Targeted next-generation sequencing for the diagnosis of gene variants in patients with 46, XY disorder of sex development.

INTRODUCTION: Disorders of sex development (DSDs) are congenital abnormalities in which chromosomal, gonadal, and anatomical sex development are atypical. One of these disorders, 46, XY DSD, is particularly difficult to diagnose and manage because its etiology and clinical phenotypes are highly heterogeneous.

METHODS: We used a gene panel containing 141 genes implicated in DSDs to perform targeted next-generation sequencing (NGS) in 50 patients with 46, XY DSD.

RESULTS: Gene variants were detected in 23 patients (46%). Among them, thirteen patients had previously reported pathogenic or likely pathogenic variants, nine patients had novel variants, and one patient had a previously reported variant of uncertain significance. Three of the patients with novel variants were pathogenic and the remaining are variants of uncertain significance; therefore, 16 patients had pathogenic or likely pathogenic variants according to ACMG guidelines, and the overall diagnostic rate of 46, XY DSD was 32%. The most common gene variants were SRD5A2 variants, followed by the AR variant. In addition, we analyzed the association between gene variants and clinical phenotypes. Most patients presented with multiple DSD phenotypes (i.e., two or more DSD phenotypes were observed, such as micropenis, hypospadias, and cryptorchidism), but the phenotype with the highest diagnostic rate was micropenis.

CONCLUSION: Our results indicate that targeted NGS can effectively detect pathogenic gene variants in patients with 46, XY DSD.