L’anonymat du don de gamètes à l’heure des tests génétiques

National audienceDevelopment of genetic testing direct-to-consumer (DTC) for recreational purposes, although prohibited in France, is a real challenge to the current practice of gamete donation. Indeed, anonymity is a fundamental principle contributing to the ethics of donation. This principle is weakened due to the availability to the general public of these tests on the Internet. Several thousands of people are conceived by gamete donation worldwide, some of whom do not know how they were conceived. Gamete donors should be informed that their anonymity is no longer guaranteed, as they can be found by homologies of their DNA, or that of a parent or a child, potentially available in databases. Thus, adults conceived by gamete donation but not informed by their parents can discover their way of conception. Recipients of gamete donation should also be informed that their child's DNA will establish the biological discrepancy and they should be encouraged to disclose the conception to their child. Several countries now allow children conceived by donation to obtain donor's identity. In France, the Bioethics Law is currently being finalized and will now allow access to donor's identity for people conceived by gamete donation

Attitude towards reciprocity as a motive for oocyte donation

International audienceObjective: Finding out whether patients would be motivated by reciprocity when considering donating oocytes to others.Study design: This is a prospective monocentric study in the CECOS of the Centre Hospitalier Universitaire (CHU) of Rennes (France) on the opinion of patients regarding reciprocity. Couples who had a child with donor sperm were asked whether they would consider oocyte donation as a way of giving something back.Results: Twenty six couples and one man answered the questionnaire. About half of the respondents (49%) felt that they should contribute to the system from which they benefitted. Although the patients would benefit from a reduction in waiting time, this advantage was only important for one in four persons. The only items on which the answers between men and women were significantly different concerned the results of the donation: women would think more often about the potential recipient and the child and they more often wanted to know whether children were born from their donation.Conclusion: The results show that beside altruism, reciprocity may be an important moral reason for people to donate gametes

Ovarian response to stimulation for fertility preservation in women with hematologic cancer

International audiencePurpose: To compare the ovarian response to controlled ovarian hyperstimulation (COH) in patients with hematologic malignancies treated for fertility preservation (FP) and healthy subjects (oocyte donors (OD)).Patients and methods: Retrospective cohort study comparing 41 women (18-37 years) who underwent COH for oocyte vitrification prior to gonadotoxic treatment for hematologic cancer (FP group) from January 2014 to February 2019 and with 117 women undergoing COH as part of an OD protocol (OD group) during the same period. The number of frozen mature oocytes, number of oocytes retrieved, total dose of rFSH, maximal estradiol levels, percentage of maturity, number of dominant follicles >14 mm, days of stimulation were evaluated. Results were adjusted for age, body mass index (BMI), anti-Mullerian hormone (AMH) and rFSH starting dose.Results: Patients in the FP group were younger and had a lower BMI than those in the OD group. rFSH starting dose was higher in the FP group (median 225UI (125;450) vs 150UI (87.5;337.5), p < 0.0001). After adjusting for age, BMI and starting rFSH dose according to ANCOVA, more frozen mature oocytes (median 10 (0;45) vs 8 (0;22] p = 0.0055) and retrieved oocytes (median 12 (0;49) vs 11 (0;29) p = 0.0468) were found in the FP group. Other outcome measures did not differ between the groups.Conclusion: Ovarian response after COH in women with a hematologic cancer is similar to that in the general population. A higher number of mature oocytes were collected in the FP group after strong COH

Pregnancies and obstetrical prognosis after oocyte donation in Turner Syndrome A multicentric study

International audienceIntroduction - Turner syndrome is one of the most frequent chromosomal abnormalities in women, with a prevalence estimated to be 1 of 2500 live birth. Pregnancy in women with Turner syndrome is known to be at high risk, whether it is spontaneous or after oocyte donation, because of miscarriages and potential cardio-vascular complications which can be life-threatening. All of these patients should therefore be screened with a comprehensive cardio-vascular assessment before pregnancy, and have a close follow-up during and after pregnancy.Patients and methods - It is a retrospective study, conducted in 10 of the 27 French oocyte donation centers between 2012 and 2016, on all the patients presenting with Turner syndrome included in an oocyte donation program.Results - 151 embryo transfers were realized in 73 patients, resulting in 39 pregnancies. Among these pregnancies, 24 children were born healthy, 11 spontaneous miscarriages, 3 voluntary abortions, 1 extra-uterine pregnancy and 1 maternal death from non-cardio-vascular origin occurred. Pregnancies were complicated by gravid arterial hypertension in 28.2% of cases, preeclampsia in 10.3% of cases, and gestational diabetes in 7.7% of cases.Conclusion - This study bring out obstetrical complications of the same magnitude than the ones described in the literature. Lead over a period of 4 years, in 10 French oocyte donation centers, it doesn't reveal any cardio-vascular complications, conversely to other studies published before French and American recommendations. This study reinforces the usefulness of specific recommendations for the care of these particular patients

Dominant TP63 missense variants lead to constitutive activation and premature ovarian insufficiency

International audiencePremature ovarian insufficiency (POI) is a leading form of female infertility, characterised by menstrual disturbance and elevated follicle-stimulating hormone before age 40. It is highly heterogeneous with variants in over 80 genes potentially causative, but the majority of cases having no known cause. One gene implicated in POI pathology is TP63. TP63 encodes multiple p63 isoforms, one of which has been shown to have a role in the surveillance of genetic quality in oocytes. TP63 C-terminal truncation variants and N-terminal duplication have been described in association with POI, however, functional validation has been lacking. Here we identify three novel TP63 missense variants in women with nonsyndromic POI, including one in the N-terminal activation domain, one in the C-terminal inhibition domain, and one affecting a unique and poorly understood p63 isoform, TA*p63. Via blue-native page and luciferase reporter assays we demonstrate that two of these variants disrupt p63 dimerization, leading to constitutively active p63 tetramer that significantly increases the transcription of downstream targets. This is the first evidence that TP63 missense variants can cause isolated POI and provides mechanistic insight that TP63 variants cause POI due to constitutive p63 activation and accelerated oocyte loss in the absence of DNA damage

Meiotic genes in premature ovarian insufficiency: variants in HROB and REC8 as likely genetic causes

International audiencePremature ovarian insufficiency (POI), affecting 1 in 100 women, is characterised by loss of ovarian function associated with elevated gonadotropin, before the age of 40. In addition to infertility, patients face increased risk of comorbidities such as heart disease, osteoporosis, cancer and/or early mortality. We used whole exome sequencing to identify the genetic cause of POI in seven women. Each had biallelic candidate variants in genes with a primary role in DNA damage repair and/or meiosis. This includes two genes, REC8 and HROB, not previously associated with autosomal recessive POI. REC8 encodes a component of the cohesin complex and HROB encodes a factor that recruits MCM8/9 for DNA damage repair. In silico analyses, combined with concordant mouse model phenotypes support these as new genetic causes of POI. We also identified novel variants in MCM8, NUP107, STAG3 and HFM1 and a known variant in POF1B. Our study highlights the pivotal role of meiosis in ovarian function. We identify novel variants, consolidate the pathogenicity of variants previously considered of unknown significance, and propose HROB and REC8 variants as new genetic causes while exploring their link to pathogenesis

New insights into the genetic basis of premature ovarian insufficiency: Novel causative variants and candidate genes revealed by genomic sequencing

International audienceOvarian deficiency, including premature ovarian insufficiency (POI) and diminished ovarian reserve (DOR), represents one of the main causes of female infertility. POI is a genetically heterogeneous condition but current understanding of its genetic basis is far from complete, with the cause remaining unknown in the majority of patients. The genes that regulate DOR have been reported but the genetic basis of DOR has not been explored in depth. Both conditions are likely to lie along a continuum of degrees of decrease in ovarian reserve. We performed genomic analysis via whole exome sequencing (WES) followed by in silico analyses and functional experiments to investigate the genetic cause of ovarian deficiency in ten affected women. We achieved diagnoses for three of them, including the identification of novel variants in STAG3, GDF9, and FANCM. We identified potentially causative FSHR variants in another patient. This is the second report of biallelic GDF9 and FANCM variants, and, combined with functional support, validates these genes as bone fide autosomal recessive “POI genes”. We also identified new candidate genes, NRIP1, XPO1, and MACF1. These genes have been linked to ovarian function in mouse, pig, and zebrafish respectively, but never in humans. In the case of NRIP1, we provide functional support for the deleterious nature of the variant via SUMOylation and luciferase/β-galactosidase reporter assays. Our study provides multiple insights into the genetic basis of POI/DOR. We have further elucidated the involvement of GDF9, FANCM, STAG3 and FSHR in POI pathogenesis, and propose new candidate genes, NRIP1, XPO1, and MACF1, which should be the focus of future studies

22q11.2 rearrangements found in women with low ovarian reserve and premature ovarian insufficiency

International audienceOvarian 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