2. Academic Validation
  3. Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player

Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player

  • Hum Genet. 2021 Jan;140(1):43-57. doi: 10.1007/s00439-020-02229-0.
Tristan Celse 1 2,  Caroline Cazin 1 2,  Flore Mietton 2,  Guillaume Martinez 1 3,  Delphine Martinez 2,  Nicolas Thierry-Mieg 4,  Amandine Septier 4,  Catherine Guillemain 5 6,  Julie Beurois 1,  Antoine Clergeau 7,  Selima Fourati Ben Mustapha 8,  Mahmoud Kharouf 8,  Abdelali Zoghmar 9,  Ahmed Chargui 10,  Aline Papaxanthos 11,  Béatrice Dorphin 12,  Bernard Foliguet 13,  Chema Triki 14,  Christophe Sifer 15,  Dominique Lauton 16,  Gérard Tachdjian 17,  Gilles Schuler 18,  Hervé Lejeune 19,  Jacques Puechberty 20,  Julien Bessonnat 21,  Laurent Pasquier 22,  Lionel Mery 23,  Marine Poulain 24,  Myriam Chaabouni 8,  Nathalie Sermondade 25,  Rosalie Cabry 26,  Sebti Benbouhadja 9,  Ségolène Veau 27,  Cynthia Frapsauce 28,  Valérie Mitchell 29,  Vincent Achard 30 31 32,  Veronique Satre 1 3,  Sylviane Hennebicq 1 21,  Raoudha Zouari 5,  Christophe Arnoult 1,  Zine-Eddine Kherraf 1 2,  Charles Coutton 1 3,  Pierre F Ray 33 34
Affiliations

Affiliations

  • 1 Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000, Grenoble, France.
  • 2 CHU Grenoble Alpes, UM GI-DPI, 38000, Grenoble, France.
  • 3 CHU Grenoble Alpes, UM de Génétique Chromosomique, 38000, Grenoble, France.
  • 4 Université Grenoble Alpes, CNRS, TIMC-IMAG, 38000, Grenoble, France.
  • 5 Pôle Femmes-Parents-Enfants, Centre Clinico-Biologique AMP-CECOS, Plateforme Cancer et Fertilité ONCOPACA-Corse, Assistance-Publique des Hôpitaux de Marseille (AP-HM), Marseille, France.
  • 6 Aix Marseille University, INSERM, MMG, UMR_S 1251, Marseille, France.
  • 7 Diabetes Care Unit, University Hospital of Caen, Caen, France.
  • 8 Polyclinique les Jasmins, Centre d'Aide Médicale à la Procréation, Centre Urbain Nord, 1003, Tunis, Tunisia.
  • 9 Reproduction Sciences and Surgery Clinique, Ibn Rochd, Constantine, Algeria.
  • 10 Faculté de Médecine, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Universitaire Paris Centre, Centre Hospitalier Universitaire (CHU) Cochin, Service d'Histologie-Embryologie-Biologie de la Reproduction, Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
  • 11 Department of Obstetrics, Gynecology and Reproductive Medicine, Bordeaux University Hospital, Bordeaux, France.
  • 12 AMP74, CH Alpes Léman, Contamine-sur-Arve, France.
  • 13 Toxicology and Molecular Biology, Institute Jean Lamour UMR 7198 du CNRS, Université de Lorraine, 54000, Nancy, France.
  • 14 Centre d'AMP, Clinique Hannibal, Les Berges du Lac, 1053, Tunis, Tunisia.
  • 15 Service de Biologie de la Reproduction, d'Histo-Embryologie et Cytogénétique, Hôpital Jean-Verdier, Avenue du 14 Juillet, 93140, Bondy, France.
  • 16 Department of Endocrinology, Diabetes, Nutrition, Montpellier University Hospital, Montpellier, France.
  • 17 UMR 967, INSERM, Service d'Histologie Embryologie et Cytogénétique, Hôpitaux Universitaires Paris-Sud, AP-HP, Clamart, France.
  • 18 Gynécologie Obstétrique, Sallanches, France.
  • 19 Reproductive Medicine Department, Hospices Civils de Lyon, Lyon, France.
  • 20 Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Hôpital Arnaud de Villeneuve, CHU de Montpellier, Université Montpelier, Montpellier, France.
  • 21 CHU de Grenoble, UF de Biologie de la Procréation, 38000, Grenoble, France.
  • 22 Service de Génétique Clinique, CLAD Ouest, CHU Rennes, Rennes, France.
  • 23 Service de Médecine de la Reproduction, CHU de Saint-Étienne, Hôpital Nord, 42055, Saint-Étienne Cedex 2, France.
  • 24 Department of Obstetrics and Gynecology, Hôpital Foch, Université de Paris Ouest (UVSQ), Suresnes, France.
  • 25 Service de Biologie de la Reproduction-CECOS, Hôpital Tenon, AP-HP, 75020, Paris, France.
  • 26 Department of Obstetrics, Gynaecology and Reproductive Medicine, Picardie University Jules Verne, Amiens University Medical Centre, Amiens, France.
  • 27 CHU, Centre d'AMP-CECOS, University Rennes, 16 Boulevard de Bulgarie, 35000, Rennes, France.
  • 28 CHU Bretonneau, Médecine et Biologie de la Reproduction-CECOS, Tours, France.
  • 29 EA 4308, Department of Reproductive Biology and Spermiology-CECOS Lille, University Medical Center, 59037, Lille, France.
  • 30 CECOS-Laboratoire de Biologie de la Reproduction, Pôle de Gynécologie Obstétrique et Reproduction (Gynépôle), Assistance Publique-Hôpitaux de Marseille (AP-HM) la Conception, 13005, Marseille, France.
  • 31 Centre Clinico-Biologique d'Assistance Médicale à la Procréation, Pôle de Gynécologie Obstétrique et Reproduction (Gynépôle), Assistance Publique-Hôpitaux de Marseille (AP-HM) la Conception, 13005, Marseille, France.
  • 32 Faculté de Médecine, Institut Méditerranéen de Biodiversité et d'Écologie (IMBE UMR 7263), Equipe Biogénotoxicologie, Santé Humaine et Environnement, Aix Marseille Université, CNRS, IRD, Université Avignon, 27, Boulevard Jean-Moulin, 13385, Marseille Cedex 5, France.
  • 33 Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000, Grenoble, France. [email protected].
  • 34 CHU Grenoble Alpes, UM GI-DPI, 38000, Grenoble, France. [email protected].
PMID: 33108537 DOI: 10.1007/s00439-020-02229-0
Abstract

Globozoospermia is a rare phenotype of primary male infertility inducing the production of round-headed spermatozoa without acrosome. Anomalies of DPY19L2 account for 50-70% of all cases and the entire deletion of the gene is by far the most frequent defect identified. Here, we present a large cohort of 69 patients with 20-100% of globozoospermia. Genetic analyses including multiplex ligation-dependent probe amplification, Sanger sequencing and whole-exome sequencing identified 25 subjects with a homozygous DPY19L2 deletion (36%) and 14 carrying other DPY19L2 defects (20%). Overall, 11 deleterious single-nucleotide variants were identified including eight novel and three already published mutations. Patients with a higher rate of round-headed spermatozoa were more often diagnosed and had a higher proportion of loss of function anomalies, highlighting a good genotype phenotype correlation. No gene defects were identified in patients carrying < 50% of globozoospermia while diagnosis efficiency rose to 77% for patients with > 50% of globozoospermia. In addition, results from whole-exome sequencing were scrutinized for 23 patients with a DPY19L2 negative diagnosis, searching for deleterious variants in the nine other genes described to be associated with globozoospermia in human (C2CD6, C7orf61, CCDC62, CCIN, DNAH17, GGN, PICK1, SPATA16, and ZPBP1). Only one homozygous novel truncating variant was identified in the GGN gene in one patient, confirming the association of GGN with globozoospermia. In view of these results, we propose a novel diagnostic strategy focusing on patients with at least 50% of globozoospermia and based on a classical qualitative PCR to detect DPY19L2 homozygous deletions. In the absence of the latter, we recommend to perform whole-exome sequencing to search for defects in DPY19L2 as well as in the other previously described candidate genes.

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