ESPE Abstracts

Disorders of sex development (DSD) refer to a group of congenital diseases with inconsistencies between chromosomal karyotypes, external genitalia, and gonadal development. Diagnosis and management strategy of DSD is difficult and various due to heterogeneous phenotype and genotype. Under widespread use of genomic sequencing technologies, multiple genes and mechanism has been identified and proposed as genetic causes of 46, XY DSD. In this study, 178 46, XY DSD patients were enrolled and underwent gene sequencing (either whole-exome sequencing or targeted panel gene sequencing). Detailed clinical phenotype and genotype information were summarized which showed that the most common clinical manifestations were micropenis (56.74%, 101/178), cryptorchidism (34.27%, 61/178), and hypospadias (17.42%, 31/178). Androgen synthesis/action disorders and idiopathic hypogonadotropic hypogonadism were the most frequent clinical diagnoses, accounting respectively for 40.9% and 21.59%. From all next-generation sequencing results, 103 candidate variants distributed across 32 genes were identified in 88 patients. The overall molecular detection rate was 49.44% (88/178), including 76.70% (79/103) pathogenic/likely pathogenic variants and 23.30% (24/103) VUS (variants of uncertain significance). Of all, 19.42% (20/103) variants were first reported in 46, XY DSD patients. Mutation c.680G>A (p.R227Q) on SRD5A2 (Steroid 5 Alpha-reductase 2) (36.67%, 11/30) was a hotspot mutation in Chinese population. New candidate genes [GHR (Growth Hormone Receptor) and RIT1 (Ras like without CAAX 1)] related to DSD were identified. Overall, this was a large cohort of 46, XY DSD patients with a common clinical classification and phenotype spectra of Chinese patients. Targeted gene panel sequencing (TPS) covered most of the genes contributing to DSD, whereas whole exome sequencing (WES) detected more candidate genes.