Abstract

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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Acknowledgements

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.

Funding

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).

Author information

Affiliations

  1. Departments of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada

    • Ngoc Minh Phuong Nguyen
    • , Nawel Mechtouf
    • , Maryam Rezaei
    •  & Rima Slim
  2. Division of Experimental Medicine, McGill University Health Centre, Montreal, Quebec, Canada

    • Yassemine Khawajkie
    •  & Rima Slim
  3. Department of Obstetrics and Gynecology, Centre Hospitalier de l’Université de Montréal (CHUM), Centre Intégré de Cancérologie du CHUM, Registre des Maladies Trophoblastiques du Québec, Montréal, Québec, Canada

    • Magali Breguet
    •  & Philippe Sauthier
  4. Department of Clinical Genetics, Tartu University Hospital United Laboratories, 6 Hariduse Street, Tallinn, 10119, Estonia

    • Elvira Kurvinen
  5. Mediscan Systems, 197, Dr. Natesan Road, Mylapore, Chennai-4, India

    • Sujatha Jagadeesh
  6. Department of Medical Genetics, Ege University Faculty of Medicine, İzmir, Turkey

    • Asli Ece Solmaz
  7. Genetics and Genomics Department, Instituto Nacional de Perinatologia, Mexico City, Mexico

    • Monica Aguinaga
  8. Obstetrics and Gynecology, Mansoura University, Mansoura, Egypt

    • Reda Hemida
  9. Departments of Obstetrics and Gynecology and Gynecologic Oncology, Bulent Ecevit University, 67100, Kozlu, Zonguldak, Turkey

    • Mehmet Ibrahim Harma
    •  & Muge Harma
  10. Unité médicale des maladies Auto-inflammatoires, Hôpital Arnaud de Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295, Montpellier Cedex 5, France

    • Cécile Rittore
  11. Department of Pathology, Hôpital Notre-Dame, Université de Montréal, Montréal, Québec, Canada

    • Kurosh Rahimi
  12. Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada

    • Jocelyne Arseneau
  13. CombiMatrix Diagnostics, Irvine, CA, USA

    • Karine Hovanes
    •  & Trilochan Sahoo
  14. Departments of Obstetrics & Gynecology, Tulane University School of Medicine, Los Angelos, CA, USA

    • Ronald Clisham
  15. Maternal Fetal Medicine and Genetics, Tennessee Maternal Fetal Medicine PLC, 300 20th Avenue North, Suite 702, Nashville, TN, 37203, USA

    • Tiffanee Lenzi
  16. Pathology Queensland, Royal Brisbane and Women’s Hospital and Lady Cilento Children’s Hospital, Brisbane, QLD, Australia

    • Bonnie Scurry
  17. Service de Médecine Génétique, CHUV-1011, Lausanne, Switzerland

    • Marie-Claude Addor
  18. Department of Obstetrics & Gynecology, Post Graduate Institute of Medical, Education and Research, PGIMER, Chandigarh, India

    • Rashmi Bagga
  19. FMH Gynécologie-Obstétrique, Genève, Switzerland

    • Genevieve Girardet Nendaz
  20. Département de médecine génétique et de laboratoire, Service de pathologie clinique, Centre Médical Universitaire (CMU), CH-1211 Genève 4, Genève, Switzerland

    • Vildana Finci
  21. Genetic Health Service, Central Hub, Wellington Hospital, Private Bag 7902, Wellington, 6242, New Zealand

    • Gemma Poke
    •  & R. J. McKinlay Gardner
  22. University of Colorado Hospital, Colorado, USA

    • Leslie Grimes
  23. Genetic Health Service New Zealand—Northern Hub, Auckland City Hospital, P/Bag 92024, Auckland, 1142, New Zealand

    • Nerine Gregersen
  24. Essentia Health, Duluth Clinic, Duluth, MN, 55805-1983, USA

    • Kayla York
  25. Department of Gynecological Surgery and Oncology, Obstetrics, and French Center for Trophoblastic Diseases, University Hospitals of Lyon, Lyon, France

    • Pierre-Adrien Bolze
  26. Genetic Health Queensland, Royal Brisbane & Women’s Hospital, Brisbane, Australia

    • Chirag Patel
  27. Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran

    • Hossein Mozdarani
  28. Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295, Montpellier cedex 5, France

    • Jacques Puechberty
  29. Tennessee Reproductive Medicine, 6031 Shallowford Rd, Suite 101, Chattanooga, TN, 37421, USA

    • Jessica Scotchie
  30. Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran

    • Majid Fardaei
  31. Departments of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada

    • R. J. McKinlay Gardner
    •  & Rima Slim
  32. Hunter Genetics and University of Newcastle, GrowUpWell Priority Research Centre, Newcastle, NSW, Australia

    • Tracy Dudding-Byth
  33. Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research PGIMER, Chandigarh, India

    • Radhika Srinivasan

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The authors declare that they have no conflict of interest.

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Correspondence to Rima Slim.

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DOI

https://doi.org/10.1038/s41379-018-0031-9