Hydatidiform mole (HM) is an abnormal human pregnancy with no embryo and cystic degeneration of placental villi. We report five mutations in the maternal gene NALP7 in individuals with familial and recurrent HMs. NALP7 is a member of the CATERPILLER protein family involved in inflammation and apoptosis. NALP7 is the first maternal effect gene identified in humans and is also responsible for recurrent spontaneous abortions, stillbirths and intrauterine growth retardation.

BackgroundLate presentation has been observed as the hallmark of breast cancer in Nigerian women and an earlier onset has been reported in this population. This study was designed to assess the awareness of female health workers about risk factors and screening methods for early detection of breast cancer.MethodsA cross-sectional descriptive study was carried out among female health workers in the two major government health institutions in Benin City, Edo State capital in Nigeria.Data analysis was by SPSS version 10 and test of significance was done with differences considered significant at p < 0.05.ResultsThree hundred and ninety-three (393) female health workers out of five hundred and five eligible subjects completed and returned the questionnaires, giving a response rate of 77.8%. One hundred and two (26%) were Doctors, two hundred and fifty-four (64.6%) Nurses, and thirty-seven (9.4%) were Radiographers, Laboratory Scientists and Pharmacists. A high proportion of our respondents had very poor knowledge about risk factors for breast cancer (55%). The awareness of mammography as a diagnostic method was very high (80.7%), but an extremely low knowledge of mammography as a screening method was found. Mammography practice of only 3.1% was found among those above 40 years of age who qualify for routine annual screening. Relatively low knowledge (45.5%) about Breast Self Examination (BSE) as a screening method was found.ConclusionThese female health workers who are expected to act as role models and educate the public had poor knowledge of risk factors for breast cancer and practice of breast cancer screening. There is very urgent need for regular update courses for health workers concerning breast cancer education including screening methods.

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.

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.

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 À/À 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.