• PMID: 31845523
• Gene Name: ADGRG2
• Condition: Congenital absence of vas deferens (CAVD)
• Association: Associated
• Mutation: c.251C > G (p.Ser84*), c.1013delC (p.Pro338Hisfs*4), c.1460delG (p.Gly487Alafs*9), c.2096dupT (p.Phe700Ilefs*29), c.2473C > T (p.Arg825*), and c.1731_1839 + 373del (p.Asn578Thrfs*12)
• Population size: 53
• Population details: 51 apparently healthy infertile men and 2 newborn twin brothers with bilateral absence of the vas deferens
• Sex: Male
• Infertility type: Male infertility
• Associated genes: NGS

Novel ADGRG2 truncating variants in patients with X-linked congenital absence of vas deferens

Pagin A, Bergougnoux A, Girodon E, Reboul MP, Willoquaux C, Kesteloot M, Raynal C, Bienvenu T, Humbert M, Lalau G, Bieth E.

BACKGROUND: Congenital absence of vas deferens (CAVD) represents a major cause of obstructive azoospermia and is mainly related to biallelic alteration of the CFTR gene, also involved in cystic fibrosis. Using whole exome sequencing, we recently identified hemizygous loss-of-function mutations in the Adhesion G Protein-coupled Receptor G2 gene (ADGRG2) as responsible of isolated CAVD in the absence of associated unilateral renal agenesis. OBJECTIVES: The objective of this study was to retrospectively perform ADGRG2 sequencing on a large cohort of patients with CAVD, and 0 or only 1 CFTR defective allele identified after comprehensive testing in order to (a) define more precisely the spectrum and the frequency of ADGRG2 mutations within Caucasian population (b) explore the possibility of co-occurrence of CFTR and ADGRG2 mutations. MATERIALS AND METHODS: We collected 53 DNA samples from CAVD patients with 0 (n = 23) or 1 (n = 30) alteration identified after comprehensive CFTR testing in order to perform ADGRG2 sequencing. Twenty patients had normal ultrasonographic renal examination, and renal status was not documented for 33 patients. RESULTS: We identified six new truncating ADGRG2 mutations in 8 patients including two twin brothers: c.251C > G (p.Ser84*), c.1013delC (p.Pro338Hisfs*4), c.1460delG (p.Gly487Alafs*9), c.2096dupT (p.Phe700Ilefs*29), c.2473C > T (p.Arg825*), and c.1731_1839 + 373del (p.Asn578Thrfs*12), which is a 596 base pair deletion affecting the last five bases of exon 21 and the whole exon 22. Five of the eight patients also harbored an heterozygous CFTR mutation which we consider as incidental regarding the high penetrance expected for ADGRG2 truncating variants. The frequency of ADGRG2 truncating mutation was 26% (5/19 unrelated patients) when presence of both kidneys was attested by ultrasonography and 6.1% (2/33) among patients with unknown renal status. DISCUSSION & CONCLUSION: Our results confirm the interest of ADGRG2 sequencing in patients with CAVD not formerly related to CFTR dysfunction, especially in the absence of associated unilateral renal agenesis. CI - © 2019 American Society of Andrology and European Academy of Andrology. FAU - Pagin, Adrien AU - Pagin A AD - CHU Lille, Service de Toxicologie et Génopathies, Lille, France. FAU - Bergougnoux, Anne AU - Bergougnoux A AD - Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, EA7402 Laboratoire de Génétique de Maladies Rares, Université de Montpellier, Montpellier, France. FAU - Girodon, Emmanuelle AU - Girodon E AD - Service de Génétique et Biologie Moléculaires, AP-HP.5, Groupe Hospitalier HUPC, Paris, France. FAU - Reboul, Marie-Pierre AU - Reboul MP AD - Service de Génétique Médicale, Centre Hospitalier Régional Universitaire, Bordeaux, France. FAU - Willoquaux, Christelle AU - Willoquaux C AD - CHU Lille, Service de Toxicologie et Génopathies, Lille, France. FAU - Kesteloot, Maryse AU - Kesteloot M AD - CHU Lille, Service de Toxicologie et Génopathies, Lille, France. FAU - Raynal, Caroline AU - Raynal C AD - Laboratoire de Génétique Moléculaire, Centre Hospitalier Universitaire de Montpellier, EA7402 Laboratoire de Génétique de Maladies Rares, Université de Montpellier, Montpellier, France. FAU - Bienvenu, Thierry AU - Bienvenu T AD - Service de Génétique et Biologie Moléculaires, AP-HP.5, Groupe Hospitalier HUPC, Paris, France. FAU - Humbert, Mathilde AU - Humbert M AD - Service de Biologie de la Reproduction, Centre Hospitalier Régional Universitaire, Bordeaux, France. FAU - Lalau, Guy AU - Lalau G AD - CHU Lille, Service de Toxicologie et Génopathies, Lille, France.