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The genetics of recurrent hydatidiform moles: new insights and lessons from a comprehensive analysis of 113 patients


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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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).

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The authors declare that they have no conflict of interest.

Correspondence to Rima Slim.

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