Exome sequencing identified compound heterozygous mutations in the SRD5A2 gene in a case of 46,XY ambiguous genitalia.

The disorders of sexual development (DSD) represent an array of phenotypes with ambiguous genitalia. The present case had microphallus with fused and bifid scrotum and was initially assigned androgen insensitivity syndrome; however, sequencing of the complete coding region of the androgen receptor gene failed to identify a causative mutation. We undertook whole exome sequencing for identification of the pathogenic mutation. The most promising pathogenic variants were genotyped using Sanger sequencing to confirm the genotypes. We found compound heterozygous mutations, c.169G>T and c.586G>A in the SRD5A2 gene in this case, resulting in a nonsense (p.Glu57Ter) and a nonsynonymous substitution (p.Gly196Ser), respectively. While the nonsense mutation would result in a truncated protein, p.Gly196Ser substitution has been previously reported to be pathogenic. The mutations were confirmed by Sanger sequencing. Sequencing of 96 normal male individuals did not show the above mutations, suggesting their pathogenic nature. In conclusion, we identified compound heterozygous pathogenic mutations, c.169G>T (p.Glu57Ter) and c.586G>A (p.Gly196Ser), in the SRD5A2 gene in a case of ambiguous genitalia. p.Glu57Ter is a novel mutation, which in compound heterozygote combination with Gly196Ser causes 5a reductase deficiency.