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Article Dans Une Revue Human Genetics Année : 2021

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

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 CHUGA - Centre Hospitalier Universitaire [CHU Grenoble]
3 TIMC-BCM - Biologie Computationnelle et Modélisation
4 MMG - Marseille medical genetics - Centre de génétique médicale de Marseille
5 LA CONCEPTION - Hôpital de la Conception [CHU - APHM]
6 Service Endocrinologie - Diabétologie [CHU Caen]
7 Polyclinique les Jasmins [Tunis]
8 CHU Ibn Rochd [Casablanca]
9 CECOS Paris Cochin - Service d'Histologie-Embryologie, Biologie de la Reproduction
10 CHU Bordeaux
11 AMP 74 - Laboratoire d’Aide Médicale à la Procréation [CH Alpes-Léman]
12 IJL - Institut Jean Lamour
13 Hôpital Jean Verdier [AP-HP]
14 CHRU Montpellier - Centre Hospitalier Régional Universitaire [Montpellier]
15 SCSR (U_967) - Stabilité génétique, Cellules Souches et Radiations
16 HCL - Hospices Civils de Lyon
17 Hôpital Arnaud de Villeneuve [CHRU Montpellier]
18 Centre Hospitalier Universitaire de Rennes [CHU Rennes] = Rennes University Hospital [Ponchaillou]
19 CHU ST-E - Centre Hospitalier Universitaire de Saint-Etienne [CHU Saint-Etienne]
20 Hôpital Foch [Suresnes]
21 UVSQ Santé - Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil
22 CHU Tenon [AP-HP]
23 CHU Amiens-Picardie
24 PERITOX - Périnatalité et Risques Toxiques - UMR INERIS_I 1
25 Hôpital Bretonneau
26 APHM - Assistance Publique - Hôpitaux de Marseille
27 IMBE - Institut méditerranéen de biodiversité et d'écologie marine et continentale
Nicolas Thierry-Mieg
Aline Papaxanthos
  • Fonction : Auteur
Chema Triki
  • Fonction : Auteur
Gilles Schuler
  • Fonction : Auteur
Nathalie Sermondade
Valérie Mitchell
  • Fonction : Auteur

Résumé

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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Dates et versions

hal-03025179 , version 1 (11-03-2021)

Identifiants

Citer

Tristan Celse, Caroline Cazin, Flore Mietton, Guillaume Martinez, Delphine Martinez, et al.. Genetic analyses of a large cohort of infertile patients with globozoospermia, DPY19L2 still the main actor, GGN confirmed as a guest player. Human Genetics, 2021, Molecular Genetics of Male Infertility, 140 (1), pp.43-57. ⟨10.1007/s00439-020-02229-0⟩. ⟨hal-03025179⟩
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