Vas Deferens, Congenital Bilateral Aplasia Of, X-Linked

A number sign (#) is used with this entry because of evidence that X-linked congenital bilateral aplasia of the vas deferens (CBAVDX) is caused by mutation in the ADGRG2 gene (300572) on chromosome Xp22.

Description

Congenital bilateral absence of the vas deferens (CBAVD) is found in more than 25% of men with obstructive azoospermia, involving a complete or partial defect of the Wolffian duct derivatives. In 80% of men with CBAVD (see 277180), mutations are identified in the CFTR gene (602421). The forms caused by mutations in the CFTR and ADGRG2 genes are clinically indistinguishable (summary by Patat et al., 2016).

Clinical Features

In their 10-year retrospective series of 379 azoospermic men with CBAVD, Patat et al. (2016) noted that 81 (21%) of the patients did not have a mutation in the CFTR gene. The authors selected 12 of 26 patients with CBAVD and no renal malformations from that cohort for further study. The epididymis caput was present in all 12 patients, whereas the corpus was absent in 3 patients and the cauda was absent in 6; all but 4 patients showed dilation of part or all of the epididymis. The vas deferens was absent in all but 1 of the patients, in whom it was present unilaterally; and seminal vesicles were hypoplastic or absent in all but 1 patient. Testicular volumes were reported as normal in all but 3 patients, who had volumes less than 13 mL. All patients were azoospermic with low semen volume, and 4 patients were also reported to have an acid pH of the semen. Histologic examination of an epididymal biopsy, obtained during an assisted reproduction procedure in 1 of the patients, revealed enlarged sections of the epididymal head containing spermatic material, lined by a cuboidal epithelium due to sperm stasis. Some sections of the efferent ducts appeared dilated with spermatozoa in the lumen, whereas other sections appeared normal.

Pathogenesis

In cases of CBAVD caused by mutation in the CFTR gene, it is generally presumed that the genital tract abnormality is due to progressive atrophy related to abnormal electrolyte balance and fluid transport in the male excurrent ducts rather than agenesis. Azoospermic men with ADGRG2-associated CBAVD are clinically indistinguishable from those with CFTR-associated CBAVD, suggesting that mutations of these 2 genes might result in obstructive azoospermia through a similar pathophysiologic mechanism (summary by Patat et al., 2016).

Molecular Genetics

By exome sequencing in 12 men with obstructive azoospermia due to CBAVD who had no renal malformations and were negative for mutation in the CFTR gene, Patat et al. (2016) identified hemizygosity for 2 truncating mutations in the ADGRG2 gene (300572): a 1-bp deletion (300572.0001) in 1 man, and a deletion/insertion frameshift mutation (300572.0002) in an affected uncle and nephew. Targeted sequencing of the ADGRG2 gene in 14 additional men with CBAVD and no renal malformations from the same cohort identified another man with a truncating mutation, a 1-bp duplication (300572.0003). No mutations in ADGRG2 were found in 28 men with CBAVD and unilateral renal agenesis, suggestive of a different pathophysiologic mechanism in those cases.