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Mod Pathol. 2018 Jul;31(7):1116-1130. doi: 10.1038/s41379-018-0031-9. Epub 2018 Feb 20.

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

Author information

1
Departments of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
2
Division of Experimental Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
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.
4
Department of Clinical Genetics, Tartu University Hospital United Laboratories, 6 Hariduse Street, Tallinn, 10119, Estonia.
5
Mediscan Systems, 197, Dr. Natesan Road, Mylapore, Chennai-4, India.
6
Department of Medical Genetics, Ege University Faculty of Medicine, İzmir, Turkey.
7
Genetics and Genomics Department, Instituto Nacional de Perinatologia, Mexico City, Mexico.
8
Obstetrics and Gynecology, Mansoura University, Mansoura, Egypt.
9
Departments of Obstetrics and Gynecology and Gynecologic Oncology, Bulent Ecevit University, 67100, Kozlu, Zonguldak, Turkey.
10
Unité médicale des maladies Auto-inflammatoires, Hôpital Arnaud de Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295, Montpellier Cedex 5, France.
11
Department of Pathology, Hôpital Notre-Dame, Université de Montréal, Montréal, Québec, Canada.
12
Department of Pathology, McGill University Health Centre, Montreal, Quebec, Canada.
13
CombiMatrix Diagnostics, Irvine, CA, USA.
14
Departments of Obstetrics & Gynecology, Tulane University School of Medicine, Los Angelos, CA, USA.
15
Maternal Fetal Medicine and Genetics, Tennessee Maternal Fetal Medicine PLC, 300 20th Avenue North, Suite 702, Nashville, TN, 37203, USA.
16
Pathology Queensland, Royal Brisbane and Women's Hospital and Lady Cilento Children's Hospital, Brisbane, QLD, Australia.
17
Service de Médecine Génétique, CHUV-1011, Lausanne, Switzerland.
18
Department of Obstetrics & Gynecology, Post Graduate Institute of Medical, Education and Research, PGIMER, Chandigarh, India.
19
FMH Gynécologie-Obstétrique, Genève, Switzerland.
20
Département de médecine génétique et de laboratoire, Service de pathologie clinique, Centre Médical Universitaire (CMU), CH-1211 Genève 4, Genève, Switzerland.
21
Genetic Health Service, Central Hub, Wellington Hospital, Private Bag 7902, Wellington, 6242, New Zealand.
22
University of Colorado Hospital, Colorado, USA.
23
Genetic Health Service New Zealand-Northern Hub, Auckland City Hospital, P/Bag 92024, Auckland, 1142, New Zealand.
24
Essentia Health, Duluth Clinic, Duluth, MN, 55805-1983, USA.
25
Department of Gynecological Surgery and Oncology, Obstetrics, and French Center for Trophoblastic Diseases, University Hospitals of Lyon, Lyon, France.
26
Genetic Health Queensland, Royal Brisbane & Women's Hospital, Brisbane, Australia.
27
Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
28
Département de Génétique Médicale, Hôpital Arnaud de Villeneuve, 371 avenue du Doyen Gaston Giraud, 34295, Montpellier cedex 5, France.
29
Tennessee Reproductive Medicine, 6031 Shallowford Rd, Suite 101, Chattanooga, TN, 37421, USA.
30
Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran.
31
Departments of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
32
Hunter Genetics and University of Newcastle, GrowUpWell Priority Research Centre, Newcastle, NSW, Australia.
33
Cytology & Gynecological Pathology, Post Graduate Institute of Medical Education and Research PGIMER, Chandigarh, India.
34
Departments of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada. rima.slim@muhc.mcgill.ca.
35
Division of Experimental Medicine, McGill University Health Centre, Montreal, Quebec, Canada. rima.slim@muhc.mcgill.ca.
36
Departments of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada. rima.slim@muhc.mcgill.ca.

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.

PMID:
29463882
DOI:
10.1038/s41379-018-0031-9
[Indexed for MEDLINE]
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