Background NLRP7 mutations are responsible for recurrent molar pregnancies and associated reproductive wastage. To investigate the role of NLRP7 in sporadic moles and other forms of reproductive wastage, the authors sequenced this gene in a cohort of 135 patients with at least one hydatidiform mole or three spontaneous abortions; 115 of these were new patients. Methods/Results All mutations were reviewed and their number, nature and locations correlated with the reproductive outcomes of the patients and histopathology of their products of conception. The presence of NLRP7 mutations was demonstrated in two patients with recurrent spontaneous abortions, and some rare non-synonymous variants (NSVs), present in the general population, were found to be associated with recurrent reproductive wastage. These rare NSVs were shown to be associated with lower secretion of interleukin 1b and tumour necrosis factor and therefore to have functional consequences similar to those seen in cells from patients with NLRP7 mutations. The authors also attempted to elucidate the cause of stillbirths observed in 13% of the patients with NLRP7 mutations by examining available placentas of the stillborn babies and live births from patients with mutations or rare NSVs. A number of severe to mild placental abnormalities were found, all of which are known risk factors for perinatal morbidity. Conclusions The authors recommend close follow-up of patients with NLRP7 mutations and rare NSVs to prevent the death of the rare or reduced number of babies that reach term.

Hydatidiform mole is an aberrant pregnancy with abnormal embryonic development and hydropic placental villi. Common moles are sporadic, not recurrent and affect one in every 1500 pregnancies in Western societies. Approximately, half of common moles are complete and mostly diploid androgenetic, whereas the remaining are partial and mostly triploid diandric. NLRP7 has been found to be responsible for a recurrent form of molar pregnancies. Recently, we showed that patients with NLRP7 mutations have an impaired inflammatory response to various stimuli. To date, molar tissues analyzed from patients with NLRP7 mutations have been found to be diploid and biparental. In this study, we report 10 new non-synonymous variants and one stop codon found in patients and not in controls. We demonstrate the presence of different types of moles, diploid biparental, diploid androgenetic, triploid and tetraploid conceptions, in patients with NLRP7 variants. We document in vitro and in vivo early embryo cleavage abnormalities in three patients. We propose a two-hit mechanism at the origin of androgenetic moles. This mechanism consists of variable degrees of early embryo cleavage abnormalities leading to chaotic mosaic aneuploidies, with haploid, diploid, triploid and tetraploid blastomeres. Surviving embryonic cells that reach implantation are then subject to the maternal immune response. Because of the patients' impaired inflammatory response, androgenetic cells, which are complete allograft, are able to grow and proliferate. In women with normal immune system, chaotic mosaic aneuploidies may also occur during early cleavage, however, androgenetic cells would die after implantation or stay undetected, confined to a small portion of the placenta.

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Hydatidiform mole (HM) is a human pregnancy with abnormal embryonic development. NLRP7 is a major autosomal recessive gene responsible for recurrent molar pregnancies and associated reproductive wastage in patients from several populations. Here, we report NLRP7 mutation analysis in 35 unrelated Chinese patients with recurrent reproductive wastage, including at least one HM. We describe three new protein-truncating mutations in NLRP7 and show the presence of three founder mutations in China and Asian populations. We determined the parental contribution to six molar tissues and show the occurrence of three diploid androgenetic moles in patients with one defective allele, while three diploid biparental moles occurred in patients with two defective alleles. We document the failure of pregnancies after assisted reproductive technologies (ARTs) in three patients with two defective alleles each and a successful pregnancy in one of two patients with one defective allele. Our data suggest that patients with a single defective allele have better reproductive outcomes than patients with two defective alleles, and some of them may benefit from ART.

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To understand the mechanisms leading to hydatidiform mole formation in patients with NLRP7 mutations, we used a combination of various approaches to characterize five products of conception, from two patients, shown by flow cytometry to contain non-diploid cells. We demonstrate that four of these conceptions are triploid and two of them originated from fertilization with more than one sperm. We show that three of these triploid conceptions fulfill the histopathological criteria of partial hydatidiform mole and one fulfills the histopathological criteria of spontaneous abortion. Our data demonstrate that oocytes from one patient with NLRP7 mutations are not able to prevent polyspermic fertilization and highlight the importance of using several approaches to characterize the genetic complexity of molar tissues and reproductive wastage.Altogether, our previous and current data show the association of NLRP7 mutations with several types of hydatidiform moles and with triploid spontaneous abortions.

Gestational choriocarcinomas are malignant tumors of trophoblastic cells that affect 5-25% of women with sporadic hydatidiform moles (HMs) depending on countries and studies. Nucleotide binding and oligomerization domain-like receptor protein 7 (NLRP7) is a major gene responsible for recurrent HMs and recently mutations in this gene have also been shown in 13% of women with sporadic, non-recurrent  moles. To investigate the role of NLRP7 in the genetic susceptibility for the malignant degeneration of moles, we sequenced its 11 exons in 43 Senegalese patients with post-molar choriocarcinomas. We report the presence of three novel NLRP7 variants that were found only in patients but not in 100 controls from the Senegalese general population, 100 controls from the Tunisian general population, and 100 controls from the Canadian population. In addition, this analysis revealed significant differences in the frequencies of four non-synonymous NLRP7 variants between European and Senegalese controls with the biggest difference being for variant G487E present at a minor allele frequency of 3.5% in Europeans, 18.1% in Tunisians and 45.6% in Senegalese. Comparing human NLRP7 and its paralog, NLRP2, with their mammalian counterparts revealed that allele E at position 487 is most likely the ancestral allele that was acquired in Africa but driven to low frequencies in Europeans and Asians due to migration, population bottlenecks and selective pressures. This study is the first attempt to investigate the role of NLRP7 in choriocarcinomas and highlights the higher frequencies of NLRP7 variants in the general Senegalese and Tunisian populations both known to have higher frequencies of moles and choriocarcinomas.