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Chromosomal inversions: two breaks in the same chromosome, causing the resulting fragments to reconnect after 180 degrees of reversal. (a) Paracentric inversion: the inverted segments do not contain chromosomes. (b) Pericentric inversion: the inverted segments contain chromosomes. (c) Possible gametes of paracentric inversion. In meiosis, a crossover between a normal chromosome and an inverted chromosome results in the loss or duplication of a segment of the gametophyte chromosome, leading to chromosome abnormality and abnormal traits in the offspring. Balanced gametes are designated by the green border. Unbalanced gametes are designated by the red border. (d) Possible gametes of pericentric inversion. Balanced gametes are designated by the green border. Unbalanced gametes are designated by the red border.
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Recurrent pregnancy loss (RPL) is both mental and physical health problem affecting about 1–5% of women of childbearing age. The etiology of RPL is complex, involving chromosomal abnormalities, autoimmune diseases, metabolic disorders, and endometrial dysfunction. The causes of abortion are still unknown in more than 50% of these cases. With the de...
Citations
... Nitric oxide metabolites in pregnancy and pregnancy complications have been extensively studied [22,23], including RPL [24][25][26][27][28]. A possible association between endothelial nitric oxide synthase and RPL has been suggested, especially in exon 8, rs1799983 (+894G>T). ...
... Evidence suggests that a reduction in nitric oxide production related to polymorphisms of the eNOS enzyme may be linked to implantation failure and frequent miscarriages [19,[23][24][25][26][27]33]. The polymorphism can affect the response of the vascular endothelium to oxidative stress and, therefore, promote vascular remodelling and cause pregnancy complications. ...
Recurrent pregnancy loss (RPL) affects around 2% of women of reproductive age. Primary RPL is defined by ≥2 pregnancy losses and no normal birth delivery. In secondary RPL, the losses are after a normal pregnancy and delivery. Most cases have no clear aetiology, although primary cases are the most complex. Several gene single nucleotide polymorphisms (SNPs) have been associated with RPL. The frequency of some SNPs is increased in women suffering from RLP from Asian or Caucasian races; however, in admixed populations, the information on possible genetic links is scarce and contradictory. This study aimed to assess the frequency of two SNPs present in two different enzymes involved in medical conditions observed during pregnancy. It is a case-control study. Microsomal epoxy hydrolase (mEPH) is involved in detoxifying xenobiotics, is present in the ovaries, and is hormonally regulated. The endothelial nitric oxide synthase (NOS3) that forms nitric is involved in vascular tone. Two SNPs, rs1051740 (mEPH) and rs1799983 (NOS3), were assessed. The study included 50 controls and 63 primary RPL patients. The frequency of mutated alleles in both SNPs was significantly higher in patients (p < 0.05). Double-mutated homozygotes were encountered only in RPL patients (p < 0.05). Genetic polymorphisms rs1051740 and rs1799983 may be involved in primary RPL in the Venezuelan admix population. Genetic studies could provide crucial information on the aetiology of primary RPL.
... Study [12] provided an understanding of the "etiopathogenesis of miscarriages" brought on by the hereditary type of thrombophilia. Chromosome variations, chromosomal polymorphisms, and genetic polymorphisms are just a few of the genetic traits linked to RPL presented in this study [13]. According to this research [14], the measurement of "antithrombin, protein S, and protein C activity, as well as other thrombophilia tests" is all affected by direct anticoagulants (DOACs). ...
Recurrent pregnancy loss (RPL) is multiple pregnancy losses. Inherited thrombophilia, which increases blood clot risk, contributes to RPL. Pre-gestational therapy with Low-Molecular-Weight Heparin (LMH) and Aspirin may improve pregnancy outcomes in these patients. This study aims to evaluate the effectiveness of pre-gestational management and the combination of LMH and Aspirin in patients with RPL and inherited thrombophilia. A hereditary thrombophilia test was performed on each of the 459 pregnant research participants, whose gestational ages ranged from 6 to 38 gestational week Medical center-Prime Clinic and KIRM-Pleven in Bulgaria period from January 2021-May 2023 were collected. Based on the treatment method, patients in a dataset with RPL and hereditary thrombophilia were split into three groups. Group I (Control) patients did not get any pre-gestational care or anticoagulant treatment. Group II: Patients who only received aspirin treatment with 100 mg. Group III: Patients receiving LMH and aspirin therapy. Compared to the treated groups (Group II and Group III), the pregnancy success rate was noticeably lower among the patients in Group I (Control). In addition, Group I experienced more thrombotic events than the groups that received treatment. Pre-gestational therapy with aspirin alone or in combination improves pregnancy outcomes and reduces thrombotic events in RPL and hereditary thrombophilia patients. LMH combined with aspirin may increase pregnancy success more than aspirin alone. These findings need further investigation and larger trials to maximize treatment for this patient population.
... Nitric oxide metabolites in pregnancy and pregnancy complications have been extensively studied [23,24], including RPL [25][26][27][28][29]. A possible association between endothelial nitric oxide synthase and RPL has been suggested, especially in exon 8, rs1799983 (+ 894G > T). ...
... Evidence suggests that a reduction in nitric oxide production related to polymorphisms of the eNOS enzyme may be related to implantation failure and frequent miscarriages [20,[24][25][26][27][28]33]. The polymorphism can affect the response of the vascular endothelium to oxidative stress and, therefore, promote vascular remodelling and cause pregnancy complications. ...
Gene polymorphism of mEPH and eNOS in recurrent pregnancy loss
... Noteworthy, a more robust negative correlation between age and methylation levels was observed in the MTHFR 677TT dysfunctional genotype, and at a greater extent in the spontaneous abortion subgroup supporting the concept that a suboptimal haplotype-driven intracellular methyl-groups availability exists 13,44 , and it may affect embryo survival and pregnancy maintenance. DNA methylation of imprinted genes, and/or genes directly or not related to methyl groups cycling, uterine immune tolerance, inflammation, neo-angiogenesis, apoptosis, cytokine expression, and lipid or folate metabolism, globally contribute to the kaleidoscope of pregnancy maintenance 100 . On the other hand, many genetic risk factors have been largely investigated, mainly by SNPs analysis and meta-analyses utilized for risk prediction, often leading to conflicting or partial results 100 . ...
... DNA methylation of imprinted genes, and/or genes directly or not related to methyl groups cycling, uterine immune tolerance, inflammation, neo-angiogenesis, apoptosis, cytokine expression, and lipid or folate metabolism, globally contribute to the kaleidoscope of pregnancy maintenance 100 . On the other hand, many genetic risk factors have been largely investigated, mainly by SNPs analysis and meta-analyses utilized for risk prediction, often leading to conflicting or partial results 100 . ...
Spontaneous abortion is a pregnancy complication characterized by complex and multifactorial etiology. About 5% of childbearing women are globally affected by early pregnancy loss (EPL) and most of them experience recurrence (RPL). Epigenetic mechanisms and controlled inflammation are crucial for pregnancy maintenance and genetic predispositions may increase the risk affecting the maternal–fetal crosstalk. Combined analyses of global methylation, inflammation and inherited predispositions may contribute to define pregnancy loss etiopathogenesis. LINE-1 epigenetic regulation plays crucial roles during embryo implantation, and its hypomethylation has been associated with senescence and several complex diseases. By analysing a group of 230 women who have gone through pregnancy interruption and comparing those experiencing spontaneous EPL (n = 123; RPL, 54.5%) with a group of normal pregnant who underwent to voluntary interruption (VPI, n = 107), the single statistical analysis revealed significant lower (P < 0.00001) LINE-1 methylation and higher (P < 0.0001) mean cytokine levels (CKs: IL6, IL10, IL17A, IL23) in EPL. Genotyping of the following SNPs accounted for different EPL/RPL risk odds ratio: F13A1 rs5985 (OR = 0.24; 0.06–0.90); F13B rs6003 (OR = 0.23; 0.047–1.1); FGA rs6050 (OR = 0.58; 0.33–1.0); CRP rs2808635/rs876538 (OR = 0.15; 0.014–0.81); ABO rs657152 (OR = 0.48; 0.22–1.08); TP53 rs1042522 (OR = 0.54; 0.32–0.92); MTHFR rs1801133/rs1801131 (OR = 2.03; 1.2–3.47) and FGB rs1800790 (OR = 1.97; 1.01–3.87), although Bonferroni correction did not reach significant outputs. Principal Component Analysis (PCA) and logistic regression disclosed further SNPs positive/negative associations (e.g. APOE rs7412/rs429358; FGB rs1800790; CFH rs1061170) differently arranged and sorted in four significant PCs: PC1 (F13A, methylation, CKs); PC3 (CRP, MTHFR, age, methylation); PC4 (F13B, FGA, FGB, APOE, TP53, age, methylation); PC6 (F13A, CFH, ABO, MTHFR, TP53, age), yielding further statistical power to the association models. In detail, positive EPL risk association was with PC1 (OR = 1.81; 1.33–2.45; P < 0.0001) and negative associations with PC3 (OR = 0.489; 0.37–0.66; P < 0.0001); PC4 (OR = 0.72; 0.55–0.94; P = 0.018) and PC6 (OR = 0.61; 0.46–0.81; P = 0.001). Moreover, significant inverse associations were detected between methylation and CKs levels in the whole group (rIL10 = − 0.22; rIL17A = − 0.25; rIL23 = − 0.19; rIL6 = − 0.22), and methylation with age in the whole group, EPL and RPL subgroups (r²TOT = 0.147; r²EPL = 0.136; r²RPL = 0.248), while VPI controls lost significance (r²VPI = 0.011). This study provides a valuable multilayer approach for investigating epigenetic abnormalities in pregnancy loss suggesting genetic-driven dysregulations and anomalous epigenetic mechanisms potentially mediated by LINE-1 hypomethylation. Women with unexplained EPL might benefit of such investigations, providing new insights for predicting the pregnancy outcome and for treating at risk women with novel targeted epidrugs.
... Recurrent pregnancy loss (RPL) is a devastating reproductive health burden, affects about 3-5% of couples trying to conceive globally (1). The etiology of RPL is complex, involving genetic abnormalities, metabolic disorders, autoimmune diseases, and endometrial dysfunction (2,3). The causes reason of RPL are still unknown in more than 50% of these couples. ...
... The causes reason of RPL are still unknown in more than 50% of these couples. With the development of detection technology, genetic factors were found may play an essential role in unexplained RPL, such as chromosome abnormalities, copy number variants, single-gene changes and others (2). Previous researches reveal that the incidence of chromosome abnormalities in sporadic pregnancy loss was signi cantly higher than RPL (4). ...
... The clinical symptoms of 3 and 5 were similar, polycystic kidney dysplasia and severe oligohydramnios. She only gave birth to one healthy daughter ( 2). The samples from the previous three abnormal pregnancies were not retained. ...
Background:Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient.
Case presentation: Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T>G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as “pathogenic”. c.1415T>G (p.V472G) located in extra-cellular region, was classified as “likely pathogenic”. Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband’s prenatal phenotype.
Conclusion: The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67and emphasizes the necessity of exome sequencing in RPL condition.
Background
Recurrent pregnancy loss (RPL) is a common pregnancy complication that brings great pain to pregnant women and their families. Genetic factors are an important cause reason of RPL. However, clinical research on monogenic diseases with recurrent miscarriage is insufficient.
Case presentation
Here we reported a Chinese family with RPL and genetic analysis of the abortion and parents. A paternally inherited heterozygous missense variant c.1415T > G (p.V472G) and a maternally inherited heterozygous nonsense variant c.2314del (p.M772*) in TMEM67 gene were identified by trio-exome sequencing. c.2314del (p.M772*) generated a premature stop codon and truncated protein, was classified as “pathogenic”. c.1415T > G (p.V472G) located in extra-cellular region, was classified as “likely pathogenic”. Biallelic variants in TMEM67 gene cause lethal Meckel syndrome 3, consistent with the proband’s prenatal phenotype.
Conclusion
The current study of the Chinese family expands the pathogenic variant spectrum of TMEM67 and emphasizes the necessity of exome sequencing in RPL condition.
Background
Although systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS) have been clinically confirmed to cause pregnancy loss and effective clinical treatment and nursing programs have been proposed to greatly improve pregnancy outcomes, the relationship between other types of autoimmune diseases (ADs) and pregnancy loss remains unclear due to inconsistent conclusions from existing observational studies. This has hindered the formation of clinical consensus and the implementation of comprehensive management for pregnant women with ADs. To address this gap, we executed a two-sample mendelian randomization(MR) approach intending to assess the potential causal impact of 29 ADs on 7 types of pregnancy loss.
Results
The two-sample MR investigations with inverse variance weighted(IVW) approach revealed strong causal relationship between broadly defined ADs and stillbirth, spontaneous miscarriage, or termination [Odd ratios (ORs), 1.00846; 95% confidence intervals (CIs), 1.00095–1.01602; p value = 0.027]. Type 1 diabetes (T1D) exhibited a positive link with the number of spontaneous miscarriages [OR, 1.00709; 95%CI, 1.00134–1.01288; p value = 0.016]. Meanwhile, autoimmune hypothyroidism was strongly linked to ever had stillbirth, spontaneous miscarriage, or termination [OR, 1.00413; 95%CI, 1.00043–1.00784; p value = 0.028]. Additionally, crohn's disease (CD), a gastrointestinal immune disease, exhibited a significantly positive correlation with spontaneous abortion [OR, 1.00036; 95%CI, 1.00012–1.00059; p value = 0.003]. Interestingly, we observed that rheumatoid arthritis (RA) indicated a negative connection with spontaneous abortion [OR, 0.99953; 95%CI, 0.99909–0.99997; p value = 0.036].
Conclusion
The findings of this study implied a causal association between different ADs and pregnancy loss, thus advancing our comprehension of the ADs-mediated etiology and pathogenesis of pregnancy loss.
