1. Novel ADGRG2 truncating variants in patients with X‐linked congenital absence of vas deferens
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Anne Bergougnoux, Guy Lalau, Christelle Willoquaux, M.-P. Reboul, Emmanuelle Girodon, Thierry Bienvenu, Maryse Kesteloot, C. Raynal, A. Pagin, Mathilde Humbert, Eric Bieth, Pôle de Biologie Pathologie Génétique [CHU Lille], Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Laboratoire de génétique des maladies rares. Pathologie moleculaire, etudes fonctionnelles et banque de données génétiques (LGMR), Université Montpellier 1 (UM1)-IFR3, Université Montpellier 1 (UM1)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Institut Mondor de recherche biomédicale (IMRB), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), CHU Bordeaux [Bordeaux], Département Toxicologie-Hydrologie-Hygiène, Université de Lille, Droit et Santé, Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Biochimie et biologie moléculaire, Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université de Bordeaux (UB), Centre de Biologie Pathologie, CHU Toulouse [Toulouse], CHU Lille, Institut Pasteur de Lille, Université de Lille, and Toxicologie et Génopathies [CHRU Lille]
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Adult ,Male ,ADGRG2 ,medicine.medical_specialty ,Urology ,Endocrinology, Diabetes and Metabolism ,Cystic Fibrosis Transmembrane Conductance Regulator ,Obstructive azoospermia ,Cystic fibrosis ,Gastroenterology ,male infertility ,Male infertility ,Receptors, G-Protein-Coupled ,03 medical and health sciences ,Exon ,0302 clinical medicine ,Endocrinology ,Vas Deferens ,Male Urogenital Diseases ,Internal medicine ,Medicine ,Humans ,In patient ,CFTR ,Gene ,Exome sequencing ,030219 obstetrics & reproductive medicine ,business.industry ,Vas deferens ,congenital absence of vas deferens ,Infant ,obstructive azoospermia ,medicine.disease ,3. Good health ,medicine.anatomical_structure ,Reproductive Medicine ,Mutation ,business ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; 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.
- Published
- 2019
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