• Tristan Celse, Caroline Cazin, Flore Mietton, Guillaume Martinez, Delphine Martinez, Nicolas Thierry-Mieg, Amandine Septier, Catherine Guillemain, Julie Beurois, Antoine Clergeau, Selima Fourati Ben Mustapha, Mahmoud Kharouf, Abdelali Zoghmar, Ahmed Chargui, Aline Papaxanthos, Béatrice Dorphin, Bernard Foliguet, Chema Triki, Christophe Sifer, Dominique Lauton, Gérard Tachdjian, Gilles Schuler, Hervé Lejeune, Jacques Puechberty, Julien Bessonnat, Laurent Pasquier, Lionel Mery, Marine Poulain, Myriam Chaabouni, Nathalie Sermondade, Rosalie Cabry, Sebti Benbouhadja, Ségolène Veau, Cynthia Frapsauce, Valérie Mitchell, Vincent Achard, Veronique Satre, Sylviane Hennebicq, Raoudha Zouari, Christophe Arnoult, Zine-Eddine Kherraf, Charles Coutton, and Pierre F Ray.
• Institute for Advanced Biosciences, Team Genetics Epigenetics and Therapies of Infertility, Université Grenoble Alpes, INSERM U1209, CNRS UMR 5309, 38000, Grenoble, France.
• Hum. Genet. 2021 Jan 1; 140 (1): 43-57.

AbstractGlobozoospermia 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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