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

Abstract

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.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. K E Y W O R D SADGRG2, CFTR, congenital absence of vas deferens, male infertility, obstructive azoospermia | 619 PAGIN et Al.

Genetics of the congenital absence of the vas deferens

“…They concluded that inactivation of ADGRG2 is responsible for approximatively 20% of CAVD not related to CFTR dysfunction. In addition, they found no case of solitary kidney among the 8 ADGRG2 mutated patients of their cohort (Pagin et al 2019 ). Interestingly, no ADGRG2 or CFTR mutations were identified by Patat et al in a cohort of 28 iCBAVD patients with URA (personal data).…”

“…These two concepts could apply to two distinct populations of CAVD men: one that combines a high frequency of mutations in CFTR or ADGRG2 and a low frequency of URA association, and one that combines the same criteria but with respectively inverted frequencies. Data from well-phenotyped CAVD cohorts with sufficient size indicates that these two populations do exist: URA is rarely observed in men with CF (CF-CAVD), while, on the other hand, CFTR or ADGRG2 mutations are rarely identified in iCAVD men with URA (Patat et al 2016 ; Pagin et al 2019 ).…”

Molecular Diagnosis and Genetic Counseling of Cystic Fibrosis and Related Disorders: New Challenges

“…CFTR-RDs principally include isolated male infertility by congenital bilateral absence of the vas deferens, idiopathic pancreatitis, disseminated bronchiectasis and chronic rhinosinusitis. The contribution of CFTR variants however varies from one condition to another, and may act in a multifactorial context, with other genes being potentially involved, such as ADGRG2 in male infertility by the absence of vas deferens [ 10 ] or PRSS1 , SPINK1 and CTRC in pancreatitis [ 11 ]. There is thus a huge diversity of diagnostic and genetic counseling indications for searching CFTR variants, and appropriate tools should be used to answer clinical questions [ 1 , 12 , 13 ].…”

Will whole-genome sequencing become the first-line genetic analysis for male infertility in the near future?

“…Eighty percent of men with CBAVD carry one or two CFTR mutations [ 13 ], and it is impossible to consider TESE before genetic testing and counseling. Furthermore, a quarter of the men without a CFTR gene mutation may have a defect in the ADGRG2 gene associated with X-linked CBAVD (OMIM #300985) [ 14 ]. Although various candidate genes (such as PANK2 and SLC9A3 ) have been suggested in the literature [ 15 ], none has been considered for CBAVD diagnosis.…”