Allelic variants in HOX genes in cryptorchidism

Cryptorchidism is one of the most common congenital anomalies and is associated with increased risk for infertility and testicular cancer later in life. Findings from animal models and small clinical studies suggest that the posterior HOX genes (paralogs 9-13) could be potential candidate genes for cryptorchidism and that the HOX genes are functionally redundant within paralogous groups.

The coding regions and exon-intron boundaries of the 16 posterior HOX genes were sequenced and analyzed in group 1 (44 nonsyndromic cryptorchidism cases and 46 healthy controls). Those specific variants found to be significantly different between cases and controls in group 1 were examined in DNA from group 2 (108 cases and 114 controls).

A total of 57 variants was found in group 1, among which the allele frequency of 180A>G (A60A) in HOXD13 alone was significantly elevated in cases versus controls (P = 0.02). In the combined 1 + 2 group, cases were also more likely than controls to have the G allele (P = 0.002). As predicted by an exonic splicing enhancer finder program, the 180A>G (A60A) variant is expected to have an influence on the splicing of transcripts from HOXD13. In group 1, case subjects were more likely to carry multiple variants in HOXA13 and HOXD13 (P = 0.02) than controls.

The variant 180A>G (A60A) in HOXD13 is a risk factor for cryptorchidism, and a dynamic equilibrium of genes in HOX paralog 13 is involved in the pathogenesis of cryptorchidism.