Hydatidiform mole is an aberrant human pregnancy characterized by early embryonic arrest and excessive trophoblastic proliferation. Recurrent hydatidiform moles are defined by the occurrence of at least two hydatidiform moles in the same patient. Fifty to eighty percent of patients with recurrent hydatidiform moles have biallelic pathogenic variants in NLRP7 or KHDC3L. However, in the remaining patients, the genotypic types of the moles are unknown. We characterized 80 new hydatidiform mole tissues, 57 of which were from patients with no mutations in the known genes, and we reviewed the genotypes of a total of 123 molar tissues. We also reviewed mutation analysis in 113 patients with recurrent hydatidiform moles. While all hydatidiform moles from patients with biallelic NLRP7 or KHDC3L mutations are diploid biparental, we demonstrate that those from patients without mutations are highly heterogeneous and only a small minority of them are diploid biparental (8%). The other mechanisms that were found to recur in patients without mutations are diploid androgenetic monospermic (24%) and triploid dispermic (32%); the remaining hydatidiform moles were misdiagnosed as moles due to errors in the analyses and/or their unusual mechanisms. We compared three parameters of genetic susceptibility in patients with and without mutations and show that patients without mutations are mostly from non-familial cases, have fewer reproductive losses, and more live births. Our data demonstrate that patients with recurrent hydatidiform moles and no mutations in the known genes are, in general, different from those with mutations; they have a milder genetic susceptibility and/or a multifactorial etiology underlying their recurrent hydatidiform moles. Categorizing these patients according to the genotypic types of their recurrent hydatidiform moles may facilitate the identification of novel genes for this entity.
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Grimes DA. Epidemiology of gestational trophoblastic disease. Am J Obstet Gynecol. 1984;150:309–18.
Savage P, Williams J, Wong SL, et al. The demographics of molar pregnancies in England and Wales from 2000–2009. J Reprod Med. 2010;55:341–5.
Berkowitz RS, Im SS, Bernstein MR, et al. Gestational trophoblastic disease. Subsequent pregnancy outcome, including repeat molar pregnancy. J Reprod Med. 1998;43:81–6.
Boufettal H, Coullin P, Mahdaoui S, et al. Complete hydatiforme mole in Morocco: epidemiological and clinical study. J Gynecol Obstet Biol Reprod. 2011;40:419–29.
Horn LC, Kowalzik J, Bilek K, et al. Clinicopathologic characteristics and subsequent pregnancy outcome in 139 complete hydatidiform moles. Eur J Obstet Gynecol Reprod Biol. 2006;128:10–4.
Kim JH, Park DC, Bae SN, et al. Subsequent reproductive experience after treatment for gestational trophoblastic disease. Gynecol Oncol. 1998;71:108–12.
Kronfol NM, Iliya FA, Hajj SN. Recurrent hydatidiform mole: a report of five cases with review of the literature. J Med Liban. 1969;22:507–20.
Sebire NJ, Fisher RA, Foskett M, et al. Risk of recurrent hydatidiform mole and subsequent pregnancy outcome following complete or partial hydatidiform molar pregnancy. BJOG. 2003;110:22–6.
Baergen RN, Kelly T, McGinniss MJ, et al. Complete hydatidiform mole with a coexistent embryo. Hum Pathol. 1996;27:731–4.
Zaragoza MV, Keep D, Genest DR, et al. Early complete hydatidiform moles contain inner cell mass derivatives. Am J Med Genet. 1997;70:273–7.
Szulman AE, Surti U. The syndromes of hydatidiform mole. II. Morphologic evolution of the complete and partial mole. Am J Obstet Gynecol. 1978;132:20–7.
Gupta M, Vang R, Yemelyanova AV, et al. Diagnostic reproducibility of hydatidiform moles: ancillary techniques (p57 immunohistochemistry and molecular genotyping) improve morphologic diagnosis for both recently trained and experienced gynecologic pathologists. Am J Surg Pathol. 2012;36:1747–60.
Murphy KM, McConnell TG, Hafez MJ, et al. Molecular genotyping of hydatidiform moles: analytic validation of a multiplex short tandem repeat assay. J Mol Diagn. 2009;11:598–605.
Murdoch S, Djuric U, Mazhar B, et al. Mutations in NALP7 cause recurrent hydatidiform moles and reproductive wastage in humans. Nat Genet. 2006;38:300–2.
Parry DA, Logan CV, Hayward BE, et al. Mutations causing familial biparental hydatidiform mole implicate c6orf221 as a possible regulator of genomic imprinting in the human oocyte. Am J Hum Genet. 2011;89:451–8.
Reddy R, Nguyen NM, Sarrabay G, et al. The genomic architecture of NLRP7 is Alu rich and predisposes to disease-associated large deletions. Eur J Hum Genet. 2016;24:1516.
Ulker V, Gurkan H, Tozkir H, et al. Novel NLRP7 mutations in familial recurrent hydatidiform mole: are NLRP7 mutations a risk for recurrent reproductive wastage? Eur J Obstet Gynecol Reprod Biol. 2013;170:188–92.
Fallahian M, Sebire NJ, Savage PM, et al. Mutations in NLRP7 and KHDC3L confer a complete hydatidiform mole phenotype on digynic triploid conceptions. Hum Mutat. 2013;34:301–8.
Qian J, Deveault C, Bagga R, et al. Women heterozygous for NALP7/NLRP7 mutations are at risk for reproductive wastage: report of two novel mutations. Hum Mutat. 2007;28:741.
Reddy R, Akoury E, Phuong Nguyen NM, et al. Report of four new patients with protein-truncating mutations in C6orf221/KHDC3L and colocalization with NLRP7. Eur J Hum Genet. 2013;21:957–64.
Castrillon DH, Sun D, Weremowicz S, et al. Discrimination of complete hydatidiform mole from its mimics by immunohistochemistry of the paternally imprinted gene product p57KIP2. Am J Surg Pathol. 2001;25:1225–30.
Hedley DW. Flow cytometry using paraffin-embedded tissue: five years on. Cytometry. 1989;10:229–41.
Khawajkie Y, Buckett W, Nguyen NMP, et al. Recurrent triploid digynic conceptions and mature ovarian teratomas: Are they different manifestations of the same genetic defect? Genes Chromosomes Cancer. 2017;56:832–40.
Surti U, Hoffner L, Kolthoff M, et al. Persistent gestational trophoblastic disease after an androgenetic/biparental fetal chimera: a case report and review. Int J Gynecol Pathol. 2006;25:366–72.
Sahoo T, Dzidic N, Strecker MN, et al. Comprehensive genetic analysis of pregnancy loss by chromosomal microarrays: outcomes, benefits, and challenges. Genet Med. 2017;19:83–9.
Pallares-Ruiz N, Philibert L, Dumont B, et al. Combined mutation and rearrangement screening by quantitative PCR high-resolution melting: is it relevant for hereditary recurrent Fever genes? PLoS ONE. 2010;5:e14096.
Deveault C, Qian JH, Chebaro W, et al. NLRP7 mutations in women with diploid androgenetic and triploid moles: a proposed mechanism for mole formation. Hum Mol Genet. 2009;18:888–97.
Messaed C, Chebaro W, Di Roberto RB, et al. NLRP7 in the spectrum of reproductive wastage: rare non-synonymous variants confer genetic susceptibility to recurrent reproductive wastage. J Med Genet. 2011;48:540–8.
Nguyen NM, Zhang L, Reddy R, et al. Comprehensive genotype-phenotype correlations between NLRP7 mutations and the balance between embryonic tissue differentiation and trophoblastic proliferation. J Med Genet. 2014;51:623–34.
Qian J, Cheng Q, Murdoch S, et al. The genetics of recurrent hydatidiform moles in China: correlations between NLRP7 mutations, molar genotypes, and reproductive outcomes. Mol Hum Reprod. 2011;17:612–9.
Slim R, Bagga R, Chebaro W, et al. A strong founder effect for two NLRP7 mutations in the Indian population: an intriguing observation. Clin Genet. 2009;76:292–5.
Hayward BE, De Vos M, Talati N, et al. Genetic and epigenetic analysis of recurrent hydatidiform mole. Hum Mutat. 2009;30:E629–39.
Wang M, Dixon PH, Decordova S, et al. Identification of 13 novel NLRP7 mutations in 20 families with recurrent hydatidiform mole; missense mutations cluster in the leucine rich region. J Med Genet. 2009;46:569–55.
Dixon PH, Trongwongsa P, Abu-Hayyah S, et al. Mutations in NLRP7 are associated with diploid biparental hydatidiform moles, but not androgenetic complete moles. J Med Genet. 2012;49:206–11.
Rezaei M, Nguyen NM, Foroughinia L, et al. Two novel mutations in the KHDC3L gene in Asian patients with recurrent hydatidiform mole. Hum Genome Var. 2016;3:16027.
Sebire NJ, Savage PM, Seckl MJ, et al. Histopathological features of biparental complete hydatidiform moles in women with NLRP7 mutations. Placenta. 2013;34:50–6.
Sunde L, Lund H, J Sebire N, et al. Paternal hemizygosity in 11p15 in mole-like conceptuses: two case reports. Medicine. 2015;94:e1776.
Eagles N, Sebire NJ, Short D, et al. Risk of recurrent molar pregnancies following complete and partial hydatidiform moles. Hum Reprod. 2015;30:2055–63.
We thank the patients and their families for their cooperation. We thank Sam Dougaparsad from Affymetrix for his kind technical assistance in the analysis of Cytoscan HD; Urvashi Surti and Lori Hoffner for performing FISH on tissue sections; and Judith St-Onge for her help in the primer design for long-range PCR. We acknowledge the use of the McGill University and Génome Québec Innovation Centre for Sanger sequencing. We also thank the Departments of Pathology of the following hospitals and medical centers, Greater Nashville Perinatology (TN, USA), Nashville Fertility Center (TN, USA), INTEGRIS Baptist Medical Center (OK, USA), Wellington Hospital-Genetics Health Service (New Zealand), Essentia Health Duluth (MN, USA), Falls Memorial Hospital (MN, USA), Maisonneuve Rosemont Hospital (QC, Canada), Notre Dame Hospital (QC, Canada), Pathology Queensland Laboratory (Australia), Toowooba Hospital (Australia), Auckland City Hospital (New Zealand), Touro Laboratory (NO, USA), Saint Justine Hospital (QC, Canada), Vaudois University Hospital (Switzerland), Evergreen Hospital Medical Center (Kirkland, USA), Providence Regional Laboratories (Portland, USA), St Mary’s Hospital Center (QC, Canada), Johnston Memorial Hospital (NC, USA), Erlanger Medical Center (TN, USA), Pole Hospitalo-Universitaire Naissance Et Pathologie De La Femme (Montpellier, France), East Tallinn Central Hospital (Estonia), IWK Health Centre (Halifax, Canada), Victoria General Hospital (Nova Scotia, Canada), for providing archived molar tissues.
NMPN was supported by fellowships from Réseau Québécois en Reproduction, McGill Faculty of Medicine, RI-MUHC Desjardins Studentship in Child Health Research, and CRRD. Yassemine Khawajkie was supported by a CRRD trainee fellowship. RS is supported by the Canadian Institute of Health Research (MOP-86546, POP-122897, and MOP-130364).