Study of the Genetic and Epigenetic Causes of Recurrent Hydatidiform Moles

NCT ID: NCT01008501

Last Updated: 2025-02-20

Basic Information

• Recruitment Status: ACTIVE_NOT_RECRUITING
• Total Enrollment: 100 participants
• Study Classification: OBSERVATIONAL
• Study Start Date: 2000-11-07
• Study Completion Date: 2030-01-31

Brief Summary

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

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.

Conditions

Hydatidiform Moles

Study Design

• Observational Model Type: OTHER
• Study Time Perspective: PROSPECTIVE

Study Groups

Experimental

Individuals with recurrent or sporadic hydatidiform moles and their first-degree family members. Sometimes additional family members are also enrolled.

No interventions assigned to this group

Eligibility Criteria

Inclusion Criteria

• Personal or family history of recurrent moles or a sporadic mole
• Presence of a mutation in NLRP7

Exclusion Criteria

• None

• Eligible Sex: ALL
• Accepts Healthy Volunteers: Yes

Sponsors

Baylor College of Medicine

OTHER

Sponsor Role: lead

Responsible Party

Ignatia Van den Veyver

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Ignatia B Van den Veyver, MD

Role: PRINCIPAL_INVESTIGATOR

Baylor College of Medicine

Locations

Baylor College of Medicine

Houston, Texas, United States

Countries

United States

References

Kou YC, Shao L, Peng HH, Rosetta R, del Gaudio D, Wagner AF, Al-Hussaini TK, Van den Veyver IB. A recurrent intragenic genomic duplication, other novel mutations in NLRP7 and imprinting defects in recurrent biparental hydatidiform moles. Mol Hum Reprod. 2008 Jan;14(1):33-40. doi: 10.1093/molehr/gam079. Epub 2007 Nov 26.

Reference Type: BACKGROUND

PMID: 18039680 (View on PubMed)

Van den Veyver IB, Al-Hussaini TK. Biparental hydatidiform moles: a maternal effect mutation affecting imprinting in the offspring. Hum Reprod Update. 2006 May-Jun;12(3):233-42. doi: 10.1093/humupd/dmk005. Epub 2006 Mar 15.

Reference Type: BACKGROUND

PMID: 16540529 (View on PubMed)

Panichkul PC, Al-Hussaini TK, Sierra R, Kashork CD, Popek EJ, Stockton DW, Van den Veyver IB. Recurrent biparental hydatidiform mole: additional evidence for a 1.1-Mb locus in 19q13.4 and candidate gene analysis. J Soc Gynecol Investig. 2005 Jul;12(5):376-83. doi: 10.1016/j.jsgi.2005.02.011.

Reference Type: BACKGROUND

PMID: 15979551 (View on PubMed)

Al-Hussaini TK, Abd el-Aal DM, Van den Veyver IB. Recurrent pregnancy loss due to familial and non-familial habitual molar pregnancy. Int J Gynaecol Obstet. 2003 Nov;83(2):179-86. doi: 10.1016/s0020-7292(03)00209-1.

Reference Type: BACKGROUND

PMID: 14550593 (View on PubMed)

Saxena A, Frank D, Panichkul P, Van den Veyver IB, Tycko B, Thaker H. The product of the imprinted gene IPL marks human villous cytotrophoblast and is lost in complete hydatidiform mole. Placenta. 2003 Sep-Oct;24(8-9):835-42. doi: 10.1016/s0143-4004(03)00130-9.

Reference Type: BACKGROUND

PMID: 13129680 (View on PubMed)

Van den Veyver IB, Norman B, Tran CQ, Bourjac J, Slim R. The human homologue (PEG3) of the mouse paternally expressed gene 3 (Peg3) is maternally imprinted but not mutated in women with familial recurrent hydatidiform molar pregnancies. J Soc Gynecol Investig. 2001 Sep-Oct;8(5):305-13. doi: 10.1016/s1071-5576(01)00129-0.

Reference Type: BACKGROUND

PMID: 11677152 (View on PubMed)

Moglabey YB, Kircheisen R, Seoud M, El Mogharbel N, Van den Veyver I, Slim R. Genetic mapping of a maternal locus responsible for familial hydatidiform moles. Hum Mol Genet. 1999 Apr;8(4):667-71. doi: 10.1093/hmg/8.4.667.

Reference Type: BACKGROUND

PMID: 10072436 (View on PubMed)

Qian J, Deveault C, Bagga R, Xie X, Slim R. Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations. Hum Mutat. 2007 Jul;28(7):741. doi: 10.1002/humu.9498.

Reference Type: BACKGROUND

PMID: 17579354 (View on PubMed)

Slim R, Mehio A. The genetics of hydatidiform moles: new lights on an ancient disease. Clin Genet. 2007 Jan;71(1):25-34. doi: 10.1111/j.1399-0004.2006.00697.x.

Reference Type: BACKGROUND

PMID: 17204043 (View on PubMed)

Djuric U, El-Maarri O, Lamb B, Kuick R, Seoud M, Coullin P, Oldenburg J, Hanash S, Slim R. Familial molar tissues due to mutations in the inflammatory gene, NALP7, have normal postzygotic DNA methylation. Hum Genet. 2006 Oct;120(3):390-5. doi: 10.1007/s00439-006-0192-3. Epub 2006 Jul 28.

Reference Type: BACKGROUND

PMID: 16874523 (View on PubMed)

Murdoch S, Djuric U, Mazhar B, Seoud M, Khan R, Kuick R, Bagga R, Kircheisen R, Ao A, Ratti B, Hanash S, Rouleau GA, Slim R. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006 Mar;38(3):300-2. doi: 10.1038/ng1740. Epub 2006 Feb 5.

Reference Type: BACKGROUND

PMID: 16462743 (View on PubMed)

Fisher RA, Hodges MD, Newlands ES. Familial recurrent hydatidiform mole: a review. J Reprod Med. 2004 Aug;49(8):595-601.

Reference Type: BACKGROUND

PMID: 15457849 (View on PubMed)

Zhao J, Moss J, Sebire NJ, Cui QC, Seckl MJ, Xiang Y, Fisher RA. Analysis of the chromosomal region 19q13.4 in two Chinese families with recurrent hydatidiform mole. Hum Reprod. 2006 Feb;21(2):536-41. doi: 10.1093/humrep/dei357. Epub 2005 Oct 20.

Reference Type: BACKGROUND

PMID: 16239310 (View on PubMed)

Fisher RA, Hodges MD, Rees HC, Sebire NJ, Seckl MJ, Newlands ES, Genest DR, Castrillon DH. The maternally transcribed gene p57(KIP2) (CDNK1C) is abnormally expressed in both androgenetic and biparental complete hydatidiform moles. Hum Mol Genet. 2002 Dec 15;11(26):3267-72. doi: 10.1093/hmg/11.26.3267.

Reference Type: BACKGROUND

PMID: 12471053 (View on PubMed)

van der Smagt JJ, Scheenjes E, Kremer JA, Hennekam FA, Fisher RA. Heterogeneity in the origin of recurrent complete hydatidiform moles: not all women with multiple molar pregnancies have biparental moles. BJOG. 2006 Jun;113(6):725-8. doi: 10.1111/j.1471-0528.2006.00929.x.

Reference Type: BACKGROUND

PMID: 16709217 (View on PubMed)

Mahadevan S, Wen S, Balasa A, Fruhman G, Mateus J, Wagner A, Al-Hussaini T, Van den Veyver IB. No evidence for mutations in NLRP7 and KHDC3L in women with androgenetic hydatidiform moles. Prenat Diagn. 2013 Dec;33(13):1242-7. doi: 10.1002/pd.4239. Epub 2013 Oct 4.

Reference Type: BACKGROUND

PMID: 24105752 (View on PubMed)

Mahadevan S, Wen S, Wan YW, Peng HH, Otta S, Liu Z, Iacovino M, Mahen EM, Kyba M, Sadikovic B, Van den Veyver IB. NLRP7 affects trophoblast lineage differentiation, binds to overexpressed YY1 and alters CpG methylation. Hum Mol Genet. 2014 Feb 1;23(3):706-16. doi: 10.1093/hmg/ddt457. Epub 2013 Sep 18.

Reference Type: BACKGROUND

PMID: 24105472 (View on PubMed)

Other Identifiers

BCM Hydatidiform Mole H7345

Identifier Type: -

Identifier Source: org_study_id