Fructose as a key biomarker for prognostication in idiopathic obstructive azoospermia associated with CFTR and ADGRG2 gene variants.

Abstract

Background: Isolated obstructive azoospermia (iOA) is classified as a type of obstructive azoospermia (OA) where cases remain "unexplained" even after excluding congenital absence of the vas deferens and external factors. This study aimed to determine if certain semen characteristics in iOA patients could indicate underlying genetic variants.

Objectives: To investigate CFTR and ADGRG2 gene variants in patients with idiopathic obstructive azoospermia (iOA) and identify semen parameters associated with these variants to guide genetic testing.

Materials and methods: Seventy-six iOA patients were divided into three groups based on variant status: Group I, patients with at least two CFTR variants or a hemizygous ADGRG2 variant; Group II, patients with one CFTR variant and no ADGRG2 variants; Group III, patients without any CFTR or ADGRG2 variants. Associations between genotypes and clinical parameters were analyzed using univariate and multivariate logistic regression to identify potential biomarkers.

Result(s): Thirty-six of the 76 patients (47.37%) carried one or more CFTR or ADGRG2 variants. Twenty distinct variants, including three novel variants (c.1851A > T and c.2426C > T in CFTR, c.1105G > A in ADGRG2), were identified. The most common variant was c.1210-12T[5] (5T) (18.42%), followed by c.1666A > G (4.61%) and c.4056G > C (3.95%). Group I patients had significantly lower ejaculate volume, pH, and fructose levels compared with Groups II and III. The combined area under the curve (AUC) for fructose, age, pH, and volume was 0.979, with fructose alone achieving an AUC of 0.952. Diagnostic efficacy for variant detection was highest (88.1%) at a fructose cutoff of 0.591 µmol/ejaculate, with a sensitivity of 0.958, a specificity of 0.923, a positive predictive value (PPV) of 0.895 and a negative predictive value (NPV) of 0.877.

Discussion and conclusion: Approximately 47% of iOA patients carry CFTR and ADGRG2 variants, characterized by significantly lower semen volume, fructose, and pH. Fructose was identified as an independent predictor of CFTR and ADGRG2 variants, highlighting its potential utility in guiding genetic testing and clinical decision-making in iOA patients.