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in sex chromosomes associated with gonadal dysgenesis in Turner and Swyer syndromes. See Table 2 for ZFX and BMP15 genes. Superscripts correspond to the literature reference relating each gene with POI
Source publication
Primary ovarian insufficiency is one of the main causes of female infertility owing to an abnormal ovarian reserve. Its relevance has increased in more recent years due to the fact that age of motherhood is being delayed in developed countries, with the risk of having either primary ovarian insufficiency or less chances of pregnancy when women cons...
Contexts in source publication
Context 1
... candidate gene for gonadal dysgenesis in these patients is USP9X (Ubiquitin-Specific Protease 9), which escapes the X inactivation process and is located on chromo- some Xp11.4, a critical region for ovarian development [10]; see Table 1. Other candidate genes include ZFX (Zinc Finger Protein, X-linked) and BMP15 (Bone Morphogenetic Protein 15), which will be described later. ...Similar publications
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Oxygen metabolism has an important role in the normal functioning of reproductive system, as well as the pathogenesis of female infertility. Oxidative stress seems to be responsible for the initiation or development of reproductive organ diseases, including polycystic ovary syndrome, endometriosis, preeclampsia, etc. Given the important role of mai...
Objective
To estimate the prevalence of low-prognosis patients according to the POSEIDON criteria using real-world data.
Design
Multicenter population-based cohort study.
Settings
Fertility clinics in Brazil, Turkey, and Vietnam.
Patients
Infertile women undergoing assisted reproductive technology using standard ovarian stimulation with exogenou...
Citations
... Another region of utmost importance for the POI phenotype spans from Xq13-Xq21 to Xq23-Xq27. Within the Xq13-Xq21 region, epigenetic regulation controls the down-regulation of oocyte expression motifs on autosomal genes [8][9][10][11]. Terminal deletions encompassing Xq13 are often associated with primary amenorrhea, breast hypoplasia, and complete ovarian failure [12,13]. Terminal deletions in Xq25 or Xq26 more commonly lead to POF than primary amenorrhea. ...
Background
Premature ovarian insufficiency (POI) is a clinical condition characterized by ovarian dysfunction in women under 40. The etiology of most POI cases remains unidentified and is believed to be multifactorial, including factors such as autoimmunity, metabolism, infection, and genetics. POI exhibits significant genetic heterogeneity, and it can result from chromosomal abnormalities and monogenic defects.
Case presentation
The study participant, a 33-year-old woman, presented with a history of irregular menstruation that commenced two years ago, progressing to prolonged menstrual episodes and eventual cessation. The participant exhibits a rearrangement of the X chromosome, characterized by heterozygosity duplication on the long arm and heterozygosity deletion on the short arm by whole exome sequencing(WES) combined with cell chromosome detection.
Conclusions
This study expands the spectrum of mutations associated with POI resulting from X chromosomal abnormalities. WES-Copy number variation analysis, in conjunction with chromosome karyotype analysis and other detection techniques, can provide a more comprehensive understanding of the genetic landscape underlying complex single or multi-system diseases.
... Genetic factors account for approximately 10%-17% of POI cases, with many of the cases being abnormalities associated with the X chromosome; additionally, numerical, structural, and genetic abnormalities on the X chromosome have been reported [7][8][9][10]. Numerical abnormalities include 45, X (Turner syndrome), 47, XXX, and their mosaic. ...
... Reportedly, DIAPH2, DACH2, XIST, etc., which are genes on the X chromosome, are involved in the onset of POI. Besides X chromosome abnormalities, blepharophimosis, ptosis, and epicanthus inversus syndrome, which develops due to mutations in FOXL2 found on an autosome, have also been reported [7][8][9]. In a study using genetically modified mice, numerous genetic abnormalities exhibiting the POI phenotype have been reported; in fact, NOBOX, BMP15, FSHR, etc have been confirmed in humans [10]. ...
BACKGROUND
Premature ovarian insufficiency (POI) is a condition that causes secondary amenorrhea owing to ovarian hypofunction at an early stage. Early follicular depletion results in intractable infertility, thereby considerably reducing the quality of life of females. Given the continuum in weakened ovarian function, progressing from incipient ovarian failure (IOF) to transitional ovarian failure and further to POI, it is necessary to develop biomarkers for predicting POI. The oxidative stress states in IOF and POI were comprehensively evaluated via oxidative stress [diacron-reactive oxygen metabolites (d-ROMs)] test and antioxidant capacity [biological antioxidant potential (BAP)].
AIM
To explore the possibilities of oxidative stress and antioxidant capacity as biomarkers for the early detection of POI.
METHODS
Females presenting with secondary amenorrhea over 4 mo and a follicle stimulating hormone level of > 40 mIU/mL were categorized into the POI group. Females presenting with a normal menstrual cycle and a follicle stimulating hormone level of > 10.2 mIU/mL were categorized into the IOF group. Healthy females without ovarian hypofunction were categorized into the control group. Among females aged < 40 years who visited our hospital from January 2021 to June 2022, we recruited 11 patients into both POI and IOF groups. For the potential antioxidant capacity, the relative oxidative stress index (BAP/d-ROMs × 100) was calculated, and the oxidative stress defense system was comprehensively evaluated.
RESULTS
d-ROMs were significantly higher in the POI and IOF groups than in the control group, (478.2 ± 58.7 U.CARR, 434.5 ± 60.6 U.CARR, and 341.1 ± 35.1 U.CARR, respectively) (U.CARR is equivalent to 0.08 mg/dL of hydrogen peroxide). However, no significant difference was found between the POI and IOF groups. Regarding BAP, no significant difference was found between the control, IOF, and POI groups (2078.5 ± 157.4 μmol/L, 2116.2 ± 240.2 μmol/L, and 2029.0 ± 186.4 μmol/L, respectively). The oxidative stress index was significantly higher in the POI and IOF groups than in the control group (23.7 ± 3.3, 20.7 ± 3.6, and 16.5 ± 2.1, respectively). However, no significant difference was found between the POI and IOF groups.
CONCLUSION
High levels of oxidative stress suggest that evaluating the oxidative stress state may be a useful indicator for the early detection of POI.
... Patients with the X chromosome translocation and premature ovarian insufficiency (POI) constitute an interesting study in regard to the location of breakpoints. The Xq critical region is known for its role in maintaining ovarian function and normal reproductive lifespan and is located ranging between Xq13 and Xq27 [21][22][23]. To investigate the effects of balanced X-autosome translocation resulting in POI, Di Battista fine-mapped breakpoints in six patients with POI and balanced X-autosome translocation and addressed gene expression and chromatin accessibility changes in four of them. ...
Background
Individuals with X chromosomal translocations, variable phenotypes, and a high risk of live birth defects are of interest for scientific study. These characteristics are related to differential breakpoints and various types of chromosomal abnormalities. To investigate the effects of X chromosome translocation on clinical phenotype, a retrospective analysis of clinical data for patients with X chromosome translocation was conducted. Karyotype analysis plus endocrine evaluation was utilized for all the patients. Additional semen analysis and Y chromosome microdeletions were assessed in male patients.
Results
X chromosome translocations were detected in ten cases, including seven females and three males. Infantile uterus and no ovaries were detected in case 1 (FSH: 114 IU/L, LH: 30.90 mIU/mL, E2: < 5.00 pg/ml), and the karyotype was confirmed as 46,X,t(X;22)(q25;q11.2) in case 1. Infantile uterus and small ovaries were both visible in two cases (FSH: 34.80 IU/L, LH: 17.06 mIU/mL, E2: 15.37 pg/ml in case 2; FISH: 6.60 IU/L, LH: 1.69 mIU/mL, E2: 23.70 pg/ml in case 3). The karyotype was detected as 46,X,t(X;8)(q13;q11.2) in case 2 and 46,X,der(X)t(X;5)(q21;q31) in case 3. Normal reproductive hormone levels and fertility abilities were found for cases 4, 6 and 7. The karyotype were detected as 46,X,t(X;5)(p22.3;q22) in case 4 and 46,X,der(X)t(X;Y)(p22.3;q11.2) in cases 6 and 7. These patients exhibited unremarkable clinical manifestations but experienced a history of abnormal chromosomal pregnancy. Normal phenotype and a complex reciprocal translocation as 46,X,t(X;14;4)(q24;q22;q33) were observed in case 5 with a history of spontaneous abortions. In the three male patients, multiple semen analyses confirmed the absence of sperm. Y chromosome microdeletion and hormonal analyses were normal. The karyotypes were detected as 46,Y,t(X;8)(q26;q22), 46,Y,t(X;1)(q26;q23), 46,Y,t(X;3)(q26;p24), respectively.
Conclusions
Our study provides insights into individuals with X chromosome translocations. The clinical phenotypes are variable and unpredictable due to differences in breakpoints and X chromosome inactivation (XCI) patterns. Our results suggest that physicians should focus on the characteristics of the X chromosome translocations and provide personalized clinical evaluations in genetic counselling.
... TruSight TM Exome focuses on a subset of disease-causing genes shown to be important in specific inherited conditions. The coding region of more than 4,800 genes, including a total of sixty-four non-syndromic POI genes ( (5). The genes that are known or suspected to be involved in hypergonadotropic hypogonadism were selected (6). ...
Objective
The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel based on next generation sequencing analysis and to establish the relationship between genotype and phenotype.
Subjects and methods
Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSightTM Exome panel.
Results
Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In 2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype.
Conclusion
Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.
Keywords
Primary ovarian insufficiency; candidate genes; next generation sequencing analysis
... Females with triple X syndrome or trisomy X (47, XXX) can experience primary infertility and clinical manifestations of POI [61,62]. While POI is not a consistent feature of X chromosome tetrasomy (48, XXXX), it has been linked to it in some cases [63]. Additionally, a 16-year-old girl with pentasomy X mosaicism (47, XXX (1) 48, XXXX (12)/ 49, X) reported primary amenorrhea [64]. ...
... Genetic factors, including genes on both the long and short arms of the X chromosome, play a significant role in primary ovarian insufficiency (POI) [63]. The FMR1 gene on the X chromosomes long arm, responsible for the fragile X mental retardation protein, has been linked to POI, with a premutation found in 15% of affected women, underscoring the genetic contribution [70]. ...
... Autosomal genes, including FSHR, GNAS, GALT, AIRE, StAR, CYP17A1, CYP19A1, EIF2B, NOG, POLG, PMM1, BMPR1B, GJA4, and others, have been extensively investigated for their associations with syndromic primary ovarian insufficiency (POI) [63]. Mutations in FSHR, such as the p.R59X mutation, have been linked to POI by halting folliculogenesis [78]. ...
Primary ovarian insufficiency (POI) is a medical condition where ovarian function stops prematurely, typically before the age of 40. This condition leads to infertility and produces symptoms similar to those experienced during menopause. Although the origins of POIs are diverse, genetic elements substantially influence their emergence. This assessment delves into the genetic facets of POI, covering genetic triggers, detection, and genetic consultation. We scrutinize the genes linked to POI and their function in ovarian activity, as well as the genetic deviations and mutations that foster POI onset. We also examine the challenges and limitations of genetic testing and counseling for POI and suggest ways to address these challenges. This review offers a thorough examination of the existing understanding of the genetic factors linked to Primary Ovarian Insufficiency (POI) emphasizing the critical need for further investigation in this field.
... Genetic causes of POI have been reported in 1-10% of cases, whereas other causes include autoimmune and iatrogenic conditions [5][6][7] . Around 50-90% of POI cases are idiopathic 8,9 , 10-30% of those being familial, suggesting a genetic basis. Furthermore, heritability estimates of menopausal age from mother-daughter pairs range from 44% to 65% 10,11 and there is a six times increased risk of early menopause in daughters of affected mothers 12,13 . ...
... Variants in other genes are described as being inherited in an autosomal recessive (AR) manner, requiring both copies of the gene to be disrupted to cause the phenotype (for example, HFM1, LARS2 and MCM8). In addition to the autosomal genes, X chromosome genes have long been suggested to play an essential role in the maintenance of ovarian development and function, with X chromosome structural variants representing about 13% of POI cases in some published series 8,14,15 . ...
Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported at natural menopause under the age of 40 years. We found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes, we ruled out even modest penetrance, with 99.9% (13,699 out of 13,708) of all protein-truncating variants found in reproductively healthy women. We found evidence of haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P = 1.59 × 10⁻⁶) and SOHLH2 (3.48 years earlier menopause, P = 1.03 × 10⁻⁴). Collectively, our results suggest that, for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. Our findings, plus previous studies, suggest that most POI cases are likely oligogenic or polygenic in nature, which has important implications for future clinical genetic studies, and genetic counseling for families affected by POI.
... Despite the rareness of patients with this type of rearrangements (1:30,000) [12,13], clear patterns in the localization of their X-chromosome breakpoints have been recognized. Most female patients with premature ovarian failure (POI) present breakpoints within a specific region of the X-chromosome long arm, spanning from Xq13 to Xq27, named the "Xq critical region" for its role in the maintenance of ovarian function and normal reproductive lifespan [14,15]. This Xq critical region for the ovarian function is divided into two smaller intervals, Xq13.1-Xq21. ...
Background:
Patients with balanced X-autosome translocations and premature ovarian insufficiency (POI) constitute an interesting paradigm to study the effect of chromosome repositioning. Their breakpoints are clustered within cytobands Xq13-Xq21, 80% of them in Xq21, and usually, no gene disruption can be associated with POI phenotype. As deletions within Xq21 do not cause POI, and since different breakpoints and translocations with different autosomes lead to this same gonadal phenotype, a "position effect" is hypothesized as a possible mechanism underlying POI pathogenesis.
Objective and methods:
To study the effect of the balanced X-autosome translocations that result in POI, we fine-mapped the breakpoints in six patients with POI and balanced X-autosome translocations and addressed gene expression and chromatin accessibility changes in four of them.
Results:
We observed differential expression in 85 coding genes, associated with protein regulation, multicellular regulation, integrin signaling, and immune response pathways, and 120 differential peaks for the three interrogated histone marks, most of which were mapped in high-activity chromatin state regions. The integrative analysis between transcriptome and chromatin data pointed to 12 peaks mapped less than 2 Mb from 11 differentially expressed genes in genomic regions not related to the patients' chromosomal rearrangement, suggesting that translocations have broad effects on the chromatin structure.
Conclusion:
Since a wide impact on gene regulation was observed in patients, our results observed in this study support the hypothesis of position effect as a pathogenic mechanism for premature ovarian insufficiency associated with X-autosome translocations. This work emphasizes the relevance of chromatin changes in structural variation, since it advances our knowledge of the impact of perturbations in the regulatory landscape within interphase nuclei, resulting in the position effect pathogenicity.
... The glycolytic gene CITED2 is also a hypoxia-related gene. It has been reported that CITED2 is associated with primary ovarian insufficiency [29]. ...
Purpose
The objective of this study was to investigate the key glycolysis-related genes linked to immune cell infiltration in endometriosis and to develop a new endometriosis (EMS) predictive model.
Methods
A training set and a test set were created from the Gene Expression Omnibus (GEO) public database. We identified five glycolysis-related genes using least absolute shrinkage and selection operator (LASSO) regression and the random forest method. Then, we developed and tested a prediction model for EMS diagnosis. The CIBERSORT method was used to compare the infiltration of 22 different immune cells. We examined the relationship between key glycolysis-related genes and immune factors in the eutopic endometrium of women with endometriosis. In addition, Gene Ontology (GO)-based semantic similarity and logistic regression model analyses were used to investigate core genes. Reverse real-time quantitative PCR (RT-qPCR) of 5 target genes was analysed.
Results
The five glycolysis-related hub genes (CHPF, CITED2, GPC3, PDK3, ADH6) were used to establish a predictive model for EMS. In the training and test sets, the area under the curve (AUC) of the receiver operating characteristic curve (ROC) prediction model was 0.777, 0.824, and 0.774. Additionally, there was a remarkable difference in the immune environment between the EMS and control groups. Eventually, the five target genes were verified by RT-qPCR.
Conclusion
The glycolysis-immune-based predictive model was established to forecast EMS patients’ diagnosis, and a detailed comprehension of the interactions between endometriosis, glycolysis, and the immune system may be vital for the recognition of potential novel therapeutic approaches and targets for EMS patients.
... Evidence shows that the prevalence of autoimmune disease in the general population of women is 5.8%, for women with POI 15%, and for women with TS 37% [6]. X chromosome abnormalities in the form of microdeletions, permutations, and mutations of genes are established factors in the origin of POI [8,9]. A stepwise decrease in the dosage of X chromosome genes is observed from the general population of women (two normal X chromosomes) to women with POI (macro-microdeletion of the X chromosome) to women with TS (complete absence of one X chromosome or a portion of the X chromosome) [6]. ...
Introduction:
Autoimmune diseases occur more often in females, suggesting a key role for the X chromosome. Curiously, individuals with Turner syndrome (TS), with fewer copies of X-linked genes, are prone to develop autoimmune conditions. Hashimoto's thyroiditis (HT) is described with a relatively high frequency in patients with TS while the association with Graves' disease (GD) is rare. Here we report a rare case of TS with GD in a young patient.
Method:
A 14-year-old girl presented with hyperthyroid symptoms and eye signs that developed over the past six months. She had somatic stigmata of TS. TS was diagnosed by karyotyping (45,XO/46,XX del Xq22) and GD was diagnosed by a thyroid function test and the presence of autoantibodies. She was treated effectively with carbimazole for GD. Estrogen replacement therapy was also initiated to induce the development of secondary sex characteristics.
Conclusion:
X chromosome inactivation, an epigenetic process that establishes and maintains dosage compensation of X-linked genes, is especially vulnerable to disruption and may contribute to an autoimmune disease process. The occurrence of autoimmune diseases in patients with TS is discussed with regard to possible abnormalities in X-linked dosage compensation.
... Genetic causes of POI have been reported in 1-10% of cases while other causes include autoimmune and iatrogenic [5][6][7] . Approximately 50-90% of POI cases are idiopathic 8,9 , 10-30% of those being familial, suggesting a genetic basis. Furthermore, heritability estimates of menopausal age from mother-daughter pairs range from 44% to 65% 10,11 and there is a six times increased risk of early menopause in daughters of affected mothers 12,13 . ...
... HFM1, LARS2 and MCM8). In addition to the autosomal genes, X chromosome genes have long been suggested to play an essential role in the maintenance of ovarian development and function, with X chromosome structural variants representing about 13% of POI cases in some published series 8,14,15 . ...
Premature ovarian insufficiency (POI) affects 1% of women and is a leading cause of infertility. It is often considered to be a monogenic disorder, with pathogenic variants in ~100 genes described in the literature. We sought to systematically evaluate the penetrance of variants in these genes using exome sequence data in 104,733 women from the UK Biobank, 2,231 (1.14%) of whom reported natural menopause under the age of 40. In the largest study of POI to date, we found limited evidence to support any previously reported autosomal dominant effect. For nearly all heterozygous effects on previously reported POI genes we were able to rule out even modest penetrance, with 99.9% (13,699/13,708) of all identified protein truncating variants found in reproductively healthy women. We found evidence of novel haploinsufficiency effects in several genes, including TWNK (1.54 years earlier menopause, P=1.59*10-6) and SOHLH2 (3.48 years earlier menopause, P=1.03*10-4). Collectively our results suggest that for the vast majority of women, POI is not caused by autosomal dominant variants either in genes previously reported or currently evaluated in clinical diagnostic panels. We suggest that the majority of POI cases are likely oligogenic or polygenic in nature, which has major implications for future clinical genetic studies, and genetic counselling for families affected by POI.
