1 Department of Human Genetics, McGill University Health Centre, Montreal, Quebec, Canada.
2 Department of Biology, McGill University, Montreal, Quebec, Canada.
3 Department of Medical Genetics, Shiraz University of Medical Sciences, Shiraz, Iran.
4 Center for Advanced Reproductive Services, Farmington, Connecticut, USA.
5 Department of Obstetrics and Gynecology, Mansoura University, Mansoura, Egypt.
6 Department of Obstetrics and Gynecology, Jordan Hospital, Amman, Jordan.
7 Department of Surgery and Cancer, Imperial College London, London, United Kingdom.
8 Department of Human Genetics, Medical Research Institute, Alexandria University, Alexandria, Egypt.
9 Department of Obstetrics and Gynecology, McGill University Health Centre, Montreal, Quebec, Canada.
10 Université Lyon 1, Service de Chirurgie Gynécologique et Ontologique, Obstétrique, Centre Français de Référence des Maladies Trophoblastiques, Hospices Civils de Lyon, Hôpital Lyon Sud, Pierre Bénite, France.
11 Security Research Center, Concordia University, Montreal, Quebec, Canada.
12 Department of Medical Genetics, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India.
13 Department of Gynecology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
14 Centre d'Aide Médicale à la Procréation Fertilys, Laval, Quebec, Canada.
15 Institut National de Recherche Scientifique-Centre Armand-Frappier Santé Biotechnologie, Laval, Quebec, Canada.
16 Department of Pathology, Hospices Civils de Lyon, Centre, Hospitalier Lyon Sud, Pierre-Bénite, France.
17 Department of Medical Biochemistry and Molecular Biology, Mansoura University, Mansoura, Egypt.
18 Department of Obstetrics and Gynecology, Gynecologic Oncology Division, Centre Hospitalier de l'Université de Montréal, Réseau des Maladies Trophoblastiques du Québec, Montreal, Quebec, Canada.
19 Department of Genetics CHU of Montpellier, University of Montpellier, INSERM, Montpellier, France.
20 OriginElle Fertility Clinic and Women's Health Centre, Montreal, Quebec, Canada.
21 Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada.

To identify novel genes responsible for recurrent hydatidiform moles (HMs), we performed exome sequencing on 75 unrelated patients who were negative for mutations in the known genes. We identified biallelic deleterious variants in 6 genes, FOXL2, MAJIN, KASH5, SYCP2, MEIOB, and HFM1, in patients with androgenetic HMs, including a familial case of 3 affected members. Five of these genes are essential for meiosis I, and their deficiencies lead to premature ovarian insufficiency. Advanced maternal age is the strongest risk factor for sporadic androgenetic HM, which affects 1 in every 600 pregnancies. We studied Hfm1-/- female mice and found that these mice lost all their oocytes before puberty but retained some at younger ages. Oocytes from Hfm1-/- mice initiated meiotic maturation and extruded the first polar bodies in culture; however, their meiotic spindles were often positioned parallel, instead of perpendicular, to the ooplasmic membrane at telophase I, and some oocytes extruded the entire spindle with all the chromosomes into the polar bodies at metaphase II, a mechanism we previously reported in Mei1-/- oocytes. The occurrence of a common mechanism in two mouse models argues in favor of its plausibility at the origin of androgenetic HM formation in humans.