DAAM2 gene variants p.(Asp165Glu) and p.(Asn614ThrfsTer2) in pediatric cryptorchidism: a hypothesis-generating pilot case-control study from the Eastern Black Sea region of Türkiye

Abstract

Background/aim Cryptorchidism is the most common congenital anomaly of the male genitourinary system, characterized by a multifactorial etiology. The disheveled-associated activator of morphogenesis 2 (DAAM2) gene regulates androgen receptor (AR)-dependent transcription; its variants are associated with partial androgen insensitivity. Since the inguinoscrotal phase of testicular descent is androgen-dependent, we hypothesized that DAAM2 variants contribute to cryptorchidism susceptibility. This pilot study, designed to generate hypotheses rather than to establish association, investigated the frequency of two functionally characterized DAAM2 variants, p.(Asp165Glu) and p.(Asn614ThrfsTer2), in pediatric cryptorchidism. Materials and methods This prospective case-control study included 40 male pediatric cryptorchidism patients and 39 age- and sex-matched healthy male controls. Genomic DNA was extracted from peripheral blood. The p.(Asp165Glu) variant was genotyped by TaqMan allelic discrimination and p.(Asn614ThrfsTer2) by ARMS-PCR with melting curve analysis. Genotype distributions were compared using linear-by-linear association testing with exact p-values, and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated by binary logistic regression. Results Heterozygous p.N614Tfs*2 carriage was more frequent in cryptorchidism patients (12.5%, n = 5) than in controls (2.6%, n = 1), with an unadjusted OR of 5.43 (95% CI: 0.6048.78, p = 0.131). Heterozygous p.D165E frequency was similar in both groups (7.5% vs. 7.7%; OR: 1.03, 95% CI: 0.19–5.45, p = 0.974), whereas homozygous p.D165E was identified exclusively in 2 of 40 cryptorchidism patients (5.0%) and in none of the controls, resulting in complete separation in the regression model. Conclusion Although statistical significance could not be reached due to the limited size of the study group, the observed fivefold increase in heterozygosity of p.(Asn614ThrfsTer2) and the presence of homozygosity of p.(Asp165Glu) in cryptorchidism cases contribute to the literature. These data suggest that DAAM2 variants may play a potential role in the etiology of cryptorchidism.