Reappraisal and refined diagnosis of ultrasonography and histological findings for hydatidiform moles: a multicentre retrospective study of 821 patients.

AIMS: Specific identification of a hydatidiform mole (HM) and subclassification of a complete hydatidiform mole (CHM) or partial hydatidiform mole (PHM) are critical. This study aimed to reappraise the diagnostic performance of ultrasonography and histology with a refined diagnosis. METHODS: This was a retrospective, multicentre cohort study of 821 patients with histologically suspected HM specimens. Refined diagnostic algorithms with p57 immunohistochemistry and short tandem repeat (STR) genotyping were performed and used as the true standard for assessing the diagnostic performance of the original ultrasonography and morphology methods. The diagnostic performance was calculated using accuracy, agreement rate, sensitivity and the positive predictive value (PPV) compared with refined diagnostic results. RESULTS: Of the 821 histologically suspected HM cases included, 788 (95.98%) were successfully reclassified into 448 CHMs, 213 PHMs and 127 non-molar (NM) abortuses. Ultrasonography showed an overall accuracy of 44.38%, with a sensitivity of 44.33% for CHM and 37.5% for PHM. The overall classification accuracy of the original morphological diagnosis was 65.97%. After exclusion of the initially untyped HMs, the overall agreement rate was 59.11% (κ=0.364, p<0.0001) between the original and refined diagnoses, with a sensitivity of 40.09% and PPV of 96.05% for diagnosing CHMs and a sensitivity of 84.98% and a PPV of 45.59% for diagnosing PHMs. The interinstitutional variability of morphology in diagnosing HMs was significant among the 15 centres (range, 8.33%-100.00%, p<0.0001). CONCLUSION: The current diagnosis of HM based solely on ultrasound or morphology remains problematic, and ancillary techniques, particularly p57 immunohistochemistry and DNA genotyping, should be integrated into routine practice as much as possible.

The biological roles of CD47 in ovarian cancer progression.

Ovarian cancer is one of the most lethal malignant tumors, characterized by high incidence and poor prognosis. Patients relapse occurred in 65-80% after initial treatment. To date, no effective treatment has been established for these patients. Recently, CD47 has been considered as a promising immunotherapy target. In this paper, we reviewed the biological roles of CD47 in ovarian cancer and summarized the related mechanisms. For most types of cancers, the CD47/Sirpα immune checkpoint has attracted the most attention in immunotherapy. Notably, CD47 monoclonal antibodies and related molecules are promising in the immunotherapy of ovarian cancer, and further research is needed. In the future, new immunotherapy regimens targeting CD47 can be applied to the clinical treatment of ovarian cancer patients.

The Enrichment of Docosahexaenoic Acid from Microalgal Oil by Urea Complexation via Rotary-evaporation Crystallization.

Urea complexation is a widely used method for enriching polyunsaturated fatty acids, and cooling is the traditional approach for urea crystallization. This study aimed to investigate the potential of rotary-evaporation under vacuum as an alternative method for urea crystallization in urea complexation to enrich docosahexaenoic acid (DHA). DHA-containing microalgal oil was converted to ethyl esters (EE) as the raw material. In comparison to cooling, rotary-evaporation crystallization, as a post-treatment method for urea complexation, led to higher DHA contents in the non-urea included fractions. The ratios of urea to EE converted from DHA-containing microalgal oil was found to be the primary factors influencing urea complexation when using rotary-evaporation crystallization. Through an orthogonal test, optimal process conditions were determined, including a urea/EE ratio of 2, an ethanol/urea ratio of 7, and a rotary-evaporation temperature of 75℃. Under these conditions, a concentrate containing more than 90% DHA could be obtained.

The Effect of Feeding Sequence on the Structure and Properties of the Ethylene/1-Octene Copolymer in the Semi-Continuous Polymerization Reaction System.

The performance of ethylene/1-octene copolymer primarily depends on the microstructure of the polymer chain. This study employed a new method to control the inter-distribution of hexyl chain branches directly on the backbone of the ethylene/1-octene copolymer. Three ethylene/1-octene copolymers with different inter-distributions of hexyl chain branches were synthesized using [Me2Si(C5Me4) (NtBu)] TiCl2 (Ti-CGC) by different feeding sequences in the semi-continuous polymerization reaction system. The three copolymers were named according to the feeding sequence of the materials: ethylene/1-octene/Ti-CGC (EOC), 1-octene/Ti-CGC/ethylene (OCE), and ethylene/Ti-CGC/1-octene (ECO), respectively. The structure and properties of the copolymers were characterized using HT-GPC, 13C-NMR, DSC, WAXD, DMA, MI, and Uniaxial Tension Test. The results showed that the feeding sequence greatly affected the comonomer distribution of the molecular chains, molecular weight, molecular weight distribution, and chemical composition of the copolymers, consequently influencing their thermal performance and mechanical properties. Thus, it is probable that one could obtain an ethylene/1-octene copolymer with designed properties by controlling the feeding sequence during the ethylene/1-octene semi-continuous copolymerization process.

Hematoxylin and Eosin Staining Helps Reduce Maternal Contamination in Short Tandem Repeat Genotyping for Hydatidiform Mole Diagnosis.

Short tandem repeat (STR) genotyping provides parental origin information about aneuploidy pregnancy loss and has become the current gold standard for hydatidiform mole diagnosis. STR genotyping diagnostic support most commonly relies on formalin-fixed paraffin-embedded samples, but maternal contamination is one of the most common issues based on traditional unstained sections. To evaluate the influence of hematoxylin and eosin (H&E) staining on DNA quality and STR genotyping, DNA was isolated from unstained, deparaffinized hydrated, and H&E-stained tissue sections (i.e. 3 groups) from each of 6 formalin-fixed paraffin-embedded placentas. The macrodissected view field, DNA quality, and polymerase chain reaction amplification efficiency were compared among groups. STR genotyping analysis was performed in both the test cohort (n = 6) and the validation cohort (n = 149). H&E staining not only did not interfere with molecular DNA testing of formalin-fixed paraffin-embedded tissue but also had a clearer macrodissected field of vision. In the test cohort, H&E-stained sections were the only group that did not exhibit maternal miscellaneous peaks in STR genotyping results. In the validation cohort, 138 (92.62%) cases yielded satisfactory amplification results without maternal contamination. Thus, H&E staining helped to reduce maternal contamination in STR genotyping for hydatidiform mole diagnosis, suggesting that H&E-stained sections can be incorporated into the hydatidiform mole molecular diagnostic workflow.

Facile Fabrication of Nickel Supported on Reduced Graphene Oxide Composite for Oxygen Reduction Reaction.

Due to the depletion of fossil fuels, the demand for renewable energy has increased, thus stimulating the development of novel materials for energy conversion devices such as fuel cells. In this work, nickel nanoparticles loaded on reduced graphene oxide (Ni/rGO) with small size and good dispersibility were successfully prepared by controlling the pyrolysis temperature of the precursor at 450 °C, assisted by a microwave-assisted hydrothermal method, and exhibited enhanced electrocatalytic activity towards oxygen reduction reaction (ORR). Additionally, the electron enrichment on Ni NPs was due to charge transfer from the rGO support to metal nickel, as evidenced by both experimental and theoretical studies. Metal-support interactions between nickel and the rGO support also facilitated charge transfer, contributing to the enhanced ORR performance of the composite material. DFT calculations revealed that the first step (from O2 to HOO*) was the rate-determining step with an RDS energy barrier lower than that of the Pt(111), indicating favorable ORR kinetics. The HOO* intermediates can be transferred onto rGO by the solid-phase spillover effect, which reduces the chemical adsorption on the nickel surface, thereby allowing continuous regeneration of active nickel sites. The HO2- intermediates generated on the surface of rGO by 2e- reduction can also efficiently diffuse towards the nearby Ni surface or the interface of Ni/rGO, where they can be further rapidly reduced to OH-. This mechanism acts as the pseudo-four-electron path on the RRDE. Furthermore, Ni/rGO-450 demonstrated superior stability, methanol tolerance, and durability compared to a 20 wt% Pt/C catalyst, making it a cost-effective alternative to conventional noble metal ORR catalysts for fuel cells or metal-air batteries.

Identification and validation of a seven cuproptosis-associated lncRNA signature to predict the prognosis of endometrial cancer.

OBJECTIVE: Endometrial cancer (EC) is one of the most prevalent cancers in women. Long non-coding RNAs (lncRNAs) are potential diagnostic biomarkers in patients with EC. METHODS: We obtained clinical information and transcriptome data for 552 patients with EC from The Cancer Genome Atlas database. Cuproptosis-associated lncRNAs were obtained through Pearson's correlation analysis. Univariate and multivariate Cox regression analyses were applied and a signature predicting overall survival (OS) among patients with EC was constructed. We also analyzed the tumor immune microenvironment and drug sensitivity. The results were validated by quantitative real time-polymerase chain reaction, and 5-ethynyl-2'-deoxyuridine and wound-healing assays. RESULTS: Seven cuproptosis-associated lncRNAs related to prognosis were screened out and a signature was constructed. OS was significantly superior in the low-risk group. In addition, patients in the low-risk group had more CD8+ T cell infiltration, a stronger type II interferon response, and greater cisplatin sensitivity. Expression levels of some of the lncRNAs were significantly increased by cuproptosis. Furthermore, silencing of lncRNA AC084117.1 significantly inhibited the proliferation and migration of EC cells. CONCLUSION: We constructed a seven cuproptosis-associated lncRNA signature to predict the prognosis of patients with EC with good predictive power.

Stromal score is a promising index in tumor patients' outcome determination.

Background: Immune status is widely acknowledged as a valuable marker for predicting cancer prognosis and therapy response. However, there has been a limited understanding of the stromal landscape in cancer. Methods: By employing ESTIMATE, stromal- and immune-scores were inferred for 6193 tumor samples spanning 12 cancer types sourced from The Cancer Genome Atlas (TCGA). Subsequently, the samples were categorized into seven groups based on their stromal and immune scores. A comparison of prognosis, lymphocyte and stromal cell infiltration, and the response to programmed death ligand 1 (PD-L1) therapy was conducted among these subtypes. Results: It was unveiled by the analysis that, in the majority of cancer types, stromal score exhibited a more potent predictive capability for outcomes compared to the immune score. Furthermore, it was observed that in four cancer types, intermediate immune infiltration coupled with low stromal infiltration correlated with the most favorable overall survival, whereas an unfavorable outcome was predicted in colorectal cancer (CRC) and stomach adenocarcinoma (STAD) when high immune infiltration coexisted with intermediate or high stromal infiltration. Conclusion: In summary, while high immune scores frequently correlate with a positive prognosis, such correlation is not universal. A potential strategy to address the current limitations of the immune score in specific circumstances could involve a focus on stromal scores or a subtle integration of stromal and immune status.

HPV-related cervical diseases: Alteration of vaginal microbiotas and promising potential for diagnosis.

Vaginal microbiota is closely associated with women's health, however, the correlation between HPV-related cervical disease (HRCD) and vaginal microbiota is still obscure. In this study, patients with HRCD (n = 98) and healthy controls (n = 58) in Hangzhou were recruited, and their vaginal microbiota were collected and analyzed. The composition of the vaginal microbial community was explored, and a disease classification model was developed by random forest algorithm. The results suggested that the diversity of vaginal microbiota was significantly higher in HRCDs than that in healthy controls (p < 0.05). Firmicutes is the dominant phylum in vaginal microbiota, and Lactobacillus was identified as the most altered genus between two groups (p < 0.01). Kyoto Encyclopedia of Genes and Genomes analysis suggested the difference in vaginal microbial community functions between two groups. Furthermore, we identified 10 biomarkers as the optimal marker sets for the random forest model and found a higher probability of disease values in HRCD group in discovery cohort (p < 0.0001), with an area under the receiver operating characteristic curve reaching 89.7% (95% confidence interval: 78.3%-100%). We further validated the model in both validation and independent diagnosis cohorts, confirming its accuracy in the prediction of HRCD. In conclusion, this study revealed the community composition of vaginal microbiota in HRCDs and successfully constructed a diagnostic model for HRCD.

Challenges in diagnosing hydatidiform moles: a review of promising molecular biomarkers.

INTRODUCTION: Hydatidiform moles (HMs) are pathologic conceptions with unique genetic bases and abnormal placental villous tissue. Overlapping ultrasonographical and histological manifestations of molar and non-molar (NM) gestations and HMs subtypes makes accurate diagnosis challenging. Currently, immunohistochemical analysis of p57 and molecular genotyping have greatly improved the diagnostic accuracy. AREAS COVERED: The differential expression of molecular biomarkers may be valuable for distinguishing among the subtypes of HMs and their mimics. Thus, biomarkers may be the key to refining HMs diagnosis. In this review, we summarize the current challenges in diagnosing HMs, and provide a critical overview of the recent literature about potential diagnostic biomarkers and their subclassifications. An online search on PubMed, Web of Science, and Google Scholar databases was conducted from the inception to 1 April 2022. EXPERT OPINION: The emerging biomarkers offer new possibilities to refine the diagnosis for HMs and pregnancy loss. Although the additional studies are required to be quantified and investigated in clinical trials to verify their diagnostic utility. It is important to explore, validate, and facilitate the wide adoption of newly developed biomarkers in the coming years.

Intestinal metastasis from choriocarcinoma: a case series and literature review.

BACKGROUND: Gestational choriocarcinoma is a rare trophoblastic tumor that spreads mainly to the lung, liver, and central nervous system. Fewer than 5% of patients present with metastasis to the gastrointestinal system and have a poor prognosis CASE PRESENTATION: We describe four cases of patients with intestinal metastasis from choriocarcinoma who visited the First Affiliated Hospital of Zhejiang University School of Medicine and the First People's Hospital of Hangzhou between April 2012 and October 2019. Four patients presented with gastrointestinal symptoms or developed gastrointestinal symptoms during treatment for choriocarcinoma. Three patients had these intestinal lesions surgically removed, and the postoperative pathology results suggested choriocarcinoma. All patients received multiple chemotherapy regimens during treatment for suboptimal human chorionic gonadotropin (hCG) levels; one patient died 22 months after a definitive diagnosis was made, and the other three patients are still undergoing regular follow-up. CONCLUSION: Given the low incidence of intestinal metastases from choriocarcinoma, the metastatic route of intestinal metastases from choriocarcinoma remains to be elucidated, and diagnosis mainly depends on pathology findings. An effective treatment has not been determined, and surgical excision with chemotherapy is generally accepted.

Role of Emergency Surgery for Fatal Complications of Gestational Trophoblastic Neoplasia: A Single-Center Experience.

PURPOSE: High-risk gestational trophoblastic neoplasia (GTN) can lead to fatal complications; however, few reports have assessed emergency surgery as a treatment option for such complications. Thus, this study aimed to analyze the clinical features and prognosis of patients with GTN who underwent emergency surgery. PATIENTS AND METHODS: Thirteen patients with high-risk or ultra-high-risk GTN who underwent emergency surgery for fatal complications in the First Affiliated Hospital of Zhejiang University, School of Medicine from 2013 to 2020 were analyzed, and their medical records were reviewed. The patients' characteristics and treatment were evaluated with respect to outcomes. RESULTS: Thirteen patients with GTN who underwent 15 emergency surgical procedures were identified in our center. The mean International Federation of Gynecology and Obstetrics score of these patients was 14.8 (range, 11-19). Of the 13 patients, six underwent brain surgeries, such as tumor resection (n = 5) and conservative surgery (n = 1). All the patients received multi-agent chemotherapy after emergency surgery, and the mean time from emergency surgery to subsequent chemotherapy was 12.7 days. Of the 13 patients, 10 (77%) were cured and disease-free, with a follow-up period ranging from 3 months to 8 years. All the patients (n = 6) who underwent emergency brain surgery survived and achieved complete remission. CONCLUSION: For patients with high-risk GTN with fatal complications, especially brain lesions, emergency surgery combined with subsequent chemotherapy may provide a favorable prognosis.

PADI6 Regulates Trophoblast Cell Migration-Invasion Through the Hippo/YAP1 Pathway in Hydatidiform Moles.

PURPOSE: Peptidyl arginine deiminase, type VI (PADI6), a member of the subcortical maternal complex, plays an important role in oocyte growth and the development of fertilized oocytes. Human patients with PADI6 mutations can suffer from multiple reproductive deficiencies including hydatidiform moles and miscarriages. Recent studies have demonstrated that the Hippo signaling pathway plays a central role in the specification of the first cell fates and the maintenance of the human placental trophoblast epithelium. The present study aimed to verify the hypothesis that PADI6 regulates the biological functions of trophoblast cells by targeting YAP1 and to explore the mechanism by which PADI6 accomplishes this in trophoblast cells. METHODS: Villi from HMs and human trophoblast cell lines were used to identify the localization of PADI6 and YAP1 by immunohistochemistry and immunocytochemistry. PADI6 overexpression and knockdown were induced in human trophoblast cells. Co-immunoprecipitation was used to explore the interaction between PADI6 and YAP1. Wound healing, Transwell and EdU staining assays were used to detect migration, invasion and proliferation. Flow cytometric analysis was used to analyze the cell cycle and apoptosis. ß-Tubulin and F-actin levels were determined by Western blot, quantitative real-time PCR and phalloidin staining. RESULTS: The results showed that PADI6 and YAP1 had the same expression pattern in villi and colocalized in the cytotrophoblast. An interaction between PADI6 and YAP1 was also confirmed in human trophoblast cell lines. We found that PADI6 positively regulated the expression of YAP1. Functionally, overexpression of PADI6 promoted cell cycle progression and enhanced migration, invasion, proliferation and apoptosis, whereas downregulation of PADI6 showed the opposite effects. CONCLUSION: This study demonstrates that YAP1 is a novel target of PADI6 that serves as an important regulator of trophoblast dysfunction. The crosstalk between the Hippo/YAP1 pathway and the SCMC might be a new topic to explore to uncover the pathological mechanisms of HMs.

Reprogramming of human peripheral blood mononuclear cells from a patient suffering from recurrent hydatidiform mole to an iPSC line FAHZUi001-A carrying a homozygous p.Gln421Ter mutation in NLRP7 gene.

Recurrent hydatidiform mole (RHM) is characterized by the occurrence of at least twice hydatidiform mole. Unlike sporadic complete hydatidiform moles (CHMs), which are androgenetic with 2 paternal chromosomes, CHMs associated with familial recurrence are genetically biparental with a maternal and a paternal chromosome. NLRP7 mutations have been reported in 55% of RHM cases. Here, we generated induced pluripotent stem cells (iPSCs) from a patent with NLRP7 gene mutation c.1261C > T by reprogramming peripheral blood mononuclear cells by non-integrated method. The resulting iPSCs carrying NLRP7 mutation, had normal karyotype, expressed pluripotency markers, and could differentiate into three germ layersin vivo.

N-methyladenosine reader YTHDF2-mediated long noncoding RNA FENDRR degradation promotes cell proliferation in endometrioid endometrial carcinoma.

Dysregulation of long noncoding RNA (LncRNA) FENDDR has been shown to be closely related to the progression of several cancers. However, its role and upstream regulatory mechanism in endometrioid endometrial carcinoma (EEC) remains unclear. This study was conducted using the cancerous tissues of EEC patients (n = 60), EEC cell lines, and a xenograft mouse model. The expression level of LncRNA FENDRR was decreased and the N-methyladenosine (m6A) methylation levels of LncRNA FENDRR was elevated in cancerous tissues of EEC patients. In vitro experiments demonstrated that YTH domain-containing 2 (YTHDF2), an m6A reader, recognized the abundance of m6A-modified LncRNA FENDRR in EEC cells and promoted its degradation. LncRNA FENDRR overexpression suppressed cell proliferation and facilitated cell apoptosis in the EEC cell line HEC-1B by reducing the protein level of SRY-related HMG box transcription factor 4 (SOX4). Interference of LncRNA FENDRR reversed the inhibitory effect of sh-YTHDF2 on cell proliferation and the promoting effect of sh-YTHDF2 on cell apoptosis in HEC-1B cells by silencing FENDRR. Finally, in vivo experiments confirmed that overexpression of LncRNA FENDRR retarded the growth of EEC cells. In conclusion, YTHDF2-mediated LncRNA FENDRR degradation promotes cell proliferation by elevating SOX4 expression in EEC.

Novel pathogenic variants in NLRP7, NLRP5, and PADI6 in patients with recurrent hydatidiform moles and reproductive failure.

Recurrent hydatidiform moles (RHMs) are human pregnancies with abnormal embryonic development and hyperproliferating trophoblast. Biallelic mutations in NLRP7 and KHDC3L, members of the subcortical maternal complex (SCMC), explain the etiology of RHMs in only 60% of patients. Here we report the identification of seven functional variants in a recessive state in three SCMC members, five in NLRP7, one in NLRP5, and one in PADI6. In NLRP5, we report the first patient with RHMs and biallelic mutations. In PADI6, the patient had four molar pregnancies, two of which had fetuses with various abnormalities including placental mesenchymal dysplasia and intra-uterine growth restriction, which are features of Beckwith-Wiedemann syndrome and Silver Russell syndrome, respectively. Our findings corroborate recent studies and highlight the common oocyte origin of all these conditions and the continuous spectrum of abnormalities associated with deficiencies in the SCMC genes.

MST4 Regulates Epithelial-Mesenchymal Transition of Choriocarcinoma by Mediating TGF-ß1 Expression.

BACKGROUND: Mammalian Ste20-like kinase 4 (MST4), also known as serine/threonine kinase 26 (STK26), promotes development of several cancers and is found to be highly expressed in the placenta. However, in choriocarcinoma that originated from the placenta, the expression of MST4 was undetermined and its mechanism was unknown. In this study, the expression of MST4 in choriocarcinoma as well as the underlying mechanism was explored. PURPOSE: To detect the expression of MST4 in patient samples and mechanism of mediating EMT by MST4 in choriocarcinoma. PATIENTS AND METHODS: The metastatic lesions of choriocarcinoma (n=17) and volunteer villus (n=17) were collected to determine MST4 expression using immunohistochemistry and H&E staining. We use siRNA and lentiviral vector to knockdown MST4 and use plasmid to overexpress MST4 in choriocarcinoma. Then, we apply real-time polymerase chain reaction (RT-PCR), Western blot assay and immunofluorescence assay to detect target protein expressions. Cell invasion and migration and cell proliferation were detected by transwell assay and wound healing assay and CCK-8 and cell colony formation. RESULTS: MST4 is lowly expressed in the metastatic lesions of choriocarcinoma patients when compared with normal villus. Knockdown of MST4 activated epithelial-mesenchymal transition (EMT) process, significantly increasing the ability of invasion and migration in choriocarcinoma cell lines (JAR and JEG-3). In contrast, the EMT process was restrained in choriocarcinoma cell lines with overexpressed MST4. Meanwhile, genome-wide gene expression array, Western blot and ELISA revealed that tumor growth factor-beta 1 (TGF-ß1) has significantly increased. The EMT process and metastatic prompting biofunction were reversed after using TGF-ß1 inhibitor (LY364947) in the choriocarcinoma cell lines with MST4 knockdown. CONCLUSION: Our studies demonstrated that MST4 was lowly expressed in patient samples. Additionally, JAR and JEG-3 increase cell invasion and migration ability while there is no influence on cell proliferation with MST4 knockdown. Conversely, the metastatic ability of JAR and JEG-3 was decreased with overexpressed MST4. Moreover, TGF-ß1 was a key factor after MST4 knockdown. In conclusion, MST4 affects choriocarcinoma EMT by mediating TGF-ß1 expression.

Can ovaries be preserved after an ovarian arteriovenous disconnection? One case report and a review of surgical treatment using Da Vinci robots for aggressive ovarian fibromatosis.

BACKGROUND: The ovary is an important organ of the female reproductive system, which produces oocytes and secretes reproductive hormones. Ovaries have complex dual blood supplies with their blood supply being the core component to protect and ensure ovarian function. Ovarian preservation surgery often encounters problems related to whether or not to preserve ovarian vessels on the affected side. CASE PRESENTATION: This study reports on the case of a 30-year-old female patient with the retroperitoneal fibromatosis that had a history of uterine leiomyoma. During the operation, the ovarian arteries and veins were separated according to what was found during the procedure. A postoperative examination demonstrated good function and morphology of the ovary. CONCLUSIONS: A thorough review of academic journals combined with our collection of clinical data was conducted, which confirmed the double blood supply source to the ovaries. As a result of this exploration, a new surgical method is being proposed that is designed to protect the ovaries. By conducting this new procedure, the patient's disease was not only halted and ultimately cured, but results demonstrate that the method was also able to retain the shape and function of the ovary. The postoperative satisfaction of the patient was significantly improved.

Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles.

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.