Worldwide Cohort Study of 46, XY Differences/Disorders of Sex Development Genetic Diagnoses: Geographic and Ethnic Differences in Variants

This worldwide cohort study on 46, XY differences/disorders of sex development (DSD) highlights the genetic diversity and complexity of these conditions across different geographic and ethnic groups. The study involved 278 patients with 46, XY DSDs and 48 with 46, XX DSDs from 12 countries. The molecular diagnostic rate varied from 24.3% to 64.3%, with AR, NR5A1, and SRD5A2 being the most commonly mutated genes. The study found no clear geographic or ethnic predominance in mutations, and patients with multiple mutations often had more severe clinical manifestations. The research underscores the importance of whole-genome sequencing (WGS) for better diagnosis, as many patients still lack a definitive molecular diagnosis. The study also emphasizes the need for timely diagnosis and the challenges in treatment, particularly concerning gender identity and the risk of germ cell tumors.