Genetics of the congenital absence of the vas deferens

Abstract

Congenital absence of the vas deferens (CAVD) may have various clinical presentations depending on whether it is bilateral (CBAVD) or unilateral (CUAVD), complete or partial, and associated or not with other abnormalities of the male urogenital tract. CBAVD is usually discovered in adult men either during the systematic assessment of cystic fibrosis or other CFTR-related conditions, or during the exploration of isolated infertility with obstructive azoospermia. The prevalence of CAVDs in men is reported to be approximately 0.1%. However, this figure is probably underestimated, because unilateral forms of CAVD in asymptomatic fertile men are not usually diagnosed. The diagnosis of CAVDs is based on clinical, ultrasound, and sperm examinations. The majority of subjects with CAVD carry at least one cystic fibrosis-causing mutation that warrants CFTR testing and in case of a positive result, genetic counseling prior to conception. Approximately 2% of the cases of CAVD are hemizygous for a loss-of-function mutation in the ADGRG2 gene that may cause a familial form of X-linked infertility. However, despite this recent finding, 10-20% of CBAVDs and 60-70% of CUAVDs remain without a genetic diagnosis. An important proportion of these unexplained CAVDs coexist with a solitary kidney suggesting an early organogenesis disorder (Wolffian duct), unlike CAVDs related to CFTR or ADGRG2 mutations, which might be the result of progressive degeneration that begins later in fetal life and probably continues after birth. How the dysfunction of CFTR, ADGRG2, or other genes such as SLC29A3 leads to this involution is the subject of various pathophysiological hypotheses that are discussed in this review.

OUP accepted manuscript

“…An understanding of the shared mechanisms between male infertility diseases and cancers is imperative for predicting the risk of cancers and efficient clinical management in individuals suffering from male infertility ( 49 ). Additionally, the information in MIK also indicates a strong association between inflammatory diseases and defects in vas deferens, thus substantiating reports of an increased risk of inflammatory diseases and cancers ( 49 , 50 ) in patients with complete or partial absence of vas deferens broadly termed as a congenital absence of the vas deferens ( 51 ).…”

Disease gene discovery in male infertility: past, present and future

“…The high prevalence of CFTR mutations in the global population, particularly in individuals of European descent where 1 in 25 are carriers of pathogenic variants, explains why CFTR gene mutations cause 60-70% of congenital absence of the vas deferens (CAVD) cases (Weiske et al 2000). Overall, however, CAVDs is a rare condition found in only 1-2% of all infertile men (Bieth et al 2020).…”

Cystic fibrosis being a polyendocrine disease (Review)

“…Гипотеза о причине недоразвития протоков является аналогией аномальной секреции, обструкции и атрофии протоков ПЖ при дефекте хлорного транспорта. Предполагается, что CFTR играет роль в дифференцировке мезонефротических протоков, реализации собственно ветвления -фундаментального процесса создания канальцев, поддерживаемого ростовыми факторами и требующего участия консервативных сигнальных путей (в частности, Wnt/β-катенин [53,54]), заключающегося в пролиферации, миграции, морфогенезе клеток, взаимодействиях посредством межклеточного матрикса [55].…”