Clinical and genetic characteristics of patients with disorders of sex development in a large unselected cohort of China

Disorders of sex development (DSD) encompass a range of congenital conditions characterized by atypical chromosomal, gonadal, or anatomical sex development. Accurate diagnosis and management of DSD are crucial for optimal patient outcomes. This research aims to characterize the clinical and genetic characteristics of a large Chinese cohort of children with non‑chromosomal DSD, with particular focus on the most frequently implicated genes and their diagnostic implications. Index cases of non-chromosomal DSD from 24 Chinese DSD centers were enrolled. Individuals were initially classified clinically following the 2006 Chicago consensus and its modifications. Targeted next generation sequencing was performed to identify possible pathogenic variants. We enrolled 494 individuals with 46,XY DSD and 45 individuals with 46,XX DSD. A likely genetic diagnosis was established in 35.44% of patients (36.44% in 46,XY and 24.44% in 46,XX). The most frequently implicated genes were SRD5A2 , AR , FGFR1 and NR5A1 , which together accounted for more than half of all molecularly diagnosed cases in 46,XY DSD. In total, 59 DSD‑related genes were found to harbor pathogenic or likely pathogenic variants, and 144 of the 495 identified variants (29.09%) had not been previously reported, substantially expanding the mutational spectrum of DSD. Diagnostic rates varied considerably across clinical subtypes, with the highest yield observed in cases presenting with severe undermasculinization or syndromic features. This study, conducted in the largest reported collection of non‑chromosomal DSD cases, demonstrates a genetic diagnostic rate of 35.44% and highlights SRD5A2 , AR , ANOS1 , FGFR1 and NR5A1 as the most frequently implicated genes in 46,XY DSD. These findings underscore the clinical utility of targeted gene panel testing in DSD and provide a valuable reference for genetic counseling and clinical management in diverse DSD subtypes.