WT1 pathogenic variant in azoospermic infertile men with an isolated undescended testis

An undescended testis (UDT) is a testicle that has not moved into the scrotum before birth. UDTs are linked to reduced fertility, primarily due to compromised semen quality and potential dysfunction in Sertoli and Leydig cells. Additionally, the Wilms tumor 1 (WT1) gene is crucial for spermatogenesis, as it regulates the polarity of Sertoli cells and the steroidogenesis in Leydig cells. Our study aimed to identify novel UDT-causing WT1 variants within a cohort of 60 unrelated men with infertile hypergonadotropic hypogonadism.

In this case-control study, the coding regions and the intronic boundaries of the second and ninth exon of WT1 were sequenced using Sanger sequencing. DNA from 60 fertile men served as the control group. In silico analysis of the variants was also conducted.

The study identified multiple intronic and exonic variations in both the patient and control groups. Notably, a haplotype consisting of two heterozygous C>T variations in the intronic region of the splice donor site of exon 9 was observed in 11 patients but was absent in the control group. Of these variations, only one has been previously reported in Single Nucleotide Polymorphism Database (dbSNP) as rs587776576 (NC_000011.10: g.32391967C>T; NM_000378.4:c.1372+14G>A).

The rs587776576 mutation is pathogenic. It exhibited a significant association (p=0.022), indicating its association with infertility and UDT in the Iranian population. This research could broaden the spectrum of WT1 variations and underscore the importance of these variants in the genetic etiology of UDT and infertility. These findings provide a foundation for clinical diagnosis and genetic counseling.