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Breakpoint definitions. Ideograms showing each specific chromosomal aberration found in cases 1–4 and breakpoint localization
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The importance of the genetic factor in the aetiology of premature ovarian failure (POF) is emphasized by the high percentage of familial cases and X chromosome abnormalities account for 10% of chromosomal aberrations. In this study, we report the detailed analysis of 4 chromosomal abnormalities involving the X chromosome and associated with POF th...
Context in source publication
Context 1
... the observed CNVs overlapped with previously described CNVs: some of them are described as polymorphic on the Database of Genomic Variants [20], others are included in an Italian Database of Human CNVs collected in patients with mental retardation [21] and in none of our patients was any mental retardation noticed. The results of each specific chromosomal aberration, the breakpoint pos- ition and the related karyotype are summarized in Figure 3. ...Similar publications
Background
In acute myeloid leukemia (AML), the MDS1 and EVI1 complex locus - MECOM, also known as the ecotropic virus integration site 1 - EVI1, located in band 3q26, can be rearranged with a variety of partner chromosomes and partner genes. Here we report on a 57-year-old female with AML who presented with the rare translocation t(3;10)(q26;q21)...
Chromoanagenesis is a phenomenon of highly complex rearrangements involving the massive genomic shattering and reconstitution of chromosomes that has had a great impact on cancer biology and congenital anomalies. Complex chromosomal rearrangements (CCRs) are structural alterations involving three or more chromosomal breakpoints between at least two...
Standard cytogenetic techniques (chromosomal banding analysis-CBA, and fluorescence in situ hybridization-FISH) show limits in characterizing complex chromosomal rearrangements and structural variants arising from two or more chromosomal breaks. In this study, we applied optical genome mapping (OGM) to fully characterize two cases of complex chromo...
Male infertility is a multifactorial reproductive disorder. The effect of genetic factors on male infertility has been the focus of research. Although a variety of genetic techniques are applied to male infertility in clinical practice, karyotype analysis remains a powerful and inexpensive technology. Reciprocal chromosomal translocation (RCT) is c...
Male infertility is a multifactorial condition that is closely associated with chromosomal abnormalities. Reciprocal chromosomal translocation (RCT) is a significant structural genetic abnormality. The specific mechanisms of forms of RCT affecting male infertility include the product of chromosomally unbalanced gametes, thereby disrupting the struc...
Citations
... The results of a previous structural and functional analysis revealed that p.Lys273Arg substitution did not seem to have a damaging effect on the protein, although the contribution to the disease phenotype could not be ruled out [24]. A bioinformatic analysis of the breakpoint regions identified putative candidate gene, HS6ST2 for ovarian failure that were involved in the translocation event and its function with a literature review revealed a potential connection to the POI phenotype [51]. The detected p. Ser49Leu SNV was firstly described in our article. ...
Background
Premature ovarian insuffiency (POI) is one of the main cause behind infertility. The genetic analysis of POI should be part of the clinical diagnostics, as several genes have been implicated in the genetic background of it. The aim of our study was to analyse the genetic background of POI in a Hungarian cohort.
Methods
The age of onset was between 15 and 39 years. All patients had the 46,XX karyotype and they were prescreened for the most frequent POI associated FMR1 premutation. To identify genetic alterations next-generation sequencing (NGS) of 31 genes which were previously associated to POI were carried out in 48 unrelated patients from Hungary.
Results
Monogenic defect was identified in 16.7% (8 of 48) and a potential genetic risk factor was found in 29.2% (14 of 48) and susceptible oligogenic effect was described in 12.5% (6 of 48) of women with POI using the customized targeted panel sequencing. The genetic analysis identified 8 heterozygous damaging and 4 potentially damaging variants in POI-associated genes. Further 10 potential genetic risk factors were detected in seven genes, from which EIF2B and GALT were the most frequent. These variants were related to 15 genes: AIRE, ATM, DACH2, DAZL, EIF2B2, EIF2B4, FMR1, GALT, GDF9, HS6ST2, LHCGR, NOBOX, POLG, USP9X and XPNPEP2. In six cases, two or three coexisting damaging mutations and risk variants were identified.
Conclusions
POI is characterized by heterogenous phenotypic features with complex genetic background that contains increasing number of genes. Deleterious variants, which were detected in our cohort, related to gonadal development (oogenesis and folliculogenesis), meiosis and DNA repair, hormonal signaling, immune function, and metabolism which were previously associated with the POI phenotype. This is the first genetic epidemiology study targeting POI associated genes in Hungary. The frequency of variants in different POI associated genes were similar to the literature, except EIF2B and GALT. Both of these genes potential risk factor were detected which could influence the phenotype, although it is unlikely that they can be responsible for the development of the disease by themselves. Advances of sequencing technologies make it possible to aid diagnostics of POI Since individual patients show high phenotypic variance because of the complex network controlling human folliculogenesis. Comprehensive NGS screening by widening the scope to genes which were previously linked to infertility may facilitate more accurate, quicker and cheaper genetic diagnoses for POI. The investigation of patient’s genotype could support clinical decision-making process and pave the way for future clinical trials and therapies.
... Mutations in HS6ST1 have been identified among different families with idiopathic hypogonadotropic hypogonadism (IHH) [23]. These patients typically exhibit several clinical phenotypes, including infertility and incomplete or absent puberty [23,24]. In the case of our patient (POI-1), two compound homozygous variants (c.261C>A and c.341T>G) were detected in the HS6ST1 gene. ...
Background and objectives: Post-pubertal disappearance of menstrual cycles (secondary amenorrhea) associated with premature follicular depletion is a heterogeneous condition. Patients with this disease have low levels of gonadal hormones and high levels of gonadotropins. It is one of the causes of female infertility and a strong genetic component is attributed as an underlying cause of this condition. Although variants in several genes have been associated with the condition, the cause of the disease remains undetermined in the vast majority of cases. Methodology and Materials: Ten Saudi married women experiencing secondary amenorrhea were referred to a center for genetics and inherited diseases for molecular investigation. A family-based study design was used. Intensive clinical examinations, including pelvic ultra-sonography (U/S) and biochemical evaluations, were carried out. Karyotypes were normal in all cases and polycystic ovarian syndrome (PCOS) was excluded by using Rotterdam consensus criteria. Patients’ DNA samples were whole-exome sequenced (WES). Bidirectional Sanger sequencing was then utilized to validate the identified candidate variants. The pathogenicity of detected variants was predicted using several types of bioinformatics software. Results: Most of the patients have a normal uterus with poor ovarian reserves. Exome sequence data analysis identified candidate variants in genes associated with POI in 60% of cases. Novel variants were identified in HS6ST1, MEIOB, GDF9, and BNC1 in POI-associated genes. Moreover, a homozygous variant was also identified in the MMRN1 gene. Interestingly, mutations in MMRN1 have never been associated with any human disease. The variants identified in this study were not present in 125 healthy Saudi individuals. Conclusions: WES is a powerful tool to identify the underlying variants in genetically heterogeneous diseases like secondary amenorrhea and POI. In this study, we identified six novel variants and expanded the genotype continuum of POI. Unravelling the genetic landscape of POI will help in genetic counselling, management, and early intervention.
... Patients with type "other" were more likely to have gonadal abnormalities (14/21). Almost all patients had at least one complete X-chromosome segment (details shown in Table 4) [5][6][7][8][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. ...
... The AMH level (ELISA) was extremely low, indicating ovarian dysfunction. Currently, across eight articles, nine patients had the Xq/Yq translocation, including a family study where phenotypes varied in severity and included menstrual disorders, primary/secondary amenorrhea, POF, streak gonads, and non-pregnant chorionic carcinoma [29,31]. Studies by Tharapel et al. showed that deletion of different regions of the long arm of the X chromosome can be associated with GD or POF. ...
... in which the daughter's der(X)t(X;Y)(q26.2;q11.223) came from the mother, and both the mother and daughter had symptoms of POF [29]. This indicated that it is still possible to have children with X(q26.2-qter) ...
Background
X/Y translocations are highly heterogeneity in terms of clinical genetic effects, and most patients lack complete pedigree analysis for clinical and genetic characterization.
Results
This study comprehensively analyzed the clinical and genetic characteristics of three new patients with X/Y translocations. Furthermore, cases with X/Y translocations reported in the literature and studies exploring the clinical genetic effects in patients with X/Y translocations were reviewed. All three female patients were carriers of X/Y translocations with different phenotypes. The karyotype for patient 1 was 46,X,der(X)t(X;Y)(p22.33;q12)mat, patient 2 was 46,X,der(X)t(X;Y)(q21.2;q11.2)dn, and patient 3 was 46,X,der(X)t(X;Y)(q28;q11.223)t(Y;Y)(q12;q11.223)mat. C-banding analysis of all three patients revealed a large heterochromatin region in the terminal region of the X chromosome. All patients underwent chromosomal microarray analysis, which revealed the precise copy number loss or gain. Data on 128 patients with X/Y translocations were retrieved from 81 studies; the phenotype of these patients was related to the breakpoint of the chromosome, size of the deleted region, and their sex. We reclassified the X/Y translocations into new types based on the breakpoints of the X and Y chromosomes.
Conclusion
X/Y translocations have substantial phenotypic diversity, and the genetic classification standards are not unified. With the development of molecular cytogenetics, it is necessary to combine multiple genetic methods to obtain an accurate and reasonable classification. Thus, clarifying their genetic causes and effects promptly will help in genetic counseling, prenatal diagnosis, preimplantation genetic testing, and improvement in clinical treatment strategies.
... The most common genetic cause of POI is Turner syndrome due to monosomy X in complete or mosaic forms. Chromosomal aberrations such as X chromosome deletions and translocations account for 5-10% of all cases with POI [8]. Approximately 2-5% of sporadic cases with POI and secondary amenorrhea can be explained by the FMR1 premutation. ...
Premature ovarian insufficiency (POI) has a strong genetic component, but, in most cases, the etiology remains unidentified. PSMC3IP is an autosomal recessive gene for POI and ovarian dysgenesis, and so far, biallelic mutations in this gene have been described in only four independent families, with all affected members showing primary amenorrhea. Here, we report on the first family with recessive variants in the PSMC3IP gene and POI in a patient with secondary amenorrhea. Whole-exome sequencing (WES) was performed on a 29-year-old woman with secondary amenorrhea and POI; she was found to carry compound heterozygous variants in the PSMC3IP gene: c.206_208delAGA and c.189 G > T. Her younger sister, who also presented with a suspect of POI due to infertility and very low levels of anti-müllerian hormone (AMH), was found to carry the same PSMC3IP variants. Our case report shows the importance to include PSMC3IP in designed POI NGS panels or in WES/WGS studies in patients with either primary or secondary amenorrhea.
... Trisomy X (47, XXX) is an X chromosome aneuploidy presenting with POI characterized by elevated FSH levels. Other X chromosome aberrations include deletions/duplications and balanced/unbalanced X-autosome rearrangements [6][7][8][9]. Many regions on the X chromosome are critical for healthy ovarian development, and these also contain multiple genes (e.g., DIAPH2, XPNPEP2, DACH2) associated with POI. ...
Premature ovarian insufficiency (POI) is one of the main causes of female premature
infertility. POI is a genetically heterogeneous disorder with a complex molecular etiology; as such, the genetic causes remain unknown in the majority of patients. Therefore, this study aimed to identify mutations and characterize the associated molecular contribution of gonadogenesis-determinant genes to POI. Genomic assays, including PCR-SSCP and Sanger sequencing, followed by in silico analyses were used to investigate the underpinnings of ovarian deficiency in 11 women affected by POI. Large deletions and nucleotide insertions and duplications were excluded by PCR. Thirteen genetic variants were identified in the WT1 (c.213G>T, c.609T>C, c.873A>G, c.1122G>A), NR0B1 (c.353C>T, c.425G>A), NR5A1 (c.437G>C, IVS4-20C>T), LHX9 (IVS2-12G>C, IVS3+13C>T, c.741T>C),
ZNF275 (c.969C>T), and NRIP1 (c.3403C>T) genes. Seven novel genetic variants and five unpublished substitutions were identified. No genetic aberrations were detected in the ZFP92 and INSL3 genes. Each variant was genotyped using PCR-SSCP in 100 POI-free subjects, and their allelic frequencies were similar to the patients. These analyses indicated that allelic variation in the WT1, NR0B1, NR5A1, LHX9, ZFP92, ZNF275, INSL3, and NRIP1 genes may be a non-disease-causing change or may not contribute significantly to the genetics underlying POI disorders. Findings support the polygenic nature of this clinical disorder, with the SNVs identified representing only a probable contribution to the variability of the human genome.
... The efficiency of this compensation mechanism appears to be incomplete, and all the cases, but one, of unbalanced X;autosome translocations described so far show a "syndromic" clinical presentation with a constellation of medical issues, including intellectual disability (ID) [Eggermann et al., 1998;Chen et al., 2006;Watanabe et al., 2018]. Also in familial cases, the XCI pattern is considered one of the variables that, along with environmental factors, determines the phenotypic differences between members of the same family that may show different expression of the same cytogenetic alteration [Baronchelli et al., 2012]. ...
Unbalanced X;autosome translocations are a rare occurrence with a wide variability in clinical presentation in which the X chromosome unbalance is usually mitigated by a favorable X inactivation pattern. In most cases, this compensation mechanism is incomplete, and the patients show a syndromic clinical presentation. We report the case of a family with 4 women, of 3 different generations, carrying an unbalanced X;7 translocation with a derivative X;7 chromosome and showing a skewed X inactivation pattern with a preferential activation of the normal X. None of the carriers show intellectual disability, and all of them have a very mild clinical presentation mainly characterized by gynecological/hormonal issues and autoimmune disorders. We underline the necessity of family testing for a correct genetic consultation, especially in the field of prenatal diagnosis. We indeed discuss the fact that X;autosome translocations may lead to self-immunization, as skewed X chromosome inactivation has already been proved to be related to autoimmune disorders.
... Precise identification of the breakpoints has been one of the most interesting and technically challenging field in cytogenetics for investigating the possible genotype and phenotypic outcomes of carriers of chromosomal rearrangements. Conventional techniques, such as in situ hybridization with fluorescent dye-labelled bacterial artificial chromosome clones and DNA array hybridization combined with chromosome sorting have been adopted to characterize the chromosome breakpoints to the kilobase level [22][23][24][25]. However, these techniques are laborious and expensive. ...
Background:
The study is aimed to provide prediction for fertility risk in the setting of assisted reproduction for a woman with complex chromosomal rearrangements (CCRs).
Methods:
We implemented a robust approach, which combined whole-genome low-coverage mate-pair sequencing (WGL-MPS), junction-spanning PCR and preimplantation genetic testing for aneuploidy (PGT-A) method to provide accurate chromosome breakpoint junctional sequences in the embryo selection process in the setting of assisted reproduction for a couple with recurrent abortions due to CCRs.
Result:
WGL-MPS was applied to a female carrying CCRs which consisted of 9 breakpoints and 1 cryptic deletion related to fertility risks. Sequencing data provided crucial information for designing junction-spanning PCR and PGT-A process, which was performed on the 11 embryos cultivated. One embryo was considered qualified for transplanting, which carried the exact same CCRs as the female carrier, whose phenotype was normal. The amniotic fluid was also investigated by WGL-MPS and karyotyping at 19 weeks' gestation, which verified the results that the baby carried the same CCRs. A healthy baby was born at 39 weeks' gestation by vaginal delivery.
Conclusion(s):
Our study illustrates the WGL-MPS approach combining with junction-spanning PCR and PGT-A is a powerful and practical method in the setting of assisted reproduction for couples with recurrent miscarriage due to chromosomal abnormalities, especially CCRs carriers.
... Although in 80 to 90% of cases, a complete etiological work-up produces no specific cause, POI is thought to have three principal causes (Shelling, 2010): iatrogenic (Hoover et al., 2011), autoimmune (Proust-Lemoine et al., 2012;Kahaly, 2012), and genetic. The bestknown anomalies concern the X chromosome: Turner syndrome (45,X) or other X chromosome anomalies (Baronchelli et al, 2012) or the presence of a premutation of the FMR1 gene (fragile-X syndrome) (Sherman, 2000). Numerous other genetic causes have been identified in recent years due to new genetic analysis technologies (sequence variants of BMP15, AFF2,LHCGR,FSHR,INHA,FOXL2,FOXO3,ESR1,ESR2,NR5A1,CYP19A1,etc.) (Cordts et al., 2011). ...
Research question:
Primary ovarian insufficiency (POI) is defined as the early exhaustion of ovarian function, before the age of 40 years. Its origin is genetic in 20-25% of cases. In rare cases, sequence variants of the NR5A1/SF-1 gene may result in POI, or in various disorders of gonadal development (DGD) or adrenal insufficiency.
Design:
This study describes the cases of two families in which the association of DGD and POI enabled a diagnosis of NR5A1 deleterious variations. Their clinical, hormonal, ultrasound and genetic characteristics are reported.
Results:
The mothers of the affected children were 21 and 29 years when POI was diagnosed. Each nonetheless had two spontaneous pregnancies. The children have different phenotypes and different forms of DGD. None of the affected family members had adrenal insufficiency. A new sequence variant of the NR5A1 gene was identified in one family: p.Cys283Phe (c.848G>T), and the NR5A1 sequence variant c.86G>C was found in the other family.
Conclusion:
Sequence variation of the NR5A1 gene is a possibility that must be considered when a woman with POI or a diminished ovarian reserve has a family member or child with DGD. If a variant is identified, genetic counselling is essential for the patient and his/her family.
... which encodes a mitochondrial protein, as many of the genes known to underlie cases of POI are involved in metabolism or mitochondrial function [9]. Chromosomal alterations involving the X chromosome have also been identified in women with normal ovarian function [22], suggesting for patient 4 the potential involvement of both rearrangements in the phenotype. ...
Ovarian reserve represents the number of available follicles/oocytes within ovaries and it can be assessed by follicle stimulating hormone levels, anti-Müllerian hormone levels, and/or antral follicle count determined by ultrasounds. A low ovarian reserve is defined by an abnormal ovarian reserve test. This condition can be considered premature if it occurs before the age of 40, leading to premature ovarian insufficiency. Despite the growing knowledge concerning the genetic basis of ovarian deficiency, the majority of cases remain without a genetic diagnosis. Although 22q11.2 deletions and duplications have been associated with genitourinary malformations, ovarian deficiency is not a commonly reported feature. We report here four patients bearing a 22q11.2 rearrangement, identified during the clinical assessment of their low ovarian reserve or premature ovarian insufficiency, and discuss the molecular basis of the ovarian defects.
... Premature ovarian failure (POF, OMIM 311360), a different feature of female infertility has become an attractive subject for investigation due to its increasingly high incidence and the lack of effective cure. 1 Premature ovarian failure is presently one of the clinical conflicts of our century, a common disease that affects approximately 1% of under 40 year old women. It is believed that 10-28 percent of them prove primary amenorrhea 2 while 74-90% suffers of unknown etiology. ...
... q31), have been reported in different populations previously. 1,29,30 Molecular cytogenetic analysis of Xq critical regions in premature ovarian failure has revealed that Ch.Xq21.31-q28 is an exciting genomic region with association to POF phenotype. 9 ...
