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Hydatidiform mole (HM) is an aberrant human pregnancy characterized by excessive trophoblastic proliferation and abnormal embryonic development. HM has two morphological types, complete (CHM) and partial (PHM), and non-recurrent ones have three genotypic types, androgenetic monospermic, androgenetic dispermic, and triploid dispermic. Most available studies on risk factors predisposing to different types of HM and their malignant transformation mainly suffer from the lack of comprehensive genotypic analysis of large cohorts of molar tissues combined with accurate postmolar hCG follow-up. Moreover, 10–20% of patients with one HM have at least one non-molar miscarriage, which is higher than the frequency of two pregnancy losses in the general population (2–5%), suggesting a common genetic susceptibility to HM and miscarriages. However, the underlying causes of the miscarriages in these patients are unknown. Here, we comprehensively analyzed 204 HM, mostly from patients referred to the Quebec Registry of Trophoblastic Diseases and for which postmolar hCG monitoring is available, and 30 of their non-molar miscarriages. We revisited the risk of maternal age and neoplastic transformation across the different HM genotypic categories and investigated the presence of chromosomal abnormalities in their non-molar miscarriages. We confirm that androgenetic CHM is more prone to gestational trophoblastic neoplasia (GTN) than triploid dispermic PHM, and androgenetic dispermic CHM is more prone to high-risk GTN and choriocarcinoma (CC) than androgenetic monospermic CHM. We also confirm the association between increased maternal age and androgenetic CHM and their malignancies. Most importantly, we demonstrate for the first time that patients with an HM and miscarriages are at higher risk for aneuploid miscarriages [83.3%, 95% confidence interval (CI): 0.653–0.944] than women with sporadic (51.5%, 95% CI: 50.3–52.7%, p value = 0.0003828) or recurrent miscarriages (43.8%, 95% CI: 40.7–47.0%, p value = 0.00002). Our data suggest common genetic female germline defects predisposing to HM and aneuploid non-molar miscarriages in some patients.

Significance This study improves our understanding of the role of Müllerian inhibiting substance (MIS/AMH) in antagonizing primordial follicle activation. By applying scRNA-seq methods to neonatal mouse ovaries, we revealed transcriptional signatures associated with MIS treatment in ovarian cell types present during the first wave of folliculogenesis and follicle development. We showed that MIS inhibits pregranulosa cell differentiation and the proliferation of ovarian surface epithelium and stromal cells. MIS also uncoupled granulosa and germ cell maturation, leading to abnormal development of activated follicles. These findings identify markers and pathways related to primordial follicle quiescence that could be targeted in contraception, preservation of ovarian reserve during aging or chemotherapy, or synchronization of preantral follicle growth for IVF., Müllerian inhibiting substance (MIS/AMH), produced by granulosa cells of growing follicles, is an important regulator of folliculogenesis and follicle development. Treatment with exogenous MIS in mice suppresses follicle development and prevents ovulation. To investigate the mechanisms by which MIS inhibits follicle development, we performed single-cell RNA sequencing of whole neonatal ovaries treated with MIS at birth and analyzed at postnatal day 6, coinciding with the first wave of follicle growth. We identified distinct transcriptional signatures associated with MIS responses in the ovarian cell types. MIS treatment inhibited proliferation in granulosa, surface epithelial, and stromal cell types of the ovary and elicited a unique signature of quiescence in granulosa cells. In addition to decreasing the number of growing preantral follicles, we found that MIS treatment uncoupled the maturation of germ cells and granulosa cells. In conclusion, MIS suppressed neonatal follicle development by inhibiting proliferation, imposing a quiescent cell state, and preventing granulosa cell differentiation.

SARS-CoV-2 infection causes more severe disease in pregnant women compared to age-matched non-pregnant women. Whether maternal infection causes changes in the transfer of immunity to infants remains unclear. Maternal infections have previously been associated with compromised placental antibody transfer, but the mechanism underlying this compromised transfer is not established. Here, we used systems serology to characterize the Fc-profile of influenza-, pertussis-, and SARS-CoV-2-specific antibodies transferred across the placenta. Influenza- and pertussis-specific antibodies were actively transferred. However, SARS-CoV-2-specific antibody transfer was significantly reduced compared to influenza- and pertussis-specific antibodies, and cord titers and functional activity were lower than in maternal plasma. This effect was only observed in third trimester infection. SARS-CoV-2-specific transfer was linked to altered SARS-CoV-2-antibody glycosylation profiles and was partially rescued by infection-induced increases in IgG and increased FCGR3A placental expression. These results point to unexpected compensatory mechanisms to boost immunity in neonates, providing insights for maternal vaccine design., Highlights • SARS-CoV-2-specific antibodies have a decreased placental transfer • SARS-CoV-2-spike antibodies have altered glycosylation profiles in pregnant women • Pregnant women with SARS-CoV-2 during the third trimester have elevated IgG levels • SARS-CoV-2-specific antibody transfer is efficient after second trimester infection, Atyeo et al. reveals a deficiency in SARS-CoV-2-antibody placental transfer among women infected during the third trimester. While bulk antibody transfer remains unaltered, SARS-CoV-2-antibodies show perturbed Fc glycosylation profiles and elevated IgG and FCGR3A placental expression that suggest compensation for poor transfer.

Androgenetic complete hydatidiform moles are human pregnancies with no embryos and affect 1 in every 1,400 pregnancies. They have mostly androgenetic monospermic genomes with all the chromosomes originating from a haploid sperm and no maternal chromosomes. Androgenetic complete hydatidiform moles were described in 1977, but how they occur has remained an open question. We identified bi-allelic deleterious mutations in MEI1, TOP6BL/C11orf80, and REC114, with roles in meiotic double-strand breaks formation in women with recurrent androgenetic complete hydatidiform moles. We investigated the occurrence of androgenesis in Mei1-deficient female mice and discovered that 8% of their oocytes lose all their chromosomes by extruding them with the spindles into the first polar body. We demonstrate that Mei1−/− oocytes are capable of fertilization and 5% produce androgenetic zygotes. Thus, we uncover a meiotic abnormality in mammals and a mechanism for the genesis of androgenetic zygotes that is the extrusion of all maternal chromosomes and their spindles into the first polar body. © 2018 American Society of Human Genetics

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Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases.

WOS: 000440567300011, PubMed ID: 29463882, Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity., Reseau Quebecois en Reproduction; McGill Faculty of Medicine; RI-MUHC Desjardins Studentship in Child Health Research; CRRD; Canadian Institute of Health ResearchCanadian Institutes of Health Research (CIHR) [MOP-86546, POP-122897, MOP-130364], NMPN was supported by fellowships from Reseau Quebecois en Reproduction, McGill Faculty of Medicine, RI-MUHC Desjardins Studentship in Child Health Research, and CRRD. Yassemine Khawajkie was supported by a CRRD trainee fellowship. RS is supported by the Canadian Institute of Health Research (MOP-86546, POP-122897, and MOP-130364).

Background Hydatidiform mole (HM) is a human pregnancy with excessive trophoblastic proliferation and abnormal embryonic development that may be sporadic or recurrent. In the sporadic form, the HM phenotype is driven by an abnormal ratio of paternal to maternal genomes, whereas in the recurrent form, the HM phenotype is caused by maternal-recessive mutations, mostly in NLRP7 , despite the diploid biparental origin of the HM tissues. In this study, we characterised the expression of the imprinted, maternally expressed gene, CDKN1C (p57 KIP2 ), the genotype, and the histopathology of 36 products of conception (POC) from patients with two defective alleles in NLRP7 and looked for potential correlations between the nature of the mutations in the patients and the various HM features. Methods/results We found that all the 36 POCs are diploid biparental and have the same parental contribution to their genomes. However, some of them expressed variable levels of p57 KIP2 and this expression was strongly associated with the presence of embryonic tissues of inner cell mass origin and mild trophoblastic proliferation, which are features of triploid partial HMs, and were associated with missense mutations. Negative p57 KIP2 expression was associated with the absence of embryonic tissues and excessive trophoblastic proliferation, which are features of androgenetic complete HMs and were associated with protein-truncating mutations. Conclusions Our data suggest that NLRP7 , depending on the severity of its mutations, regulates the imprinted expression of p57 KIP2 and consequently the balance between tissue differentiation and proliferation during early human development. This role is novel and could not have been revealed by any other approach on somatic cells.

Recurrent hydatidiform mole (RHM) is defined by the occurrence of repeated molar pregnancies in affected women. Two genes, NLRP7 and KHDC3L, play a causal role in RHM and are responsible for 48–80% and 5% of cases, respectively. Here, we report the results of screening these two genes for mutations in one Iranian and one Indian patient with RHM. No mutations in NLRP7 were identified in the two patients. KHDC3L sequencing identified two novel protein-truncating mutations in a homozygous state, a 4-bp deletion, c.17_20delGGTT (p.Arg6Leufs*7), in the Iranian patient and a splice mutation, c.349+1G>A, that affects the invariant donor site at the junction of exon 2 and intron 2 in the Indian patient. To date, only four mutations in KHDC3L have been reported. The identification of two additional mutations provides further evidence for the important role of KHDC3L in the pathophysiology of RHM and increases the diversity of mutations described in Asian populations. Two new mutations have been identified in a gene associated with recurrent hydatidiform moles (RHMs). A RHM is a form of non-viable pregnancy in which the placenta develops into a mass of cysts. This condition occurs in higher frequencies in the Middle and Far East. Majid Fardaei of Shiraz University of Medical Science in Iran and colleagues screened Iranian and Indian women for mutations in two genes, NLRP7 and KHDC3L. These genes have been implicated as having a role in 48—80% and 5% of RHMs, respectively. In two patients, no mutations were found in NLRP7, but two new mutations were identified in KHDC3L that were not found in controls or two large gene databases. The findings confirm a causal role for KHDC3L in RHMs, which should be screened for when mutations are not detected in NLRP7.

To date, two maternal-effect genes have been shown to have causative roles in recurrent hydatidiform moles (RHMs); NLRP7 that is mutated in 48-60% of patients with RHMs and C6orf221 (HUGO-approved nomenclature is now KHDC3L), a recently identified gene, that is mutated in 14% of patients with RHMs who are negative for NLRP7 mutations. We sequenced KHDC3L in 97 patients with RHMs and reproductive loss who are mostly negative for NLRP7 mutations. We identified three unrelated patients, each homozygous for one of the two protein-truncating mutations, a novel 4-bp deletion resulting in a frameshift, c.299_302delTCAA, p.Ile100Argfs*2, and a previously described 4-bp deletion, c.322_325delGACT, p.Asp108Ilefs*30, transmitted on a shared haplotype to three patients from different populations. We show that five HM tissues from one of these patients are diploid and biparental similar to HMs from patients with two defective NLRP7 mutations. Using immunofluorescence, we show that KHDC3L protein displays a juxta perinuclear signal and colocalizes with NLRP7 in lymphoblastoid cell lines from normal subjects. Using cell lines from patients, we demonstrate that the KHDC3L mutations do not change the subcellular localization of the protein in hematopoietic cells. Our data highlight the similarities between the two causative genes for RHMs, KHDC3L and NLRP7, in their subcellular localization, the parental contribution to the HM tissues caused by them, and the presence of several founder mutations and variants in both of them indicating positive selection and adaptation.

In July 1996, because of concern regarding the possible transmission of Creutzfeldt-Jakob disease, the province of Quebec stopped the reuse of percutaneous transluminal coronary angioplasty (PTCA) catheters. Prior to this time, PTCA balloon catheters were used a maximum of four times and guide catheters a maximum of two times in the cardiac catheterization laboratory at our institution. After this time, only new catheters were used. In order to examine the effects of catheter reuse on duration of PTCA procedures and clinical outcomes, we compared 53 consecutive patients undergoing PTCA prior to 21 July 1996 with 54 consecutive patients undergoing PTCA after that time. A total of 81 men and 26 women underwent PTCA (average age, 64 +/- 12 years). There were no significant differences between the single-use and reuse groups with respect to baseline characteristics. There were also no significant differences in the numbers of PTCA catheters used (97 vs. 103, P = NS) or angiographic success rates (88% vs. 83%, P = NS). There was a trend for total procedure time and fluoroscopy time to be slightly longer for single-use compared with reuse cases (49.2 vs. 45.7 min and 19.7 vs. 16.8 min, respectively; P = NS for both comparisons). However, after controlling for case severity and the use of stents, there were no significant differences in total procedure time or fluoroscopy time between the two groups. We found little evidence to suggest that the reuse of PTCA catheters is associated with longer total procedure time or fluoroscopy time. We conclude that if catheter reuse is not found to be associated with infectious disease transmission, its widespread use should be considered. Cathet. Cardiovasc. Intervent. 48:54-60, 1999.

Gestational trophoblastic disease (GTD) is a group of conditions that originate from the abnormal hyperproliferation of trophoblastic cells, which derive from the trophectoderm, the outer layer of the blastocyst that would normally develop into the placenta during pregnancy. GTDs encompass hydatidiform mole (HM) (complete and partial), invasive mole, gestational choriocarcinoma, placental-site trophoblastic tumor, and epithelioid trophoblastic tumor. Of these, the most common is HM, and it is the only one that has been reported to recur in the same patients from independent pregnancies, which indicates the patients’ genetic predisposition. In addition, HM is the only GTD that segregates in families according to Mendel’s laws of heredity, which made it possible to use rare familial cases of recurrent HMs (RHMs) to identify two maternal-effect genes, NLRP7 and KHDC3L, responsible for this condition. Here, we recapitulate current knowledge about RHMs and conclude with the role and benefits of testing patients for mutations in the known genes.