Intact spermatogenesis in an azoospermic patient with AZFa (sY84 and sY86) microdeletion and a homozygous TG12-5T variant in CFTR.

Background: Azoospermia, the most severe form of male infertility, is categorized into two types: non-obstructive azoospermia (NOA) and obstructive azoospermia (OA), which exhibit significant genetic heterogeneity. Azoospermia factor (AZF) deletion is a common cause of NOA, whereas congenital bilateral absence of the vas deferens (CBAVD), a severe subtype of OA, is frequently linked to cystic fibrosis transmembrane conductance regulator (CFTR) gene variants. This case report is the first to document the coexistence of a partial AZFa microdeletion and a homozygous CFTR variant in a CBAVD-affected azoospermic patient with intact spermatogenesis.

Case Presentation: A 32-year-old man presented with primary infertility and azoospermia. Clinical evaluation revealed CBAVD (normal hormone levels, low semen volume, pH 6.0, and absence of the vas deferens). Genetic analysis accidentally revealed a 384.9 kb AZFa deletion (sY84 and sY86, but not sY1064, 1182) that removed USP9Y but retained DDX3Y in the proband, his fertile brother, and his father. A homozygous CFTR variant (TG12-5T) was also detected in the proband and his brother and was inherited from heterozygous parental carriers. Microdissection testicular sperm extraction (micro-TESE) revealed intact spermatogenesis, confirmed by histology and immunofluorescence, indicating normal germ cell development.

Conclusion: This case expands the intricate genetic spectrum of azoospermia by illustrating the critical role of DDX3Y in the AZFa region in spermatogenesis and the variable penetrance of CFTR variant (TG12-5T) in CBAVD. These insights may refine diagnostic strategies and underscore the necessity for tailored fertility management in individuals with multifactorial genetic anomalies.