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Maternal obesity is increasingly prevalent and is associated with elevated morbidity and mortality rates in both mothers and children. As the interface between the mother and fetus, the placenta has mediates the impact of the maternal environment on fetal development. Most of the literature data on the effects of maternal obesity on placental functions do not exclude potential confounding factors like metabolic diseases (e.g. gestational diabetes). Moreover, it is now clear that the placental response to maternal environment depends on the fetal sex. In this context, we reviewed how maternal obesity (in the absence of gestational diabetes) affects the human placenta in terms of (i) endocrine function, (ii) morphological characteristics, (iii) nutrient exchanges and metabolism, (iv) inflammatory/immune status, (v) oxidative stress, and (vi) transcriptome, with a focus on fetal sex specificities. A better understanding of sex-specific placental responses to maternal obesity is crucial for improving pregnancy outcomes and the health of mothers and children.

International audience; Objective: We aimed to gather fetal cases carrying a 7q11.23 copy number variation (CNV) and collect precise clinical data to broaden knowledge of antenatal features in these syndromes.Methods: We retrospectively recruited unrelated cases with 7q11.23 deletion, known as Williams-Beuren syndrome (WBS), or 7q11.23 duplication who had prenatal ultrasound findings. We collected laboratory and clinical data, fetal ultrasound, cardiac ultrasound and fetal autopsy reports from 18 prenatal diagnostic centers throughout France.Results: 40 fetuses with WBS were collected and the most common features were intra-uterine growth retardation (IUGR) (70.0%, 28/40), cardiovascular defects (30.0%, 12/40), polyhydramnios (17.5%, 7/40) and protruding tongue (15.0%, 6/40). Fetal autopsy reports were available for 11 cases and were compared with ultrasound prenatal features. Four cases of fetuses with 7q11.23 microduplication were collected and prenatal ultrasound signs were variable and often isolated.Conclusion: This work strengthens the fact that 7q11.23 CNVs are associated with a broad spectrum of antenatal presentations. IUGR and cardiovascular defects were the most frequent ultrasound signs. By reporting the biggest series of antenatal WBS, we aim to better delineate distinctive signs in fetuses with 7q11.23 CNVs.

OBJECTIVE To evaluate the impact of implementing cell-free DNA (cfDNA) testing on gestational age (GA) at termination of pregnancy in a French perinatal network. METHODS We conducted a retrospective study. All women having undergone a termination of pregnancy between 1 January 2012 and 31 December 2017 were included. We compared the periods before and after the introduction of second-line cfDNA testing, which started on 1 January 2015. Throughout the study period, the invasive procedures were foetal karyotyping and chromosomal microarray analysis. The primary study outcome was GA at termination. The secondary outcomes were GA at termination for trisomy 21 and the frequency and GA at the time of invasive procedures. RESULTS During the 6-year study period, 840 women underwent termination. The median GA at termination before and after the implementation of cfDNA testing was 19.4 and 19.0 weeks, respectively (p = 0.38). Although the frequency of termination for trisomy 21 increased significantly from 23% to 32% (p

Microduplications involving the MYT1L gene have mostly been described in series of patients with isolated schizophrenia. However, few reports have been published, and the phenotype has still not been well characterized. We sought to further characterize the phenotypic spectrum of this condition by describing the clinical features of patients with a pure 2p25.3 microduplication that included all or part of MYT1L. Through a French national collaboration and a literature review, we assessed a large cohort of patients (n = 43) with pure 2p25.3 microduplications identified by chromosomal microarray analysis. For each case, we recorded clinical data, the microduplication size, and the inheritance pattern. The clinical features were variable and included developmental and speech delays (33%), autism spectrum disorder (23%), mild-to-moderate intellectual disability (21%), schizophrenia (21%), or behavioral disorders (16%). Eleven patients did not have an obvious neuropsychiatric disorder. The microduplications ranged from 62.4 kb to 3.8 Mb in size and led to either duplication of all or part of MYT1L. There were seven cases of intragenic duplication. The inheritance pattern was available for 18 patients: the microduplication was inherited in 13 cases, and all but one of the parents had a normal phenotype. Our comprehensive review and expansion of the phenotypic spectrum associated with 2p25.3 microduplications involving MYT1L (previously linked to schizophrenia) should help clinicians to better assess, counsel and manage affected individuals. MYT1L microduplications are characterized by a spectrum of neuropsychiatric phenotypes with incomplete penetrance and variable expressivity, which are probably due to as-yet unknown genetic and nongenetic modifiers.

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Chromosome 1p36 deletion syndrome (1p36DS) is one of the most common terminal deletion syndromes (incidence between 1/5000 and 1/10,000 live births in the American population), due to a heterozygous deletion of part of the short arm of chromosome 1. The 1p36DS is characterized by typical craniofacial features, developmental delay/intellectual disability, hypotonia, epilepsy, cardiomyopathy/congenital heart defect, brain abnormalities, hearing loss, eyes/vision problem, and short stature. The aim of our study was to (1) evaluate the incidence of the 1p36DS in the French population compared to 22q11.2 deletion syndrome and trisomy 21; (2) review the postnatal phenotype related to microarray data, compared to previously publish prenatal data. Thanks to a collaboration with the ACLF (Association des Cytogénéticiens de Langue Française), we have collected data of 86 patients constituting, to the best of our knowledge, the second-largest cohort of 1p36DS patients in the literature. We estimated an average of at least 10 cases per year in France. 1p36DS seems to be much less frequent than 22q11.2 deletion syndrome and trisomy 21. Patients presented mainly dysmorphism, microcephaly, developmental delay/intellectual disability, hypotonia, epilepsy, brain malformations, behavioral disorders, cardiomyopathy, or cardiovascular malformations and, pre and/or postnatal growth retardation. Cardiac abnormalities, brain malformations, and epilepsy were more frequent in distal deletions, whereas microcephaly was more common in proximal deletions. Mapping and genotype-phenotype correlation allowed us to identify four critical regions responsible for intellectual disability. This study highlights some phenotypic variability, according to the deletion position, and helps to refine the phenotype of 1p36DS, allowing improved management and follow-up of patients.

International audience; Tetrasomy 9p (ORPHA: 3310) (i(9p)) is a rare chromosomal imbalance. It is characterized by the presence of a supernumerary chromosome incorporating two copies of the short arm of chromosome 9 and is usually present in a mosaic state postnatally. Depending on the level of mosaicism, the phenotype ranges from mild developmental delay to multiple congenital anomalies with severe intellectual disability. Here, we report on a patient diagnosed with i(9p) mosaicism after the recurrent failure of in vitro fertilization. Although the patient's clinical phenotype was normal, the level of mosaicism varied greatly from one tissue to another. A sperm analysis evidenced subnormal spermatogenesis with chromosomally balanced spermatozoa and no risk of transmission to the offspring. Although individuals with i(9p) and no clinical manifestations have rarely been described, the prenatal diagnosis of this abnormality in the absence of ultrasound findings raises a number of questions.

International audience; Uterine transplantation is becoming an increasingly realistic therapeutic for uterine infertility. Surgical training on large animal models such as sheep is a prerequisite for establishing a program in humans. The objective of our study was to analyze the predictive factors for successful vascular anastomoses. We performed 40 autotransplants that involved end-to-side anastomoses from the uterine to the external iliac vessels. We analyzed vessel results in terms of success or failure; a total of 78.7% of arterial and 82.9% of venous anastomoses were successful in the immediate postoperative period. In multivariate analysis, independent factors associated with immediate successful vein anastomoses were as follows: a short warm ischemia time (

International audience; The translocation of SRY onto one of the two X chromosomes results in a 46,XX testicular disorder of sex development; this is supposedly due to non-allelic homologous recombination between the protein kinase X gene (PRKX) and the inverted protein kinase Y pseudogene (PRKY). Although 46,XX SRY-positive men are infertile, the literature data indicate that some of these individuals are of short stature (relative to the general population). We sought to determine whether short stature was linked to additional, more complex chromosomal rearrangements.Twelve laboratories gathered detailed clinical, anthropomorphic, cytogenetic and genetic data (including chromosome microarray (CMA) data) on patients with 46,XX SRY-positive male syndrome.SRY was present (suggesting a der(X)t(X;Y)) in 34 of the 38 cases (89.5%). When considering only the 20 patients with CMA data, we identified several chromosomal rearrangements and breakpoints - especially on the X chromosome. In the five cases for whom the X chromosome breakpoint was located in the pseudoautosomal (PAR) region, there was partial duplication of the derivate X chromosome. In contrast, in the 15 cases for whom the breakpoint was located downstream of the pseudoautosomal region, part of the derivate X chromosome had been deleted (included the arylsulfatase E (ARSE) gene in 11 patients). For patients with vs. without ARSE deletion, the mean height was respectively 167.7 ± 4.5 and 173.1 ± 4.0 cm; this difference was not statistically significant (p = 0.1005).Although 46,XX SRY-positive male syndromes were mainly due to imbalanced crossover between the X and Y chromosome during meiosis, the breakpoints differed markedly from one patient to another (especially on the X chromosome); this suggests the presence of a replication-based mechanism for recombination between non-homologous sequences. In some patients, the translocation of SRY to the X chromosome was associated with ARSE gene deletion, which might have led to short stature. With a view to explaining this disorder of sex development, whole exome sequencing could be suggested for SRY-negative patients. This article is protected by copyright. All rights reserved.

International audience; OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

International audience; Down syndrome (DS) is the most common chromosomal disorder. It is responsible for intellectual disability (ID) and several medical conditions. Although men with DS are thought to be infertile, some spontaneous paternities have been reported. The few studies of the mechanism of infertility in men with DS are now dated. Recent research in zebrafish has indicated that overexpression of DYRK1A (the protein primarily responsible for ID in DS) impairs gonadogenesis at the embryonic stage. To better ascertain DYRK1A’s role in infertility in DS, we investigated the effect of DYRK1A overexpression in a transgenic mouse model. We found that overexpression of DYRK1A impairs fertility in transgenic male mice. Interestingly, the mechanism in mice differs slightly from that observed in zebrafish but, with disruption of the early stages of spermatogenesis, is similar to that seen in humans. Unexpectedly, we observed hypogonadotropic hypogonadism in the transgenic mice.

BackgroundDespite the availability of whole exome (WES) and genome sequencing (WGS), chromosomal microarray (CMA) remains the first-line diagnostic test in most rare disorders diagnostic workup, looking for copy number variations (CNVs), with a diagnostic yield of 10%–20%. The question of the equivalence of CMA and WES in CNV calling is an organisational and economic question, especially when ordering a WGS after a negative CMA and/or WES.MethodsThis study measures the equivalence between CMA and GATK4 exome sequencing depth of coverage method in detecting coding CNVs on a retrospective cohort of 615 unrelated individuals. A prospective detection of WES-CNV on a cohort of 2418 unrelated individuals, including the 615 individuals from the validation cohort, was performed.ResultsOn the retrospective validation cohort, every CNV detectable by the method (ie, a CNV with at least one exon not in a dark zone) was accurately called (64/64 events). In the prospective cohort, 32 diagnoses were performed among the 2418 individuals with CNVs ranging from 704 bp to aneuploidy. An incidental finding was reported. The overall increase in diagnostic yield was of 1.7%, varying from 1.2% in individuals with multiple congenital anomalies to 1.9% in individuals with chronic kidney failure.ConclusionCombining single-nucleotide variant (SNV) and CNV detection increases the suitability of exome sequencing as a first-tier diagnostic test for suspected rare Mendelian disorders. Before considering the prescription of a WGS after a negative WES, a careful reanalysis with updated CNV calling and SNV annotation should be considered.

Infertility affects about 15% of couples of childbearing age. About half of these cases can be attributed predominantly to a male factor, such as a quantitative or qualitative impairment in spermatogenesis. The first-line genetic screening for non-obstructive azoospermia is limited to karyotyping (to identify chromosome abnormalities) and Y chromosome microdeletions screening, with a view to explaining the spermatogenetic failure and evaluating the likelihood of sperm retrieval in a testicular biopsy. For patients with de la Chapelle syndrome (a 46,XX karyotype with the presence of SRY (Sex determining region Y) gene) and/or Y chromosome microdeletions, or sex chromosome mosaicism, sperm retrieval is usually unsuccessful. Here, we report a patient with de la Chapelle syndrome and a short stature caused by mosaicism and a very rare chromosome rearrangement: mos 46,X,psu dic(X;Y)/45,X/45,psu dic(X;Y). This case indicates that in de la Chapelle syndrome, X- and Y-chromosome breakpoint variability is high.

We report on the results of array-CGH and Whole exome sequencing (WES) studies carried out in a Tunisian family with 46,XX premature ovarian insufficiency (POI). This study has led to the identification of a familial Xp22.12 tandem duplication with a size of 559.4 kb, encompassing only three OMIM genes (RPS6KA3, SH3KBP1and EIF1AX), and a new heterozygous variant in SPIDR gene: NM_001080394.3:c.1845_1853delTATAATTGA (p.Ile616_Asp618del) segregating with POI. Increased mRNA expression levels were detected for SH3KBP1 and EIF1AX, while a normal transcript level for RPS6KA3 was detected in the three affected family members, explaining the absence of intellectual disability (ID). To the best of our knowledge, this is the first duplication involving the Xp22.12 region, reported in a family without ID, but rather with secondary amenorrhea (SA) and female infertility. As EIF1AX is a regulatory gene escaping X-inactivation, which has an extreme dosage sensitivity and highly expressed in the ovary, we suggest that this gene might be a candidate gene for ovarian function. Homozygous nonsense pathogenic variants of SPIDR gene have been reported in familial cases in POI. It has been suggested that chromosomal instability associated with SPIDR molecular defects supports the role of SPIDR protein in double-stranded DNA damage repair in vivo in humans and its causal role in POI. In this family, the variant (p.Ile616_Asp618del), present in a heterozygous state, is located in the domain that interacts with BLM and might disrupt the BLM binding ability of SPIDR protein. These findings strengthen the hypothesis that the additional effect of this variant could lead to POI in this family. Although the work represents the first evidence that EIF1AX duplication might be responsible for POI through its over-expression, further functional studies are needed to clarify and prove EIF1AX involvement in POI phenotype.

Simple Summary Artificial reproduction techniques (ART) are used widely in human medicine to overcome infertility, with about one in seven couples being concerned in the Western world. Due to ethical concerns, animal models are needed to develop new methodologies. Although laboratory animals are seminal in this context, they have a short lifespan and are usually fertile. Horses are long-lived domestic animals that are bred until old age, often after they have had a career being used for equestrian activities. Their reproductive functions become altered after 20 years, in a similar way to humans, although there is no menopause per se in horses. There is also a concern for rising overweight and obesity concerns in these species. In addition, embryo transfer and ART are developed to overcome infertility, as for humans. This review details similarities and differences in the reproductive cycle, ART, and fertility concerns in women and mares and discusses the opportunity of using the horse as an appropriate model for ART in humans. Abstract Although there are large differences between horses and humans for reproductive anatomy, follicular dynamics, mono-ovulation, and embryo development kinetics until the blastocyst stage are similar. In contrast to humans, however, horses are seasonal animals and do not have a menstrual cycle. Moreover, horse implantation takes place 30 days later than in humans. In terms of artificial reproduction techniques (ART), oocytes are generally matured in vitro in horses because ovarian stimulation remains inefficient. This allows the collection of oocytes without hormonal treatments. In humans, in vivo matured oocytes are collected after ovarian stimulation. Subsequently, only intra-cytoplasmic sperm injection (ICSI) is performed in horses to produce embryos, whereas both in vitro fertilization and ICSI are applied in humans. Embryos are transferred only as blastocysts in horses. In contrast, four cells to blastocyst stage embryos are transferred in humans. Embryo and oocyte cryopreservation has been mastered in humans, but not completely in horses. Finally, both species share infertility concerns due to ageing and obesity. Thus, reciprocal knowledge could be gained through the comparative study of ART and infertility treatments both in woman and mare, even though the horse could not be used as a single model for human ART.

Resume Objectif L’objectif de notre etude etait de rechercher une association entre la fraction fœtale d’ADN circulant (ADNlc) dans le sang maternel au debut du deuxieme trimestre et les issues de grossesse. Methodes Nous avons realise une etude retrospective au sein du centre hospitalier de Poissy, en incluant toutes les patientes ayant eu une consultation de cytogenetique en vue de realiser un test d’ADNlc entre le 1er janvier 2015 et le 31 decembre 2016. Seules les grossesses singletons dont l’issue etait connue ont ete conservees dans l’analyse. Le critere de jugement principal etait un critere composite (survenue d’une complication obstetricale : accouchement premature spontane, preeclampsie, retard de croissance intra-uterin) Nous avons realise une analyse descriptive puis une analyse en sous-groupes : fraction fœtale elevee (> 90e percentile), fraction fœtale intermediaire (groupe temoin) et fraction fœtale basse ( Resultats Un total de 417 patientes ont ete incluses avec un test d’ ADNlc realise a 17,1 semaines d’amenorrhee (SA). Un total de 17 % des grossesses ont eu une complication, 8 se sont compliquees de pre-eclampsie (1,9 %), 49 de retard de croissance intra-uterin (11,8 %) et 14 d’accouchement premature (3,4 %). Concernant le critere de jugement principal, il n’y avait pas de difference significative sur la survenue d’une complication entre les groupes (p > 0,99), ni pour la survenue de chacune de ces complications. Conclusion La fraction fœtale analysee mesuree par un test d’ADNlc au debut du deuxieme trimestre n’est pas associee a un risque de complication obstetricale.

PURPOSE: To identify the FSH receptor (FSHR) variant and efficacy of in vitro maturation (IVM) in a 28-year-old woman with secondary amenorrhea, primary infertility, and ovarian resistance to FSH, and to analyze the genotype-to-phenotype relationship in cases of FSHR mutation for the development of an IVM algorithm for use in patients with gonadotropin resistance syndrome (GRS). METHODS: Oocytes retrieved after menstruation induction with norethisterone, followed by daily estrogen and an ovulatory trigger, underwent IVM, ICSI, and culture in a time-lapse (TL) incubator. Embryo transfers were performed on day 2, and after thawing on day 5. Genes associated with disorders of sex development were sequenced for both the patient and her parents. All reported cases of FSHR mutation were analyzed to investigate genotype/phenotypic relationships. RESULTS: After ovum pickup, seven of 16 oocytes matured and all fertilized. After unsuccessful day 2 transfer, our patient delivered with a thawed day 5 blastocyst, the sole embryo without abnormal TL phenotypes. Genetic analysis revealed a new composite heterozygous FSHR variant. Analysis of our patient case with published cases of GRS revealed associations among FSHR variant genotype, location on the FSHR, functionality of tested variants, and type of amenorrhea. An algorithm for application of IVM for GRS patients was developed. CONCLUSIONS: We report two novel variants of the FSHR. Although IVM successfully matured some oocytes, only one resulted in an embryo with normal TL phenotypes. We recommend FSHR genetic testing in GRS patients, which will help guide their suitability for IVM. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10815-021-02249-3.

Simple Summary The use of anti-cancer treatments in pregnant women is an increasingly common situation given the increasing age at first pregnancy. The aim of this study is to review data concerning the transplacental transfer of drugs that can be used in the management of the most common pregnancy-associated cancers. This work is intended to guide clinicians in the choice of the treatments that offer the best benefit–risk ratio for the mother and the fetus and to deliver balanced information to pregnant patients. Abstract The occurrence of cancer during pregnancy is observed in 1 in 1000 pregnancies and is expected to increase given the trend of delaying childbearing. While breast cancer is the most common, the incidence of other cancers, such as cervical, ovarian, and lung cancers as well as hemopathies and melanomas, is also increasing. Thus, cancer occurrence in pregnant women raises questions of management during pregnancy and, especially, assessment of the treatment benefit–risk ratio to ensure optimal management for the mother while ensuring the safety of the fetus. Chemotherapy remains a cornerstone of cancer management. If the use of anticancer agents appears possible during pregnancy, while avoiding the first trimester, the extent of placental transfer of different anticancer agents varies considerably thereafter. Furthermore, the significant physiological pharmacokinetic variations observed in pregnant women may have an impact on the placental transfer of anticancer agents. Given the complexity of predicting placental transfer of anticancer agents, preclinical studies are therefore mandatory. The aim of this review was to provide updated data on in vivo and ex vivo transplacental transfer of anticancer agents used in the management of the most common pregnancy-associated cancers to better manage these highly complex cases.

Background Although chromosome rearrangements are responsible for spermatogenesis failure, their impact depends greatly on the chromosomes involved. At present, karyotyping and Y chromosome microdeletion screening are the first-line genetic tests for patients with non-obstructive azoospermia. Although it is generally acknowledged that X or Y chromosome rearrangements lead to meiotic arrest and thus rule out any chance of sperm retrieval after a testicular biopsy, we currently lack markers for the likelihood of testicular sperm extraction (TESE) in patients with other chromosome rearrangements. Results We investigated the use of a single nucleotide polymorphism comparative genome hybridization array (SNP-CGH) and whole-exome sequencing (WES) for two patients with non-obstructive azoospermia and testicular meiotic arrest, a reciprocal translocation: t(X;21) and t(20;22), and an unsuccessful TESE. No additional gene defects were identified for the t(X;21) carrier - suggesting that t(X;21) alone damages spermatogenesis. In contrast, the highly consanguineous t(20;22) carrier had two deleterious homozygous variants in the TMPRSS9 gene; these might have contributed to testicular meiotic arrest. Genetic defect was confirmed with Sanger sequencing and immunohistochemical assessments on testicular tissue sections. Conclusions Firstly, TMPRSS9 gene defects might impact spermatogenesis. Secondly, as a function of the chromosome breakpoints for azoospermic patients with chromosome rearrangements, provision of the best possible genetic counselling means that genetic testing should not be limited to karyotyping. Given the risks associated with TESE, it is essential to perform WES - especially for consanguineous patients., Résumé Contexte Si les réarrangements chromosomiques sont connus pour être à l’origine d’une altération de la spermatogenèse, leur impact dépend fortement des chromosomes impliqués. À l’heure actuelle, la réalisation d’un caryotype et le dépistage des microdélétions du chromosome Y sont les tests génétiques réalisés en première intention chez les patients atteints d’azoospermie non obstructive. S’il est généralement admis que les réarrangements impliquant les chromosomes X ou Y entraînent un arrêt méiotique et réduisent fortement les chances de retrouver des spermatozoïdes après une biopsie testiculaire, nous manquons de marqueurs permettant de définir une probabilité d’extraction de spermatozoïdes testiculaires chez les patients présentant d’autres réarrangements chromosomiques. Résultats Nous avons utilisé l’hybridation génomique comparative sur puces (SNP-CGH) et le séquençage entier de l’exome (SEE) pour deux patients présentant une azoospermie non obstructive avec arrêt méiotique, une translocation réciproque: t(X;21) et t(20;22), et sans spermatozoïde retrouvé après biopsie testiculaire Aucune autre anomalie génétique n’a été identifiée chez le patient porteur de la t(X;21) - ce qui suggère que la translocation seule altére la spermatogenèse. En revanche, le patient porteur de la t(20;22), consanguin, présentait deux variants homozygotes délétères dans le gène TMPRSS9 qui pourraient contribuer à l’arrêt méiotique. Le variant génétique a été confirmé par séquençage Sanger et par immunohistochimie sur des coupes de tissu testiculaire. Conclusions Premièrement, nous faisons l’hypothèse d’un impact du défaut du gène TMPRSS9 sur la spermatogenèse. De plus, en fonction des points de cassures chromosomiques pour les patients azoospermes ayant une translocation réciproque, nous suggérons de ne pas limiter les analyses génétiques à la réalisation d’un caryotype afin d’affiner le conseil génétique. Compte tenu des risques associés à la TESE, il est essentiel de réaliser un SEE en amont et en particulier pour les patients consanguins. Mots clés Arrêt méiotique, azoospermie non obstructive, translocation, séquençage de l’exome, TMPRSS9.

Background Successful human embryo implantation requires the differentiation of endometrial stromal cells (ESCs) into decidual cells during a process called decidualization. ESCs express specific markers of decidualization, including prolactin, insulin-like growth factor-binding protein-1 (IGFBP-1), and connexin-43. Decidual cells also control of trophoblast invasion by secreting various factors, such as matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases. Preimplantation factor (PIF) is a recently identified, embryo-derived peptide with activities at the fetal-maternal interface. It creates a favorable pro-inflammatory environment in human endometrium and directly controls placental development by increasing the human trophoblastic cells’ ability to invade the endometrium. We hypothesized that PIF’s effects on the endometrium counteract its pro-invasive effects. Methods We tested sPIF effect on the expression of three decidualization markers by RT-qPCR and/or immunochemiluminescence assay. We examined sPIF effect on human ESC migration by performing an in vitro wound healing assay. We analyzed sPIF effect on endometrial control of human trophoblast invasion by performing a zymography and an invasion assay. Results Firstly, we found that a synthetic analog of PIF (sPIF) significantly upregulates the mRNA expression of IGFBP-1 and connexin-43, and prolactin secretion in ESCs - suggesting a pro-differentiation effect. Secondly, we showed that the HTR-8/SVneo trophoblastic cell line’s invasive ability was low in the presence of conditioned media from ESCs cultured with sPIF. Thirdly, this PIF’s anti-invasive action was associated with a specifically decrease in MMP-9 activity. Conclusion Taken as a whole, our results suggest that PIF accentuates the decidualization process and the production of endometrial factors that limit trophoblast invasion. By controlling both trophoblast and endometrial cells, PIF therefore appears to be a pivotal player in the human embryo implantation process.

Context Maternal obesity has a significant impact on placental development. However, this impact on the placenta’s structure and function (ie, nutrient transport and hormone and cytokine production) is a controversial subject. Objective We hypothesized that maternal obesity is associated with morphologic, secretory, and nutrient-related changes and elevated levels of inflammation in the placenta. Design We collected samples of placental tissue from 2 well-defined groups of pregnant women from 2017 to 2019. We compared the 2 groups regarding placental cytokine and hormone secretion, immune cell content, morphology, and placental nutrient transporter expressions. Setting Placenta were collected after caesarean section performed by experienced clinicians at Centre Hospitalier Intercommunal (CHI) of Poissy-Saint-Germain-en-Laye. Patients The main inclusion criteria were an age between 27 and 37 years old, no complications of pregnancy, and a first-trimester body mass index of 18–25 kg/m2 for the nonobese (control) group and 30–40 kg/m2 for the obese group. Results In contrast to our starting hypothesis, we observed that maternal obesity was associated with (1) lower placental IL-6 expression and macrophage/leukocyte infiltration, (2) lower placental expression of GLUT1 and SNAT1-2, (3) a lower placental vessel density, and (4) lower levels of placental leptin and human chorionic gonadotropin production. Conclusion These results suggest that the placenta is a plastic organ and could optimize fetal growth. A better understanding of placental adaptation is required because these changes may partly determine the fetal outcome in cases of maternal obesity.

International audience; Whereas the initially strategy for the genetic analysis of male infertility was based on a candidate gene approach, the development of next-generation sequencing technologies (such as whole-exome sequencing (WES)) provides an opportunity to analyze many genes in a single procedure. In order to recommend WES or whole-genome sequencing (WGS) after genetic counselling, an objective evaluation of the current genetic screening strategy for male infertility is required, even if, at present, we have to take into consideration the complexity of such a procedure, not discussed in this commentary.; Alors que la stratégie actuelle d'analyse de génétique moléculaire de l'infertilité masculine est basée sur une approche dite "gène candidat", le développement des technologies de séquençage de nouvelle génération, comme le séquençage complet de l'exome (WES), offre la possibilité d'analyser de nombreux gènes en une seule technique. Afin de recommander le WES ou le séquençage complet du génome, après un conseil génétique, une évaluation objective des différentes stratégies de dépistage génétique est nécessaire, tout en prenant en considération que la complexité d'une utilisation des nouvelles technologies n'est pas abordé dans ce commentaire.

International audience; Abstract Spermatogenesis is a complex process regulated by a multitude of genes. The identification and characterization of male-germ-cell-specific genes is crucial to understanding the mechanisms through which the cells develop. The term “ TEX gene” was coined by Wang et al. (Nat Genet. 2001; 27: 422–6) after they used cDNA suppression subtractive hybridization (SSH) to identify new transcripts that were present only in purified mouse spermatogonia. TEX ( Testis expressed ) orthologues have been found in other vertebrates (mammals, birds, and reptiles), invertebrates, and yeasts. To date, 69 TEX genes have been described in different species and different tissues. To evaluate the expression of each TEX/tex gene, we compiled data from 7 different RNA-Seq mRNA databases in humans, and 4 in the mouse according to the expression atlas database. Various studies have highlighted a role for many of these genes in spermatogenesis. Here, we review current knowledge on the TEX genes and their roles in spermatogenesis and fertilization in humans and, comparatively, in other species (notably the mouse). As expected, TEX genes appear to have a major role in reproduction in general and in spermatogenesis in humans but also in all mammals such as the mouse. Most of them are expressed specifically or predominantly in the testis. As most of the TEX genes are highly conserved in mammals, defects in the male (gene mutations in humans and gene-null mice) lead to infertility. In the future, cumulative data on the human TEX genes’ physiological functions and pathophysiological dysfunctions should become available and is likely to confirm the essential role of this family in the reproductive process. Thirteen TEX genes are now referenced in the OMIM database, and 3 have been linked to a specific phenotype. TEX11 (on Xq13.1) is currently the gene most frequently reported as being associated with azoospermia.; Résumé La spermatogenèse est un processus complexe régulé par une multitude de gènes. L’identification et la caractérisation des gènes spécifiques des cellules germinales mâles sont essentielles pour comprendre les mécanismes par lesquels les cellules se développent. Le terme «gène TEX » a été inventé par Wang et al. (Nat Genet. 2001; 27: 422–6) après avoir utilisé l’hybridation soustractive d’ADNc (SSH) pour identifier de nouveaux transcrits qui n’étaient présents que dans la spermatogonie de souris. Puis, des orthologues TEX ont été trouvés chez d’autres vertébrés (mammifères, oiseaux et reptiles), des invertébrés et des levures. À ce jour, 69 gènes TEX ( Testis expressed ) ont été décrits dans différentes espèces et différents tissus. Pour évaluer l’expression de chaque gène TEX/tex , nous avons compilé les données de 7 bases de données différentes d’ARNm RNA-Seq chez l’homme, et 4 chez la souris selon la base de données de l’atlas d’expression. Diverses études ont mis en évidence le rôle de plusieurs de ces gènes dans la spermatogenèse. Ici, nous passons en revue les connaissances actuelles sur les gènes TEX et leurs rôles dans la spermatogenèse et la fécondation chez l’humain et, comparativement, chez d’autres espèces (notamment la souris). Comme prévu, les gènes TEX semblent avoir un rôle majeur dans la reproduction en général et dans la spermatogenèse chez l’homme, mais aussi chez d’autres mammifères comme la souris. La plupart d’entre eux sont exprimés spécifiquement ou principalement dans les testicules. Comme la plupart des gènes TEX sont hautement conservés chez les mammifères, des défauts chez le mâle (mutations géniques chez l’homme et KO murin) conduisent à l’infertilité. À l’avenir, l’accumulation des données sur les fonctions physiologiques et les dysfonctionnements physiopathologiques des gènes TEX humains devraient devenir disponibles et confirmer le rôle essentiel de cette famille dans le processus de reproduction. Treize gènes TEX sont désormais référencés dans la base de données OMIM, et 3 ont été liés à un phénotype spécifique. TEX11 (sur Xq13.1) est. actuellement le gène le plus fréquemment rapporté comme étant associé à l’azoospermie.

The dissection of the veins is the trickiest step of Uterine transplantation (UTx). Performing the anastomosis of a single uterine vein could bring a therapeutic benefit and simplification of surgery and serve for managing unilateral venous thromboses. The objectives of this project were to evaluate the expression of early markers of ischemia-reperfusion and to compare findings following one or two vein anastomoses. Orthotopic uterine auto-transplantations were performed on an ovine model with anastomosis of either two (group 1) or one utero-ovarian veins (group 2). Blood gases, histology and ischemia- reperfusion markers transcripts (PTGS2, IL6, IL8, SOD2, C3, BAX/BCL2 and TLR4) were analyzed as well as PTGS2 protein expression using Western Blot and fluorescence immunolocalization on endometrial biopsies after 3h of reperfusion. Ten ewes were included in the experimentation, 4 were in group1, 3 in group 2, the others being sham operated controls. No significant differences were observed between the two phenotypes. Based on these results, the anastomosis of one single uterine vein appears to be an approach consistent with short-term graft survival. Further experiments will be needed to confirm the reliability of this approach, especially the long-term follow-up of the uterine graft including its ability to support gestation to term.

Maternal obesity is associated with complications of pregnancy and increases the infant's risk of developing obesity, diabetes and cardiovascular disease later in life. The placenta has an important role in determining the pregnancy outcome, and the syncytiotrophoblast (ST) is the main component of the placenta that supports the relationship between the mother and fetus. The differentiation of the cytotrophoblast (CT) into the ST is accompanied by changes in mitochondrial functions and dynamics. The objective of the present study was to investigate the effects of maternal obesity (without gestational diabetes) on the in vitro differentiation capacities of human CT isolated from term placenta by focusing on mitochondrial status. We found that, during human CT differentiation process, maternal obesity is associated with (i) a lower progesterone secretion, (ii) a transient impairment in the ST's fusion potential (via syncytin-2 and its receptor), (iii) a lower mitochondrial content, and (iv) weaker mRNA expression of oestrogen-related receptor-gamma (a key mitobiogenesis gene). Moreover, maternal obesity altered the time course of ATP and reactive oxygen species production throughout CT differentiation. The mitochondrial dysfunctions observed in isolated human CTs of obese women might explain the observed decrease in progesterone production. Our results demonstrated that obesity in pregnancy is associated with a functional impairment of the ST which might alter the foetal-maternal dialogue.

Background:Pressurized Intra-Peritoneal Aerosol Chemotherapy (PIPAC) is an innovative treatment against peritoneal carcinomatosis. Doxorubicin is a common intra-venous chemotherapy used for peritoneal carcinomatosis and for PIPAC. This study evaluated the impact of increased PIPAC intraperitoneal pressure on the distribution and cell penetration of doxorubicin in a sheep model.Methods: Doxorubicin was aerosolized using PIPAC into the peritoneal cavity of 6 ewes (pre-alpes breed): N=3 with 12mmHg intraperitoneal pressure (group 1) and N=3 with 20mmHg (group 2). Samples from peritoneum (N=6), ovarian (N=1), omentum (N=1) and caecum (N=1) were collected for each ewe. The number of doxorubicin positive cells was determined using the ratio between doxorubicine fluorescence-positive cell nuclei (DOXO+) over total number of DAPI positive cell nuclei (DAPI+). Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei over the total number of cell nuclei that were stained with DAPI. Penetration depth (μm) was defined as the distance between the luminal surface and the location of the deepest DOXO+ nuclei.Results: DOXO+ nuclei were identified in 87% of samples. All omental samples, directly localized in front of the nebulizer head, had 100% DOXO+ nuclei whereas very few nuclei were DOXO+ for caecum. Distribution patterns were not different between the two groups but penetration depth in ovary and caecum samples was significantly deeper in group 2. Conclusions:This study showed that applying a higher intra-peritoneal pressure during PIPAC treatment leads to a deeper penetration of doxorubicin in ovarian and caecum but does not affect distribution patterns.