• PMID: 27476656
• Gene Name: ADGRG2
• Condition: CBAVD, Male infertility
• Association: Associated
• Mutation: c.1545dupT (p.Glu516Ter), c.2845delT (p.Cys949AlafsTer81), and c.2002_2006delinsAGA (p.Leu668ArgfsTer21)
• Population size: 26
• Population details: 26 (12 CFTR-negative men with CBAVD, targeted sequencing on 14 additional individuals)
• Sex: Male
• Infertility type: Male infertility
• Other associated phenotypes: CBAVD, Male infertility

Truncating Mutations in the Adhesion G Protein-Coupled Receptor G2 Gene ADGRG2 Cause an X-Linked Congenital Bilateral Absence of Vas Deferens

Patat O, Pagin A, Siegfried A, Mitchell V, Chassaing N, Faguer S, Monteil L, Gaston V, Bujan L, Courtade-Saïdi M, Marcelli F, Lalau G, Rigot JM, Mieusset R, Bieth E.

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. CI - Copyright © 2016 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved. FAU - Patat, Olivier AU - Patat O AD - Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Pagin, Adrien AU - Pagin A AD - Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire, 59037 Lille, France. FAU - Siegfried, Aurore AU - Siegfried A AD - Département d'Anatomie et Cytologie Pathologiques, Institut Universitaire du Cancer Toulouse- Oncopole, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Mitchell, Valérie AU - Mitchell V AD - 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. FAU - Chassaing, Nicolas AU - Chassaing N AD - Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Faguer, Stanislas AU - Faguer S AD - Département de Néphrologie et Transplantation d'Organes, Hôpital Rangueil, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Monteil, Laetitia AU - Monteil L AD - Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Gaston, Véronique AU - Gaston V AD - Service de Génétique Médicale, Hôpital Purpan, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Bujan, Louis AU - Bujan L AD - 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. FAU - Courtade-Saïdi, Monique AU - Courtade-Saïdi M AD - Département d'Anatomie et Cytologie Pathologiques, Institut Universitaire du Cancer Toulouse- Oncopole, Centre Hospitalier Universitaire, 31059 Toulouse, France. FAU - Marcelli, François AU - Marcelli F AD - EA4308 Gamétogenèse et Qualité du Gamète, Université Lille II, 59000 Lille, France; Département d'Andrologie, Hôpital Calmette, Centre Hospitalier Régional Universitaire, 59000 Lille, France. FAU - Lalau, Guy AU - Lalau G AD - Service de Toxicologie et Génopathies, Centre de Biologie Pathologie Génétique, Centre Hospitalier Régional Universitaire, 59037 Lille, France. FAU - Rigot, Jean-Marc AU - Rigot JM AD - EA4308 Gamétogenèse et Qualité du Gamète, Université Lille II, 59000 Lille, France; Département d'Andrologie, Hôpital Calmette, Centre Hospitalier Régional Universitaire, 59000 Lille, France. FAU - Mieusset, Roger AU - Mieusset R AD - 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.