Association of CLCA4 genetic variation with non-obstructive azoospermia and its potential interaction with Y-chromosome microdeletions.

backgroundNon-obstructive azoospermia (NOA) is a severe form of male infertility with heterogeneous genetic determinants. While Y-chromosome microdeletions are established contributors, the role of autosomal variants in modulating disease susceptibility and phenotypic variability remains poorly understood.

methodsA case-control study was conducted comprising 87 NOA patients and 50 fertile controls. CLCA4 variants were analyzed using tetra-primer amplification refractory mutation system PCR (ARMS-PCR) and Sanger sequencing. Y-chromosome microdeletions were assessed by multiplex PCR targeting AZFa, AZFb, and AZFc regions. Logistic regression analyses were adjusted for age and body mass index (BMI).

resultsMissense variant rs763334876 and intronic variant rs79455835 were detected exclusively in patients and showed significant associations with NOA risk, although these estimates were imprecise due to wide confidence intervals. Y-chromosome microdeletions were identified in 20.7% of patients and were more frequently observed among individuals harboring CLCA4 variants. In silico analyses suggested potential deleterious effects of coding variants, supporting a possible functional role.

conclusionThese findings indicate that CLCA4 genetic variation is associated with NOA and may contribute to disease susceptibility. The observed enrichment of variants among patients carrying Y-chromosome microdeletions suggests a possible relationship between autosomal and chromosomal defects that warrants further investigation. Further functional studies are required to validate the biological role of these variants.