title: Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens.
abstract: In 80% of infertile men with obstructive azoospermia caused by a congenital bilateral absence of the vas deferens (CBAVD), mutations are identified in the cystic fibrosis transmembrane conductance regulator gene (CFTR). For the remaining 20%, the origin of the CBAVD is unknown. A large cohort of azoospermic men with CBAVD was retrospectively reassessed with more stringent selection criteria based on consistent clinical data, complete description of semen and reproductive excurrent ducts, extensive CFTR testing, and kidney ultrasound examination. To maximize the phenotypic prioritization, men with CBAVD and with unilateral renal agenesis were considered ineligible for the present study. We performed whole-exome sequencing on 12 CFTR-negative men with CBAVD and targeted sequencing on 14 additional individuals. We identified three protein-truncating hemizygous mutations, c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21), in ADGRG2, encoding the epididymal- and efferent-ducts-specific adhesion G protein-coupled receptor G2, in four subjects, including two related individuals with X-linked transmission of their infertility. Previous studies have demonstrated that Adgrg2-knockout male mice develop obstructive infertility. Our study confirms the crucial role of ADGRG2 in human male fertility and brings new insight into congenital obstructive azoospermia pathogenesis. In men with CBAVD who are CFTR-negative, ADGRG2 testing could allow for appropriate genetic counseling with regard to the X-linked transmission of the molecular defect.
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Patat
authors.affiliation: Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire, 59037 Lille, France.
authors.forename: Adrien
authors.initials: A
authors.lastname: Pagin
authors.affiliation: Département d'Anatomie et Cytologie Pathologiques, Institut Universitaire du Cancer Toulouse- Oncopole, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Aurore
authors.initials: A
authors.lastname: Siegfried
authors.affiliation: Spermiologie et CECOS, Institut de Biologie de la Reproduction, Hôpital Jeanne de Flandre, Centre Hospitalier Régional Universitaire, 59000 Lille, France; EA4308 Gamétogenèse et Qualité du Gamète, Université Lille II, 59000 Lille, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Mitchell
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Chassaing
authors.affiliation: Département de Néphrologie et Transplantation d'Organes, Hôpital Rangueil, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Stanislas
authors.initials: S
authors.lastname: Faguer
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Laetitia
authors.initials: L
authors.lastname: Monteil
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Véronique
authors.initials: V
authors.lastname: Gaston
authors.affiliation: Groupe Activité Médecine de la Reproduction, CECOS, Centre Hospitalier Universitaire, 31059 Toulouse, France; EA3694 Groupe de Recherche en Fertilité Humaine, Université Toulouse III, 31059 Toulouse, France.
authors.forename: Louis
authors.initials: L
authors.lastname: Bujan
authors.affiliation: Département d'Anatomie et Cytologie Pathologiques, Institut Universitaire du Cancer Toulouse- Oncopole, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Monique
authors.initials: M
authors.lastname: Courtade-Saïdi
authors.affiliation: EA4308 Gamétogenèse et Qualité du Gamète, Université Lille II, 59000 Lille, France; Département d'Andrologie, Hôpital Calmette, Centre Hospitalier Régional Universitaire, 59000 Lille, France.
authors.forename: François
authors.initials: F
authors.lastname: Marcelli
authors.affiliation: Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire, 59037 Lille, France.
authors.forename: Guy
authors.initials: G
authors.lastname: Lalau
authors.affiliation: EA4308 Gamétogenèse et Qualité du Gamète, Université Lille II, 59000 Lille, France; Département d'Andrologie, Hôpital Calmette, Centre Hospitalier Régional Universitaire, 59000 Lille, France.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Rigot
authors.affiliation: EA3694 Groupe de Recherche en Fertilité Humaine, Université Toulouse III, 31059 Toulouse, France; Groupe Activité Médecine de la Reproduction, Département d'Andrologie, Hôpital Paule de Viguier, Centre Hospitalier Universitaire, 31059 Toulouse, France.
authors.forename: Roger
authors.initials: R
authors.lastname: Mieusset
authors.affiliation: Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. Electronic address: bieth.e@chu-toulouse.fr.
authors.forename: Eric
authors.initials: E
authors.lastname: Bieth
mesh_terms: D019005:Cystic Fibrosis Transmembrane Conductance Regulator / Q000235:genetics; D004252:DNA Mutational Analysis; D059472:Exome / Q000235:genetics; D005260:Female; D017353:Gene Deletion; D050172:Genes, X-Linked / Q000235:genetics*; D006801:Humans; D008297:Male; D052801:Male Urogenital Diseases / Q000235:genetics*; D010375:Pedigree; D043562:Receptors, G-Protein-Coupled / Q000235:genetics*; D014649:Vas Deferens / Q000002:abnormalities*
chemical_list: C105986:ADGRG2 protein, human; D043562:Receptors, G-Protein-Coupled; D019005:Cystic Fibrosis Transmembrane Conductance Regulator