar in subjects with portal vein thrombosis and in controls but was increased in patients with deep vein thrombosis. De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who additionally were heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. Humpert et al. (1999) screened 384 type 1 diabetic patients for the 20210G-A prothrombin polymorphism and detected the variant in 9 patients. There was no increase in the incidence of coronary heart disease, nephropathy, or retinopathy among diabetic patients carrying the 20210G-A polymorphism. 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. Prohaska et al. (1999) studied 284 patients with angiographically confirmed coronary artery disease for the presence of the 20210G-A polymorphism of the prothrombin gene and compared them with 340 healthy controls. The prevalence of the mutation was similar in both groups. There was a mild increase in the frequency of the mutation in a group of 294 venous thrombosis patients compared with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9). One of the main factors of sudden hearing impairment, vestibular disturbance (tinnitus), is generally thought to be an acute labyrinthine ischemia; the most common mechanism of sudden hearing loss appears to be impaired cochlear blood circulation. Mercier et al. (1999) provided evidence that the 20210A allele of the prothrombin gene is a risk factor for perception deafness. Among 368 patients (median age, 41 years) with spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years of age) had also suffered from acute unilateral hearing impairment. Six of the 18 were heterozygous for the 20210A allele. In a group of 395 nonthrombotic consecutive patients studied in the same laboratory for hemorrhagic symptoms or thrombocytopenia over the same period of time, 4 had acute unilateral perception deafness; of 395 nonthrombotic and nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral perception deafness. Souto et al. (1999) reported a family illustrating the complexity of thrombotic disease in relation to the 20210A variant. The pedigree was ascertained through a proband with idiopathic thrombophilia. The family members who had a history of thromboembolism were heterozygous carriers of the 20210A variant. In addition, 4 relatives who were heterozygous as well as 2 who were homozygous for the 20210A allele failed to show clinical manifestations. The 2 homozygotes were 51 and 19 years old. Gehring et al. (2001) demonstrated that the 20210G-A mutation does not affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the length of poly(A) tail of the mature mRNA. Rather, Gehring et al. (2001) demonstrated that the physiologic F2 3-prime end cleavage signal is inefficient and that F2 20210G-A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3-prime end processing, and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3-prime end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210G-A mutation in the pathogenesis of thrombophilia. Gehring et al. (2001) concluded that their work illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. Although the 20210G-A mutation in heterozygous state carries an increased risk of a first venous thromboembolic episode, De Stefano et al. (2001) found that the risk of spontaneous recurrent venous thromboembolism was similar to that in patients with normal genotype. They concluded that carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. Laczika et al. (2002) described a 19-year-old woman with the joint occurrence of type I antithrombin III deficiency (613118) and a heterozygous prothrombin 20210G-A mutation, who developed chronic thromboembolic pulmonary hypertension on the basis of total occlusion of the right pulmonary artery. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy performed 24 weeks after the initial clinical presentation. Segal et al. (2009) provided a metaanalysis of the predictive value of the prothrombin 20210G-A mutation for venous thromboembolism using a literature review of 10 relevant articles. Although heterozygosity for prothrombin 20210G-A in probands conferred a risk of 1.45, the confidence interval ranged from 0.96 to 2.2, suggesting that the mutation was not predictive of recurrent venous thromboembolism compared to those without the mutation. In addition, there was insufficient evidence regarding the predictive value of homozygosity for prothrombin 20210G-A in probands, and for the predictive value of being a mutation carrier in relatives of probands with the mutation. It remained unknown whether testing improved clinical outcomes. Segal et al. (2009) concluded that there is insufficient evidence to support the hypothesis that 20210G-A confers a significantly increased risk for venous thromboembolism in terms of genetic testing. Ischemic Stroke In a comprehensive metaanalysis of 19 case-control studies including 3,028 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the 20210G-A substitution (odds ratio of 1.44). Budd-Chiari Syndrome In a 37-year-old Caucasian male with polycythemia vera who had developed Budd-Chiari syndrome (BDCHS; 600880), Bucciarelli et al. (1998) identified heterozygosity for the 20210G-A substitution. His paternal grandmother had died at the age of 60 due to BDCHS, and his father, who was also heterozygous for the mutation, had had a myocardial infarction at age 55. Bucciarelli et al. (1998) excluded deficiencies of antithrombin, protein C, and protein S, as well as the presence of antiphospholipid syndrome and the factor V Leiden mutation. They suggested case-control studies to establish if carriers of the 20210G-A mutation have an increased risk of developing BDCHS. Oner et al. (1999) described Budd-Chiari syndrome in a patient heterozygous for both the 20210G-A mutation of F2 and the factor V Leiden mutation; heterozygosity for the factor V Leiden mutation is a known susceptibility factor for BDCHS. Oner et al. (1999) referred to the 20210G-A mutation by the abbreviation PM, presumably for 'prothrombin mutation.' Susceptibility to Recurrent Pregnancy Loss Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). (less)

Rosendaal et al. (1998) presented data from 11 centers and 9 countries, representing a total of 5,527 tested individuals. Among these, 111 heterozygous carriers of the 20210A mutation were found, yielding an overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%, nearly twice as high as the prevalence in northern Europe (1.7%). The prothrombin variant appeared to be rare in individuals of Asian and African descent. To discern whether the 20210G-A polymorphism originated from a single or recurrent mutation event, Zivelin et al. (1998) determined allele frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (p = 0.0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p less than 0.0001). These data strongly supported a single origin for the factor II polymorphism. Because the polymorphism is rare or absent in non-Caucasian populations, it probably occurred after divergence of Africans from non-Africans and of Caucasoids from Mongoloid subpopulations. Rees et al. (1999) analyzed samples from 22 different non-European countries and found that the prothrombin 20210G-A variant, like factor V Leiden (612309.0001), is rare outside Europe. Of 1,811 non-Europeans tested, they found only 1 individual, in India, who had the mutation in heterozygous state. Zivelin et al. (2006) analyzed the frequencies of 5 SNPs and 9 microsatellites flanking the prothrombin gene in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G-A mutation, they analyzed linkage disequilibrium between the mutation and the multiple markers that had been assessed. The analysis yielded an age estimate of 23,720 years. A similar analysis was performed for factor V Leiden (612309.0001) yielding an age estimate of 21,340 years. The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggested selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections). The selected disadvantage from thrombosis is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. Thrombophilia Poort et al. (1996) found that a common genetic 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (Degen and Davie, 1987) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; 188050). The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (Doggen et al., 1998). Franco et al. (1999) found a frequency of the 20210A allele of 1% in a 400-member healthy control population and 2.7% in 263 patients with proven premature atherosclerotic disease. All heterozygotes in the patient group were found to have had a myocardial infarction. In addition, the data provided evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease. Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. The frequency of the factor V Leiden mutation (612309.0001) was similar in subjects with portal vein thrombosis and in controls but was increased in patients with deep vein thrombosis. De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who additionally were heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. Humpert et al. (1999) screened 384 type 1 diabetic patients for the 20210G-A prothrombin polymorphism and detected the variant in 9 patients. There was no increase in the incidence of coronary heart disease, nephropathy, or retinopathy among diabetic patients carrying the 20210G-A polymorphism. 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. Prohaska et al. (1999) studied 284 patients with angiographically confirmed coronary artery disease for the presence of the 20210G-A polymorphism of the prothrombin gene and compared them with 340 healthy controls. The prevalence of the mutation was similar in both groups. There was a mild increase in the frequency of the mutation in a group of 294 venous thrombosis patients compared with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9). One of the main factors of sudden hearing impairment, vestibular disturbance (tinnitus), is generally thought to be an acute labyrinthine ischemia; the most common mechanism of sudden hearing loss appears to be impaired cochlear blood circulation. Mercier et al. (1999) provided evidence that the 20210A allele of the prothrombin gene is a risk factor for perception deafness. Among 368 patients (median age, 41 years) with spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years of age) had also suffered from acute unilateral hearing impairment. Six of the 18 were heterozygous for the 20210A allele. In a group of 395 nonthrombotic consecutive patients studied in the same laboratory for hemorrhagic symptoms or thrombocytopenia over the same period of time, 4 had acute unilateral perception deafness; of 395 nonthrombotic and nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral perception deafness. Souto et al. (1999) reported a family illustrating the complexity of thrombotic disease in relation to the 20210A variant. The pedigree was ascertained through a proband with idiopathic thrombophilia. The family members who had a history of thromboembolism were heterozygous carriers of the 20210A variant. In addition, 4 relatives who were heterozygous as well as 2 who were homozygous for the 20210A allele failed to show clinical manifestations. The 2 homozygotes were 51 and 19 years old. Gehring et al. (2001) demonstrated that the 20210G-A mutation does not affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the length of poly(A) tail of the mature mRNA. Rather, Gehring et al. (2001) demonstrated that the physiologic F2 3-prime end cleavage signal is inefficient and that F2 20210G-A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3-prime end processing, and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3-prime end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210G-A mutation in the pathogenesis of thrombophilia. Gehring et al. (2001) concluded that their work illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. Although the 20210G-A mutation in heterozygous state carries an increased risk of a first venous thromboembolic episode, De Stefano et al. (2001) found that the risk of spontaneous recurrent venous thromboembolism was similar to that in patients with normal genotype. They concluded that carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. Laczika et al. (2002) described a 19-year-old woman with the joint occurrence of type I antithrombin III deficiency (613118) and a heterozygous prothrombin 20210G-A mutation, who developed chronic thromboembolic pulmonary hypertension on the basis of total occlusion of the right pulmonary artery. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy performed 24 weeks after the initial clinical presentation. Segal et al. (2009) provided a metaanalysis of the predictive value of the prothrombin 20210G-A mutation for venous thromboembolism using a literature review of 10 relevant articles. Although heterozygosity for prothrombin 20210G-A in probands conferred a risk of 1.45, the confidence interval ranged from 0.96 to 2.2, suggesting that the mutation was not predictive of recurrent venous thromboembolism compared to those without the mutation. In addition, there was insufficient evidence regarding the predictive value of homozygosity for prothrombin 20210G-A in probands, and for the predictive value of being a mutation carrier in relatives of probands with the mutation. It remained unknown whether testing improved clinical outcomes. Segal et al. (2009) concluded that there is insufficient evidence to support the hypothesis that 20210G-A confers a significantly increased risk for venous thromboembolism in terms of genetic testing. Ischemic Stroke In a comprehensive metaanalysis of 19 case-control studies including 3,028 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the 20210G-A substitution (odds ratio of 1.44). Budd-Chiari Syndrome In a 37-year-old Caucasian male with polycythemia vera who had developed Budd-Chiari syndrome (BDCHS; 600880), Bucciarelli et al. (1998) identified heterozygosity for the 20210G-A substitution. His paternal grandmother had died at the age of 60 due to BDCHS, and his father, who was also heterozygous for the mutation, had had a myocardial infarction at age 55. Bucciarelli et al. (1998) excluded deficiencies of antithrombin, protein C, and protein S, as well as the presence of antiphospholipid syndrome and the factor V Leiden mutation. They suggested case-control studies to establish if carriers of the 20210G-A mutation have an increased risk of developing BDCHS. Oner et al. (1999) described Budd-Chiari syndrome in a patient heterozygous for both the 20210G-A mutation of F2 and the factor V Leiden mutation; heterozygosity for the factor V Leiden mutation is a known susceptibility factor for BDCHS. Oner et al. (1999) referred to the 20210G-A mutation by the abbreviation PM, presumably for 'prothrombin mutation.' Susceptibility to Recurrent Pregnancy Loss Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). (less)

Rosendaal et al. (1998) presented data from 11 centers and 9 countries, representing a total of 5,527 tested individuals. Among these, 111 heterozygous carriers of the 20210A mutation were found, yielding an overall prevalence of 2.0%. In southern Europe, the prevalence was 3.0%, nearly twice as high as the prevalence in northern Europe (1.7%). The prothrombin variant appeared to be rare in individuals of Asian and African descent. To discern whether the 20210G-A polymorphism originated from a single or recurrent mutation event, Zivelin et al. (1998) determined allele frequencies of 4 dimorphisms spanning 16 of 21 kb of the factor II gene in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II 20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (p = 0.0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and in only 34% of 20210G normal alleles (p less than 0.0001). These data strongly supported a single origin for the factor II polymorphism. Because the polymorphism is rare or absent in non-Caucasian populations, it probably occurred after divergence of Africans from non-Africans and of Caucasoids from Mongoloid subpopulations. Rees et al. (1999) analyzed samples from 22 different non-European countries and found that the prothrombin 20210G-A variant, like factor V Leiden (612309.0001), is rare outside Europe. Of 1,811 non-Europeans tested, they found only 1 individual, in India, who had the mutation in heterozygous state. Zivelin et al. (2006) analyzed the frequencies of 5 SNPs and 9 microsatellites flanking the prothrombin gene in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G-A mutation, they analyzed linkage disequilibrium between the mutation and the multiple markers that had been assessed. The analysis yielded an age estimate of 23,720 years. A similar analysis was performed for factor V Leiden (612309.0001) yielding an age estimate of 21,340 years. The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggested selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections). The selected disadvantage from thrombosis is unlikely because until recent centuries humans did not live long enough to manifest a meaningful incidence of thrombosis. Thrombophilia Poort et al. (1996) found that a common genetic 20210G-A transition in the 3-prime untranslated region of the prothrombin gene (Degen and Davie, 1987) was associated with elevated plasma prothrombin levels and an increased risk of venous thrombosis (THPH1; 188050). The SNP was found in 18% of probands of families with thrombosis, 6% of unselected consecutive patients with deep vein thrombosis, and 2% of healthy controls. Rosendaal et al. (1997) found that the mutation was associated with a 4-fold increased risk of myocardial infarction in women, while among men the risk was increased 1.5-fold (Doggen et al., 1998). Franco et al. (1999) found a frequency of the 20210A allele of 1% in a 400-member healthy control population and 2.7% in 263 patients with proven premature atherosclerotic disease. All heterozygotes in the patient group were found to have had a myocardial infarction. In addition, the data provided evidence for an association of the mutation with excessive thrombin generation, which may contribute to the understanding of its role in venous and arterial disease. Chamouard et al. (1999) studied the frequency of the factor II 20210G-A mutation in 10 white European patients with idiopathic portal vein thrombosis. They studied 5 women and 5 men; mean age was 50.4 years. The frequency of the 20210G-A mutation was found to be 40% in idiopathic portal vein thrombosis compared with 4.8% in controls or patients with nonidiopathic portal vein thrombosis or deep vein thrombosis. The frequency of the factor V Leiden mutation (612309.0001) was similar in subjects with portal vein thrombosis and in controls but was increased in patients with deep vein thrombosis. De Stefano et al. (1999) found that patients who were heterozygous for both factor V Leiden (1691G-A; 612309.0001) and prothrombin 20210G-A had a 2.6-fold higher risk of recurrent thrombosis than did carriers of factor V Leiden alone. Patients who were heterozygous for factor V Leiden had a risk of recurrent deep venous thrombosis that was similar to that among patients who had no known mutations in either factor II or factor V. In a Spanish family, Corral et al. (1999) identified 3 subjects homozygous for the 20210A prothrombin mutation who additionally were heterozygous for factor V Leiden. The combination of the 2 mutations increased the risk of developing venous thrombotic episodes at an earlier age. However, even in association with factor V Leiden, the homozygous condition of the 20210A prothrombin mutation required additional risk factors to induce a thrombotic event. Humpert et al. (1999) screened 384 type 1 diabetic patients for the 20210G-A prothrombin polymorphism and detected the variant in 9 patients. There was no increase in the incidence of coronary heart disease, nephropathy, or retinopathy among diabetic patients carrying the 20210G-A polymorphism. 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. Prohaska et al. (1999) studied 284 patients with angiographically confirmed coronary artery disease for the presence of the 20210G-A polymorphism of the prothrombin gene and compared them with 340 healthy controls. The prevalence of the mutation was similar in both groups. There was a mild increase in the frequency of the mutation in a group of 294 venous thrombosis patients compared with the healthy controls (odds ratio, 2.90; 95% CI, 1.25-6.9). One of the main factors of sudden hearing impairment, vestibular disturbance (tinnitus), is generally thought to be an acute labyrinthine ischemia; the most common mechanism of sudden hearing loss appears to be impaired cochlear blood circulation. Mercier et al. (1999) provided evidence that the 20210A allele of the prothrombin gene is a risk factor for perception deafness. Among 368 patients (median age, 41 years) with spontaneous deep vein thrombosis, 18 (12 women and 6 men, 38 to 69 years of age) had also suffered from acute unilateral hearing impairment. Six of the 18 were heterozygous for the 20210A allele. In a group of 395 nonthrombotic consecutive patients studied in the same laboratory for hemorrhagic symptoms or thrombocytopenia over the same period of time, 4 had acute unilateral perception deafness; of 395 nonthrombotic and nonhemorrhagic sex- and age-matched controls, 6 had acute unilateral perception deafness. Souto et al. (1999) reported a family illustrating the complexity of thrombotic disease in relation to the 20210A variant. The pedigree was ascertained through a proband with idiopathic thrombophilia. The family members who had a history of thromboembolism were heterozygous carriers of the 20210A variant. In addition, 4 relatives who were heterozygous as well as 2 who were homozygous for the 20210A allele failed to show clinical manifestations. The 2 homozygotes were 51 and 19 years old. Gehring et al. (2001) demonstrated that the 20210G-A mutation does not affect the amount of pre-mRNA, the site of 3-prime end cleavage, or the length of poly(A) tail of the mature mRNA. Rather, Gehring et al. (2001) demonstrated that the physiologic F2 3-prime end cleavage signal is inefficient and that F2 20210G-A represents a gain-of-function mutation, causing increased cleavage site recognition, increased 3-prime end processing, and increased mRNA accumulation and protein synthesis. Enhanced mRNA 3-prime end formation efficiency emerges as a novel principle causing a genetic disorder and explains the role of the F2 20210G-A mutation in the pathogenesis of thrombophilia. Gehring et al. (2001) concluded that their work illustrates the pathophysiologic importance of quantitatively minor aberrations of RNA metabolism. Although the 20210G-A mutation in heterozygous state carries an increased risk of a first venous thromboembolic episode, De Stefano et al. (2001) found that the risk of spontaneous recurrent venous thromboembolism was similar to that in patients with normal genotype. They concluded that carriers of the prothrombin mutation should be treated with oral anticoagulants after a first deep venous thrombosis for a similar length of time as patients with a normal genotype. Laczika et al. (2002) described a 19-year-old woman with the joint occurrence of type I antithrombin III deficiency (613118) and a heterozygous prothrombin 20210G-A mutation, who developed chronic thromboembolic pulmonary hypertension on the basis of total occlusion of the right pulmonary artery. Pulmonary vascular patency was restored successfully by surgical pulmonary thromboendarterectomy performed 24 weeks after the initial clinical presentation. Segal et al. (2009) provided a metaanalysis of the predictive value of the prothrombin 20210G-A mutation for venous thromboembolism using a literature review of 10 relevant articles. Although heterozygosity for prothrombin 20210G-A in probands conferred a risk of 1.45, the confidence interval ranged from 0.96 to 2.2, suggesting that the mutation was not predictive of recurrent venous thromboembolism compared to those without the mutation. In addition, there was insufficient evidence regarding the predictive value of homozygosity for prothrombin 20210G-A in probands, and for the predictive value of being a mutation carrier in relatives of probands with the mutation. It remained unknown whether testing improved clinical outcomes. Segal et al. (2009) concluded that there is insufficient evidence to support the hypothesis that 20210G-A confers a significantly increased risk for venous thromboembolism in terms of genetic testing. Ischemic Stroke In a comprehensive metaanalysis of 19 case-control studies including 3,028 white adult patients, Casas et al. (2004) found a statistically significant association between ischemic stroke (601367) and the 20210G-A substitution (odds ratio of 1.44). Budd-Chiari Syndrome In a 37-year-old Caucasian male with polycythemia vera who had developed Budd-Chiari syndrome (BDCHS; 600880), Bucciarelli et al. (1998) identified heterozygosity for the 20210G-A substitution. His paternal grandmother had died at the age of 60 due to BDCHS, and his father, who was also heterozygous for the mutation, had had a myocardial infarction at age 55. Bucciarelli et al. (1998) excluded deficiencies of antithrombin, protein C, and protein S, as well as the presence of antiphospholipid syndrome and the factor V Leiden mutation. They suggested case-control studies to establish if carriers of the 20210G-A mutation have an increased risk of developing BDCHS. Oner et al. (1999) described Budd-Chiari syndrome in a patient heterozygous for both the 20210G-A mutation of F2 and the factor V Leiden mutation; heterozygosity for the factor V Leiden mutation is a known susceptibility factor for BDCHS. Oner et al. (1999) referred to the 20210G-A mutation by the abbreviation PM, presumably for 'prothrombin mutation.' Susceptibility to Recurrent Pregnancy Loss Pihusch et al. (2001) studied clotting factors in 102 patients with 2 or more consecutive spontaneous abortions (RPRGL2; 614390) compared to 128 women without miscarriage and found that heterozygosity for the 20210G-A mutation of prothrombin was more common in patients with abortions in the first trimester (p = 0.027; odds ratio, 8.5). (less)