Spectrum and Classification of CFTR and ADGRG2 Variants in Chinese Patients With Isolated CAVD: A Large Cohort Study...

Congenital absence of the vas deferens (CAVD) is a major cause of obstructive azoospermia and male infertility, with its genetic etiology primarily associated with CFTR (autosomal recessive) and ADGRG2 (X-linked) mutations. However, the genetic spectrum and classification of variants in isolated congenital absence of the vas deferens (iCAVD), as well as the risk of CFTR variant carriage in affected couples, remain incompletely understood. In this cross-sectional study, we enrolled 199 Chinese iCAVD patients and 148 female partners between 2012 and 2024. CFTR and ADGRG2 variants were identified in 74.87% of iCAVD patients, with CFTR being the predominant pathogenic gene. Notably, 10.14% of couples carried shared pathogenic or likely pathogenic CFTR variants, highlighting the potential reproductive risks. The most common pathogenic variants were CFTR c.1210-12T (Yu et al., 2012) (5T) and c.4056G > C (p.Gln1352His), whereas c.1666A > G (p.Ile556Val) was classified as likely benign. The c.4056G > C variant exhibited significant regional ethnic characteristics. Furthermore, genotype-phenotype correlation analysis revealed significant differences in semen volume, pH, and fructose levels among different variant subgroups in CBAVD patients. Collectively, these findings provide a comprehensive overview of the genotype-phenotype landscape in a large iCAVD cohort, emphasizing variant classification and reproductive risks associated with CFTR and ADGRG2. This study offers valuable insights for genetic counseling and reproductive planning in affected couples.