Unraveling the genetic and pathophysiological mechanisms underlying disorders of sex development

Abstract

Disorders of sex development (DSDs) encompass a spectrum of congenital conditions characterized by discordance among chromosomal, gonadal, and anatomical sex. Advances in genetic and molecular technologies have elucidated a complex landscape of underlying etiologies, including mutations in genes regulating sex determination and differentiation, copy number variations, and epigenetic alterations. These discoveries have not only enhanced diagnostic accuracy but also deepened our understanding of the molecular mechanisms driving DSDs. This review provides a comprehensive overview of the genetic architecture in DSDs, with a focus on key regulatory genes and their network interactions. We also highlight emerging concepts in the field, such as oligogenic inheritance and regulatory genomic elements, and discuss implications for personalized diagnosis, classification, and therapeutic strategies. By integrating recent advances from both clinical and basic research, this review aims to offer a framework for future investigations and translational applications in the management of DSDs.