Alternative titles; symbols
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 1q24.2 | {Pregnancy loss, recurrent, susceptibility to, 1} | 614389 | Autosomal dominant | 3 | F5 | 612309 |
A number sign (#) is used with this entry because of evidence that susceptibility to recurrent pregnancy loss-1 (RPRGL1) is conferred by variation in the coagulation factor V gene (F5; 612309) on chromosome 1q24.
Miscarriage, the commonest complication of pregnancy, is the spontaneous loss of a pregnancy before the fetus has reached viability. The term therefore includes all pregnancy losses from the time of conception until 24 weeks of gestation. Recurrent miscarriage, defined as 3 or more consecutive pregnancy losses, affects about 1% of couples; when defined as 2 or more losses, the scale of the problem increases to 5% of all couples trying to conceive (summary by Rai and Regan, 2006).
Pregnancy losses have traditionally been designated 'spontaneous abortions' if they occur before 20 weeks gestation and 'stillbirths' if they occur after 20 weeks. Subtypes of spontaneous abortions can be further distinguished on the basis of embryonic development and include anembryonic loss in the first 5 weeks after conception (so-called 'blighted ovum'), embryonic loss from 6 to 9 weeks' gestation, and fetal loss from 10 weeks' gestation through the remainder of the pregnancy. These distinctions are important because the causes of pregnancy loss vary over gestational ages, with anembryonic losses being more likely to be associated with chromosomal abnormalities, for example. Possible etiologies for RPRGL include uterine anatomic abnormalities, cytogenetic abnormalities in the parents or fetus, single gene disorders, thrombophilic conditions, and immunologic or endocrine factors as well as environmental or infectious agents (summary by Warren and Silver, 2008).
Genetic Heterogeneity of Recurrent Pregnancy Loss
Susceptibility to RPRGL2 (614390) is conferred by mutation in the coagulation factor II gene (176930) on chromosome 11p11; RPRGL3 (614391) by mutation in the ANXA5 gene (131230) on chromosome 4q27; and RPRGL4 (see 270960) by mutation in the SYCP3 gene (604759) on chromosome 12q23.
Genetic variation in the conceptus itself that results in decreased viability of the embryo or fetus is discussed in the respective gene and/or phenotype entry (see, e.g., MTHFR, 607093.0004; NLRP7, 609661; hydatidiform mole, 231090).
Kwak-Kim et al. (2009) noted that thrombotic/inflammatory processes are often observed at the maternal-fetal interface as the final pathologic insult in many cases of RPRGL. They reviewed the involvement of cellular immune responses and autoimmune abnormalities in women with RPRGL.
Disorders of Coagulation
Maternal hypercoagulability has been hypothesized to be a major causative factor in RPRGL (Allison and Schust, 2009). See, e.g., antiphospholipid syndrome (107320), which involves arterial and venous thrombosis and recurrent fetal loss, and activated protein C resistance (188055).
Braulke et al. (1993) presented data suggesting that reduced levels of factor XII activity (234000) may be a risk factor for repeated spontaneous abortions. Standen and Bowen (1993) reported a woman with factor XIII deficiency (613225) who had 2 pregnancies terminate in spontaneous abortion, but 2 further pregnancies in which she was transfused with fresh frozen plasma resulted in live offspring.
Pregnancy-Specific Glycoproteins
Pregnancy-specific beta-1-glycoprotein (176390) levels have been found to correlate well with placental function and fetal well-being (Gordon et al., 1977; Bartels and Lindemann, 1988). Low pregnancy-specific glycoprotein (PSG) levels are associated with poor pregnancy outcome (Wurz et al., 1981).
Trophoblast-Lymphocyte Crossreactive Alloantigens
McIntyre et al. (1983) proposed that trophoblast-lymphocyte crossreactive alloantigens (TLX; 120920) are central in establishing maternal recognition and protection of the blastocyst, and that lack of recognition results in implantation failure and spontaneous abortion.
P-Related IgG and IgM Antibodies
Hellberg et al. (2004) explored the molecular basis of the clinically important but rare blood group phenotypes p, P1(k), and P2(k), by analysis of the A4GALT (607922) and B3GALT3 (603094) genes, which are responsible for synthesis of the related Gb3 and Gb4 antigens, respectively. Lack of these glycolipid moieties is associated with severe transfusion reactions and recurrent spontaneous abortions but also offers immunity against infectious agents.
Other Related Factors
Salker et al. (2011) observed that SGK1 (602958), a kinase involved in epithelial ion transport and cell survival, was downregulated in midsecretory endometrial samples from women with RPRGL, whereas SGK1 was upregulated in samples from patients with unexplained infertility. Relative SGK1 deficiency was also a hallmark of decidualizing stromal cells from women with RPRGL, sensitizing those cells to oxidative cell death and rendering the fetomaternal interface vulnerable to oxidative damage.
Majerus (1994) noted that an estimated 2 to 4% of the Dutch population and 7% of the Swedish population carried a mutant R506Q allele of coagulation factor V, the 'factor V Leiden' variant (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 study of 67 women with a first episode of unexplained late fetal loss (fetal death after 20 weeks or more of gestation) 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.
Associations Pending Confirmation
Associations between certain HLA polymorphisms and RPRGL have been reported; see, e.g., HLA-G (142871), HLA-DRB1 (142857), and HLA-DQB1 (604305).
For discussion of a possible association between RPRGL and variation in the NOS3 gene, see 163729.
For discussion of a possible association between RPRGL and variation in the JAK2 gene, see 147796.
For discussion of a possible association between RPRGL and variation in the NLRP7 gene, see 609661.
Allison, J. L., Schust, D. J. Recurrent first trimester pregnancy loss: revised definitions and novel causes. Curr. Opin. Endocr. Diabetes Obes. 16: 446-450, 2009. [PubMed: 19779333] [Full Text: https://doi.org/10.1097/MED.0b013e3283327fc5]
Bartels, I., Lindemann, A. Maternal levels of pregnancy-specific beta-1-glycoprotein (SP-1) are elevated in pregnancies affected by Down's syndrome. Hum. Genet. 80: 46-48, 1988. [PubMed: 2971018] [Full Text: https://doi.org/10.1007/BF00451454]
Braulke, I., Hinney, G., Pruggmayer, M., Kostering, H., Melloh, P., Gunther, E. Factor XII (Hageman) deficiency in women with habitual abortion: new subpopulation of recurrent aborters? Fertil. Steril. 59: 98-101, 1993. [PubMed: 8419231] [Full Text: https://doi.org/10.1016/s0015-0282(16)55622-2]
Gordon, Y. B., Jeffrey, D., Grudzinska, J. G., Chard, T., Letchworth, A. T. Concentration of pregnancy-specific beta-1-glycoprotein in maternal blood in normal pregnancy and in intrauterine growth retardation. Lancet 309: 331-333, 1977. Note: Originally Volume I. [PubMed: 64859] [Full Text: https://doi.org/10.1016/s0140-6736(77)91135-7]
Hellberg, A., Ringressi, A., Yahalom, V., Safwenberg, J., Reid, M. E., Olsson, M. L. Genetic heterogeneity at the glycosyltransferase loci underlying the GLOB blood group system and collection. Brit. J. Haemat. 125: 528-536, 2004. [PubMed: 15142124] [Full Text: https://doi.org/10.1111/j.1365-2141.2004.04930.x]
Kwak-Kim, J., Yang, K. M., Gilman-Sachs, A. Recurrent pregnancy loss: a disease of inflammation and coagulation. J. Obstet. Gynaecol. Res. 35: 609-622, 2009. [PubMed: 19751318] [Full Text: https://doi.org/10.1111/j.1447-0756.2009.01079.x]
Majerus, P. W. Bad blood by mutation. Nature 369: 14-15, 1994. [PubMed: 8164730] [Full Text: https://doi.org/10.1038/369014a0]
Martinelli, I., Taioli, E., Cetin, I., Marinoni, A., Gerosa, S., Villa, M. V., Bozzo, M., Mannucci, P. M. Mutations in coagulation factors in women with unexplained late fetal loss. New Eng. J. Med. 343: 1015-1018, 2000. [PubMed: 11018168] [Full Text: https://doi.org/10.1056/NEJM200010053431405]
McIntyre, J. A., Faulk, W. P., Verhulst, S. J., Colliver, J. A. Human trophoblast-lymphocyte cross-reactive (TLX) antigens define a new alloantigen system. Science 222: 1135-1137, 1983. [PubMed: 6648525] [Full Text: https://doi.org/10.1126/science.6648525]
Rai, R., Regan, L. Recurrent miscarriage. Lancet 368: 601-611, 2006. [PubMed: 16905025] [Full Text: https://doi.org/10.1016/S0140-6736(06)69204-0]
Salker, M. S., Christian, M., Steel, J. H., Nautiyal, J., Lavery, S., Trew, G., Webster, Z., Al-Sabbagh, M., Puchchakayala, G., Foller, M., Landles, C., Sharkey, A. M., Quenby, S., Aplin, J. D., Regan, L., Lang, F., Brosens, J. J. Deregulation of the serum- and glucocorticoid-inducible kinase SGK1 in the endometrium causes reproductive failure. Nature Med. 17: 1509-1513, 2011. [PubMed: 22001908] [Full Text: https://doi.org/10.1038/nm.2498]
Standen, G. R., Bowen, D. J. Factor XIII A-Bristol 1: detection of a nonsense mutation (arg171-to-stop codon) in factor XIII A subunit deficiency. Brit. J. Haemat. 85: 769-772, 1993. [PubMed: 7918041] [Full Text: https://doi.org/10.1111/j.1365-2141.1993.tb03221.x]
Warren, J. E., Silver, R. M. Genetics of pregnancy loss. Clin. Obstet. Gynec. 51: 84-95, 2008. [PubMed: 18303502] [Full Text: https://doi.org/10.1097/GRF.0b013e318161719c]
Wurz, H., Geiger, W., Kunzig, H. J., Jabs-Lehmann, A., Bohn, H., Luben, G. Radioimmunoassay of SP1 (pregnancy-specific beta-1-glycoprotein) in maternal blood and in amniotic fluid in normal and pathologic pregnancies. J. Perinat. Med. 9: 67-78, 1981. [PubMed: 6787188] [Full Text: https://doi.org/10.1515/jpme.1981.9.2.67]