Study of the Genetic and Epigenetic Causes of Recurrent Hydatidiform Moles

Study Overview
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Brief Summary
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The researchers' laboratory is studying a rare class of highly recurrent hydatidiform moles. These are usually complete hydatidiform moles (CHM), but sometimes they are partial hydatidiform moles PHM). With sporadic moles, the difference between CHMs and PHMs is that with CHMS, there is not typically an embryo or fetus at the time of diagnosis but with a PHM there may be a fetus. Also, CHMs have 46 chromosomes in each cell. While this is the number of chromosomes that should be found, the problem is that all the chromosomes come from the father. Normally, half the chromosomes should come from the mother and half should come from the father. Unlike CHMs, PHMs have 69 chromosomes. This means that PHMs have three copies of each chromosome when they should only have two. The extra copy comes from the father. The researchers' study focuses on moles that are genetically different from these sporadic moles in that they have 23 chromosomes from the mother and 23 chromosomes from the father - just like a normally developing pregnancy. These are called biparental moles because the mutation that causes the mole comes from both parents. This mutation occurs in a gene called NLRP7. The researchers' team is working to understand how mutations in NLRP7 leads to CHMs and how these mutations may lead to other types of pregnancy loss. The researchers are also trying to discover other genetic and epigenetic factors that may lead to moles.

Detailed Description
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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.

Official Title
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Genetic Studies in Gestational Trophoblastic Disease

Conditions
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Hydatidiform Moles

Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Personal or family history of recurrent moles or a sporadic mole Presence of a mutation in NLRP7 Exclusion Criteria: None
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental<br>Individuals with recurrent or sporadic hydatidiform moles and their first-degree family members. Sometimes additional family members are also enrolled. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Identifying the change in the genetic information that causes recurrent hydatidiform moles. | The researchers will isolate genetic material from blood of women with recurrent hydatidiform molar (RHM) pregnancies, their RHM pregnancies, and for some first-degree relatives. DNA sequencing along with bioinformatic analysis will be used to find changes in the genetic code unique to individuals with RHM. When a new gene is found that shows variants that are deleterious to its function in at least 3 unrelated women with RHM, but not in healthy pregnant women, the outcome (finding a new genetic cause of RHM) will be achieved. RHM are very rare and only 70% have a known cause (known gene), thus the researchers will continue recruitment and enrollment of rare undiagnosed individuals when they are referred to the study. A key finding in one individual can provide the clue for a new disease gene in others. It cannot be predicted when this will happen, thus enrollment and data collection will continue as long as the protocol is open. | Through study completion, an average of 15 years. | 
| Identifying the changes in the genetic information that cause different forms of unexplained reproductive failure | The researchers will isolate genetic material from blood of women with recurrent unexplained reproductive failure (RF), their miscarried pregnancies if possible, and for some from first-degree relatives. DNA sequencing and bioinformatic analysis will be used to find changes in the genetic code unique to individuals with unexplained RF. When a new gene is found that shows variants that are deleterious to its function in at least 3 unrelated women with unexplained RF, but not in healthy pregnant women, the outcome (finding a new genetic cause for RF) will be achieved. Unexplained RF is relatively rare and many causes are not yet known, thus the researchers will continue recruitment and enrollment of rare undiagnosed individuals when they are referred to the study. A key finding in one individual can provide the clue for a new disease gene in others. It cannot be predicted when this will happen, thus enrollment and data collection will continue as long as the protocol is open | Through study completion, an average of 15 years. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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hydatidiform moles, complete hydatidiform moles, partial hydatidiform moles, Molar pregnancy, NLRP7, pregnancy wastage, imprinting, sporadic hydatidiform moles, recurrent hydatidiform moles