Hydatidiform mole (HM) is the product of an aberrant human pregnancy in which there is abnormal embryonic development and abnormal proliferation of placental villi. The incidence of HM varies between ethnic groups, and occurs in 1 in every 1500 pregnancies in the USA. All HM cases are sporadic except for extremely rare familial cases. The exact mechanisms leading to molar pregnancies are not known. Hydatidiform moles are classified based on histology and karyotype data into two types:

complete hydatidiform moles (CHM) and partial hydatidiform moles (PHM). The complete forms are characterized by general trophoblastic proliferation and absence of an embryo and amniotic membranes. In most of the cases, CHM have a diploid genome, and are androgenetic with two identical sets of paternal chromosomes. Partial hydatidiform moles are characterized by focal trophoblastic proliferation. Embryos and amniotic membranes are usually present in these molar pregnancies. Partial hydatidiform moles are mostly triploid with two sets of paternal chromosomes and one set of maternal chromosomes. The comparison of findings in androgenetic CHM and PHM indicate that both maternally (under) expressed and paternally (over) expressed genes play a role in the pathophysiology of molar pregnancies. Very few genetic studies have been performed on molar pregnancies or the patients who carry these pregnancies. A few studies have looked at the over- or underexpression of genes that may play a role in the progression or invasiveness of hydatidiform moles; however none have addressed the underlying genetic etiology. We have been able to study an inbred family of which several female members have had recurrent hydatidiform moles and have now genetically mapped the defective gene responsible for the molar pregnancies in this family. We then worked towards refined characterization of the genetic locus containing the mutated gene and analysis of candidate genes in this region for mutations leading to molar pregnancy. Because the hydatidiform moles in these patients have abnormal genetic imprinting, we believe that this candidate gene is important for establishment of genetic imprinting in the maternal germline. Recently, another group of investigators studying this condition identified mutations in a gene, NALP7 (now renamed to NLRP7), in some of the affected women. We confirmed this in other subjects studied by us. This is the first identified gene, but there is genetic heterogeneity and other genes still remain to be found. In addition, the normal function of this gene in reproduction and how it leads to recurrent moles when mutated remains to be determined. To study both of these, it will be very important to collect as many molar pregnancy tissue samples as possible, as well as blood samples and/or other non-invasively obtained samples, such as buccal swabs and saliva, from affected patients and their families. Recent evidence suggests that mutations in NLRP7 might cause other forms of reproductive failure, such as triploid spontaneous abortions. It has further been proposed that the mutation status of NLRP7 in women with recurrent reproductive loss is an important predictor of the outcome of Assisted Reproductive Technologies. Therefore, we are carrying out mutation analysis of NLRP2 and NLRP7 in women with unexplained infertility and other forms of reproductive failure.