Identification of a Rare Variant in the SRD5A2 Gene in Siblings With 46,XY Disorders of Sexual Development

The SRD5A2 gene encodes the steroid 5α-reductase-2 isozyme, which converts testosterone to dihydrotestosterone and plays a key role in sexual development and androgen physiology. Deficiency of this enzyme leads to an autosomal recessive sex-linked disorder associated with ambiguous genitalia and hypovirilization/complete feminization of external genitalia in individuals with a 46,XY karyotype. The present study emphasizes the indispensable role of molecular genetic testing in siblings (Probands 1 and 2) presented with disorders of sexual development (DSD). The biochemical, cytogenetics, and molecular testing, encompassing hormonal testing, chromosomal analysis, fluorescence in situ hybridization (FISH), and whole exome sequencing (WES), were carried out at our National Reference Laboratory. In addition, Sanger sequencing confirmed the identified variant, and bioinformatics tools were used to assess its impact on protein structure and stability, thereby assessing its pathogenic potential. The biochemical profile revealed highly elevated testosterone/dihydrotestosterone in Probands 1 and 2 as 45.4 and 43.2, respectively (biological reference range < 10). The cytogenetic analysis confirmed a 46,XY karyotype, and FISH validated the presence of the SRY gene. WES identified a pathogenic homozygous variant, c.737G > A(p.Arg246Gln) in the SRD5A2 gene. Protein structure predictions and stability analyses indicated the variant's damaging effects. This study supports diagnosis through comprehensive molecular testing and highlights the significance of genetic insights in managing 46,XY DSD. This case highlights phenotypic variability in siblings with the same homozygous SRD5A2 variant from a nonconsanguineous Indian family, underscoring the need for early genetic workup and multidisciplinary evaluation in 46,XY DSD.